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Turkish Journal of Medical Sciences Turk J Med Sci(2014) 44: 946-954© TÜBİTAKdoi:10.3906/sag-1310-77
Discovering missing heritability and early risk prediction for type 2 diabetes: a new perspective for genome-wide association study analysis with the Nurses’ Health Study
and the Health Professionals’ Follow-Up Study
Hüsamettin GÜL1,*, Yeşim AYDIN SON2, Cengizhan AÇIKEL3
1Department of Medical Informatics, Gülhane Military Medical Academy, Etlik, Ankara, Turkey2Department of Health Informatics, Informatics Institute, Middle East Technical University, Ankara, Turkey
3Department of Biostatistics, Gülhane Military Medical Academy, Etlik, Ankara, Turkey
* Correspondence: hgul23@gmail.com
1. IntroductionType 2 diabetes is a complex disease that is characterized by insulin resistance in peripheral tissues and dysfunction in insulin secretion. Type 2 diabetes is a major public health problem, and its prevalence is increasing at an alarming rate worldwide. It has been estimated that 371 million people are already affected by type 2 diabetes, and the number is projected to reach 552 million by 2030 (1).
The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors (2,3). Some risk factors, such as diet and obesity, are under personal control; however, genetic factors are not (4). Although the rise in type 2 diabetes prevalence can be mostly attributed to changes in diet and lifestyle, there is strong evidence of a genetic basis for type 2 diabetes (2). However, genetic risk factors have been found to have lower predictive values when compared to phenotype variables such as body
mass index (BMI), familial diabetes history (FAMDB), high blood pressure (HBP), and cholesterol (CHOL) (5,6). Furthermore, the additive contribution of genetic studies using single nucleotide polymorphisms (SNPs) to phenotype variables was found to be almost negligible in several studies (5–12). Because numerous genetic and nongenetic risk factors interact in the causation of type 2 diabetes, the predictive ability of genetic models will likely remain modest.
At present, the clinical use of genetic testing for type 2 diabetes prediction in adults is not recommended (13). Phenotypic risk factors have a higher predictive ability with area under the curve (AUC) values of 0.70–0.90, but these are in middle or later ages when the reversibility of factors is low. Therefore, a model to predict the risk score for type 2 diabetes in the early stages is needed. Additionally, as prediabetic individuals usually remain undiagnosed and
Background/aim: Despite the rise in type 2 diabetes prevalence worldwide, we do not have a method for early risk prediction. The predictive ability of genetic models has been found to be little or negligible so far. In this study, we aimed to develop a better early risk prediction method for type 2 diabetes.
Materials and methods: We used phenotypic and genotypic data from the Nurses’ Health Study and Health Professionals’ Follow-up Study cohorts and analyzed them by using binary logistic regression.
Results: Phenotypic variables yielded 70.7% overall correctness and an area under the curve (AUC) of 0.77. With regard to genotype, 798 single nucleotide polymorphisms with P-values of lower than 1.0E-3 yielded 90.0% correctness and an AUC of 0.965. This is the highest score in the literature, even including the scores obtained with phenotypic variables. The additive contributions of phenotype and genotype increased the overall correctness to 92.9% and the AUC to 0.980.
Conclusion: Our results showed that genotype could be used to obtain a higher score, which could enable early risk prediction. These findings present new possibilities for genome-wide association study analysis in terms of discovering missing heritability. These results should be confirmed by follow-up studies.
Key words: Type 2 diabetes, genome-wide association study, single nucleotide polymorphism, Affymetrix, binary logistic regression, ROC curve
Received: 21.10.2013 Accepted: 03.01.2014 Published Online: 24.10.2014 Printed: 21.11.2014
Research Article
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untreated, identifying new methods using the genotype for the screening and prediction of risk factors is very important. The early prediction of risk factors may help patients to make lifestyle modifications in connection with preventable risk factors, such as obesity (14).
Genome-wide association studies (GWASs) have been widely used to investigate the role of the genotype in the development of diseases. Although many studies have been conducted to uncover the heritability of type 2 diabetes, only a small proportion of genetic heritability can be explained by the variants identified. GWASs have shown significant genome-wide associations with type 2 diabetes at 44 susceptibility loci so far (15). The current type 2 diabetes risk variants explain only about 5%–10% of the genetic basis of type 2 diabetes; much of the genetic basis remains unexplained (16,17).
Most of these studies used logistic regression for the analysis of genetic variables. However, the maximum number of SNPs used was 42, and C-statistics results (AUC) for the genotype were lower than 0.60 (5–12). In the course of our GWAS analysis of Nurses’ Health Study (NHS) and Health Professionals’ Follow-up Study (HPFS) data, we realized that sensitivity, specificity, and C-statistics increased with the number of SNPs. As we used genotype data for the whole genome instead of a finite number of SNPs, unlike previous studies, a high number of SNPs were included in the analysis. The highest prediction risk scores and AUCs for type 2 diabetes in the literature, even when phenotype studies are included, were achieved in this study using the 798 SNPs selected with P-values of less than 1.0E-3 for the model. Our findings demonstrate the importance of genotype in the prediction of type 2 diabetes, which has been previously disregarded.
2. Materials and methods 2.1. Study populationThe NHS and HPFS are well-characterized cohorts of nurses and health professionals, conducted in order to identify novel genetic factors that contribute to type 2 diabetes through large-scale, GWASs and to investigate the role of environmental exposure on the development of type 2 diabetes. The NHS and HPFS cohorts are part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org). The NHS was established in 1976, and the HPFS study was started in 1986. Participants of the NHS and HPFS completed a mailed questionnaire on their medical history and lifestyle. Blood was collected in 1989–1990 for the NHS and in 1993–1995 for the HPFS. Genotyping was completed in December 2008 for the NHS and in March 2009 for the HPFS. Lifestyle factors, including smoking, menopausal status and postmenopausal hormone therapy, and body weight, have been updated by validated questionnaires every 2 years.
Participants meeting the following criteria were excluded from the study: 1) those with other types of diabetes (65 NHS, 68 HPFS); 2) those belonging to races other than white (61 NHS, 100 HPFS); 3) HapMap controls (45 NHS, 29 HPFS); and 4) first-degree relatives (15 NHS, 14 HPFS). The final sample included 3248 (1769 controls and 1479 cases) for the NHS and 2391 (1277 controls and 1114 cases) for the HPFS. The current analysis includes SNPs mapped to chromosomes 1 through 23, as annotated based on the Affymetrix Genome-Wide Human SNP Array 6.0 (GeneChip 6.0). 2.2. Phenotypic variablesBMI has been shown to be the most important phenotypic variable in risk prediction of type 2 diabetes. BMI data were continuous in our study, and we converted them to binary using threshold levels that were calculated separately for males and females using the Youden Index (YI = sensitivity + specificity – 1) against the status of diabetes. We found BMI threshold levels of 26.3 kg/m2 for females and 27.1 kg/m2 for males that maximized the YI. Other phenotypic data including FAMDB, CHOL, and HBP were binary.
We also analyzed other phenotypic variables. While sex, polyunsaturated fat intake, trans fat intake, and magnesium intake were statistically not important, smoking, activity levels, postmenopausal hormonal status, alcohol, cereal fiber intake, heme iron intake, and glycemic load were found to be significantly related to diabetic status (data not shown). However, since these variables mostly depend on individual declaration, they are subjective. The contribution of these variables to classification and the AUC were negligible; therefore, we excluded them from the analysis for clarity.2.3. Software Analyses were conducted using PLINK and SPSS 15.0 for Windows. Amelia software was used to fill in missing values, and R was used for graphical presentation of quantile plots and Manhattan plots (www.r-project.org).
PLINK version 1.07 was used to analyze genome-wide data (http://pngu.mgh.harvard.edu/~purcell/plink). We merged NHS and HPFS data first. SNPs that met any of the following criteria were excluded from the analysis: 1) minor allele frequencies (MAF) of <0.05; 2) call rate of <95%; 3) P for Hardy–Weinberg equilibrium of <0.001; and 4) missing rates 0.1. After applying the QC filter, 642,576 SNPs remained for the analyses. 2.4. Binary logistic regressionWe performed binary logistic regression (BLR) using NHS and HPFS genotypic and phenotypic data via SPSS to test the associations of the genotypic and phenotypic risk scores with diabetes. We coded genotypes for common allele homozygotes, heterozygotes, and rare allele
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homozygotes separately for analysis. We evaluated model discrimination by using C-statistics (areas under receiver operating characteristic curves, ROC-AUCs), which were calculated for the predicted risk of the logistic regression model.
We used SNPs with P-values of less than 1.0E-3. There were 886 SNPs with P-values below this level. However, we excluded SNPs if the missing allele number was greater than 50 (patients), except for rs10739592, since it had the lowest P-value (2.08E-14). It had 99 missing alleles. To fill in the missing alleles, we used the Amelia toolbox for imputation (18). The result of the imputation was validated by comparing ‘before’ and ‘after’ P-values of SNPs and observing the relative distribution density of the original data set and the imputed data set.
3. Results3.1. The clinical characteristics of the participantsThe clinical characteristics of the study populations are presented in Table 1. We performed a genome-wide analysis of NHS and HPFS participants. The frequency distribution of the P-value of the SNPs is given in Table 2. The P-values of 886 SNPs were less than 1.0E-03. The distribution of P-values for all SNPs (642,576) versus chromosomal distribution is shown as a Manhattan plot in Figure 1. Chromosomes, P-values, odds ratios, and MAF values of 798 SNPs are provided in the Appendix (on the journal’s website). Quantile–quantile (QQ) plots of P-values of SNPs are given against the expected P-values in Figure 2. We accepted 1.0E-3 as the threshold level to determine which SNPs would be included in the analysis (Figure 2). Initially, 886 SNPs were considered; after a quality check for missing criteria, 798 SNPs were used.3.2. BLR analysis of phenotypeThe analysis results of phenotype variables of the NHS and HPFS data sets are presented in Table 2. The summary of BMI is also listed in Table 3 as a continuous variable. As noted in Section 2, BMI was converted to a binary form before BLR analysis. Type 2 diabetes patients had significantly higher BMIs than the controls. BMI was strongly associated with type 2 diabetes; the odds ratio for
BMI was 3.86. Other important phenotypes were FAMDB, HBP, and CHOL. Their P-values and odds ratios are also given in Table 4. The combined effect of these 4 phenotype variables yielded an overall classification of 70.7% and an AUC of 0.77. We also compared rs10739592, which had the lowest P-value in GWAS analysis, with phenotypic variables. It should be noted that rs10739592 alone (OR: 1.34, P-value: 2.08E-14) increased the overall prediction by only 2.84%. The composite effect of phenotypic variables was less than the sum of the individual effects of each variable alone due to the effect of overlap.
We were able to predict individual risk scores using the following formula with constants obtained from logistic regression analyses of familial diabetes history, high blood pressure, cholesterol, and BMI.
Table 1. Clinical characteristics of the participants. Data presented as mean ± SD.
Type 2 diabetes Control subjects
n (male/female) 1114/1479 1277/1769Age (years) 57.42 ± 7.72 57.12 ± 7.66BMI (kg/m2)Female 29.91 ± 5.76 25.39 ± 4.83Male 27.89 ± 4.14 25.21 ± 2.82
Table 2. P-value distribution of SNPs (before filtering of missing alleles, see Section 2).
P-value Cumulative frequency Frequency
<1.0E-11 1 11.0E-10 6 51.0E-09 6 01.0E-08 6 01.0E-07 10 41.0E-06 29 191.0E-05 132 1031.0E-04 886 754
–log
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Figure 1. Manhattan plot of the point-wise P-values for the 642,576 SNP loci of the NHS and HPFS data sets.
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exp(-1,579+famdb+1,132+hbp×0,862+chol×0,556+BMI×1,351
1+exp(-1,579+famdb+1,132+hbp×0,862+chol×0,556+BMI×1,351P=
The C-statistics (AUC) value for the 4 phenotype variables was found to be 0.77 ± 0.003. 3.3. BLR analysis of genotypeBecause the number of SNPs (798) is high and is unusual for BLR, as reported in the literature, we used a different approach to evaluate the effect of genotype on prediction scores and AUC. First, we grouped SNPs according to their P-values. Three groups of SNPs with P-values of less than 1.0E-4 yielded a maximum prediction score of 67.4% and an AUC of 0.735; 680 SNPs with P-values between 1.0E-04 and 1.0E-03 yielded a prediction score of 87.7% and an AUC of 0.947. When we used an incremental approach, the first 3 groups containing 118 SNPs with P-values of less than 1.0E-4 yielded prediction scores that were lower than
that of the fourth group (Table 5). This showed that more SNPs should be included for higher prediction rates and explained why previous studies in the literature that used a maximum of 40 SNPs obtained lower predictive values. In addition, we tested how various threshold levels in BLR analysis affected the prediction score and AUC (Table 6). The threshold level was chosen to be 0.5 by default in BLR analysis. When the threshold level increases, negative predictive value increases, positive predictive value decreases, and AUC does not change (Table 6).
We also investigated the additive contribution of phenotypes to the model built from genotyping data. The addition of 4 phenotypes (BMI, FAMDB, CHOL, and HBP) increased the prediction score from 90.0% to 92.9% and the AUC from 0.965 to 0.980 (Figure 3).
In addition, we found important differences between females and males in SNPs corresponding to the transcription factor-7–like 2 (TCF7L2) gene (Table 7). We found that the TCF7L2 gene was more determinative in males than in females. Although the TCF7L2 gene is one of the most significant genetic marker associated with type 2 diabetes mellitus risk (19), there is no information in the literature about the relationship between the TCF7L2 gene and sex. This finding is important when interpreting literature on interethnic differences that do not mention sex.
4. DiscussionDevelopment of genotype-based prediction will help us in the early prediction, identification, and prevention of type 2 diabetes. We showed that genotype-based predictions for type 2 diabetes yielded as high a score as phenotype-based methods. We obtained 90.0% prediction correctness, and the AUC was 0.965 with only genotype (SNP) variables. According to our knowledge, this is the highest score reported in the literature for risk prediction of type 2 diabetes.
GWAS has facilitated the understanding of the genetic basis of complex traits; it is a powerful method for the detection of genetic variations that predispose individuals
Obs
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Figure 2. Quantile-quantile plots of SNP P-values in (NHS+HPFS) GWAS analysis. The x-axis is –log10 of the expected P-values and the y-axis is –log10 of the observed P-values. Detaching point from the expected –log10 is nearly 1.0E-3.
Table 3. Body mass index values of males and females in the control and diabetic groups. Data presented as mean ± SD.
Male n Female n Average n
Control 25.21 ± 2.82 1277 25.39 ± 4.83 1769 25.31 ± 4.11 3046Diabetes 27.89 ± 4.14a 1114 29.91 ± 5.76b 1479 29.04 ± 5.22c 2593Average 26.45 ± 3.74 2391 27.44 ± 5.73 3248 27.03 ± 5.01 5639
a Independent sample t-test, 3.72E-115.b Independent sample t-test, 1.52E-68.c Independent sample t-test, 1.85E-174.
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to complex chronic diseases. GWAS has provided many useful insights into the pathophysiology of type 2 diabetes by enabling the identification of novel susceptibility loci that were not identified by classical approaches. However, for most of the identified type 2 diabetes susceptibility loci, the causal variants and molecular mechanisms for diabetes risk are unknown. Our findings do not reject the importance
of susceptibility loci for causal variants, but rather provide more accurate risk prediction. It is also important to remember that the effect sizes found for SNPs thus far are not a reflection of their biological or clinical significance. Although their individual predictive values may be small, SNPs as a profile might point to important biological pathways that could be targeted for therapeutic intervention.
Table 4. P-value, odds ratio, net reclassification improvement (NRI) percentage, overall prediction percentage, and AUC of phenotypic variables (n/a, not applicable).
Phenotype P-value Odds ratio NRI % Overall prediction % AUC
Baseline n/a n/a n/a 54 n/aBody mass index 5.21E-108 3.86 13.99 68.0 0.68a
Familial diabetes history 4.32E-69 3.10 9.70 63.7 0.63b
High blood pressure 3.25E-39 2.37 9.68 63.7 0.62b
Cholesterol 7.76E-15 1.74 4.40 58.4 0.56
Four phenotypes (BMI+FAMDB+HBP+CHOL) 1.56E-187 n/a 16.70 70.7 0.77c
rs10739592 2.08E-14 1.34 2.84 56.9 0.55
a P < 0.001, significantly higher than other groups except BMI+FAMDB+HBP+CHOL.b P < 0.001, significantly higher than cholesterol and rs10739592.c P < 0.001, significantly higher than others.BMI: Body mass index, FAMDB: familial diabetes history, HBP: high blood pressure, CHOL: cholesterol.
Table 5. Additive binary logistic regression analysis of SNPs grouped according to their P-values obtained in GWAS analysis.NPV: Negative predictive value, PPV: positive predictive value, AUC: area under curve.
SNP groups accordingto their P-values Number of SNPs (n) NPV (percentage
correct for control)PPV (percentage correct for diabetes) Overall % AUC
<1.0E-06 10 75.0 38.7 58.3 0.602<1.0E-05 27 (10+17) 72.8 45.3 60.2 0.636<1.0E-04 118 (91+27) 74.3 59.3 67.4 0.735<1.0E-03 798 (680+118) 90.7 89.1 90.0 0.965
Table 6. Effects of cut-off value on classification correctness and AUC.
ROC cutoff value SNPs (n) NPV PPV Overall % AUC
0.5 798 90.7 89.1 90.0 0.965 ± 0.0020.6 798 94.0 83.7 89.3 0.965 ± 0.0020.7 798 96.8 76.8 87.6 0.965 ± 0.0020.8 798 98.4 67.5 84.2 0.965 ± 0.0020.9 798 99.3 52.6 77.8 0.965 ± 0.002
NPV: Negative predictive value, PPV: positive predictive value, AUC: area under curve.
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Fortunately, the incidence of type 2 diabetes can be delayed or prevented by maintaining healthy lifestyle behaviors (14). The early identification of population subgroups that are at particularly high risk for type 2 diabetes might facilitate the targeting of prevention efforts to those who might benefit from them the most. Until these findings, genetic associations have not appeared to improve type 2 diabetes risk prediction, which has already been achieved through clinical risk predictors alone.
In the time since the first GWAS data were published in 2007 by the Wellcome Trust Case Control Consortium (20), significant progress has been made and much information has been obtained from GWASs. However, GWAS-based studies to improve clinical decisions are still in their initial stages (21). Previous studies have focused mostly on causative loci rather than the entire risk prediction approach. In addition, the results of risk prediction models are not satisfactory for type 2 diabetes. Nearly 40 susceptible loci have been identified in European and Asian populations, but the heritability of type 2 diabetes remains largely unexplained (22). Only ~10% of the known type 2 diabetes heritability could be explained by the results of a European twin study (23). This evidence suggests that information on a large portion of heritability is missing. Since a statistical P-value of 5 × 10–8 is generally accepted for genome-wide significance (24), previous studies did not use SNPs that had P-values
greater than this. Several limitations of the current approach for GWASs in revealing the missing heritability information have been proposed. One limitation is that the accepted importance threshold level for GWASs (P < 5 × 10–8) may produce type 2 errors (false-negative results). Therefore, many important loci could be obscured among other loci having only borderline associations. In addition, Imamura et al. suggested that the other reason for the low percentage of genetic contribution might be the omission of susceptibility variants that have an MAF value of less than 1% (22). However, our findings do not agree with these suggestions. In this study, we used SNPs that had P-values of greater than 5 × 10–8, accepted 5% as the threshold for MAF, and thereby obtained a higher risk prediction score. The most important reason for the low genetic contribution reported so far is that the use of a small number of SNPs for analysis fails to yield a sufficient composite risk score. We proposed that SNPs that have P-values of less than the detaching point of a distribution (in QQ plot), 1.0E-3 in our study, could contribute to risk prediction. Furthermore, Imamura et al. (22) suggested
Specificity1.0 0.8 0.6 0.4 0.2 0.0
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Figure 3. ROC plot for the BLR model containing type 2 diabetes and 4 phenotype variants, body mass index, familial diabetes history, high blood pressure, and cholesterol (black line, AUC = 0.77), for the 798 SNP variants (red line, AUC = 0.965) and genotype plus phenotype (blue line, AUC = 0.980).
Table 7. SNPs corresponding to the TCF7L2 gene in our GWAS analysis. The P-values of some SNPs differ between males and females.
SNPP-value
General NHS (Female) HPFS (Male)
rs12255372 4.37E-10 9.72E-05 5.52E-07rs12243326 6.12E-10 1.80E-04 3.47E-07rs4132670 6.53E-10 2.56E-04 1.94E-07rs7901695 8.18E-10 1.53E-04 5.83E-07rs4506565 9.48E-10 1.67E-04 5.92E-07rs11196208 2.40E-05 3.67E-03 2.08E-03rs10885409 2.71E-05 5.33E-03 1.50E-03rs11196205 3.49E-05 5.59E-03 1.91E-03rs4074720 1.30E-04 1.22E-02 3.29E-03rs7077039 1.35E-04 1.50E-02 2.77E-03rs10787472 1.38E-04 1.36E-02 3.09E-03rs6585201 3.96E-04 3.57E-02 2.95E-03rs4073288 3.88E-03 >0.05 1.40E-02rs7901275 4.71E-03 >0.05 2.25E-03rs11196212 7.30E-03 4.39E-02 >0.05rs7917983 7.76E-03 >0.05 2.62E-03rs11196181 2.67E-02 >0.05 >0.05rs12266632 3.28E-02 4.17E-02 >0.05rs11196203 3.39E-02 >0.05 1.64E-02
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that genome-wide exon (exome) sequencing by next-generation sequencers might help explain the missing heritability. Our findings suggest that this might not be necessary in order to obtain a high risk-prediction score. However, next-generation sequencing technology may help find the exact causative loci near or encompassing the newly discovered SNPs.
Because individual SNPs do not yield adequate prediction scores, combining SNPs to yield composite genotype risk scores has also been tested. In such a simulation study by Janssens et al., risk alleles were weighted according to the type 2 diabetes effect size from the original GWAS; this might not substantially improve the C-statistic for alleles with small effect sizes (odds ratio: 1.10–1.25) (25). However, we found that 680 SNPs with P-values between 1.0E-04 and 1.0E-03 yielded an overall prediction score of 87.7% and AUC of 0.947, while 118 SNPs, with P-values of less than 1.0E-04, yielded an overall prediction score of 67.4% and AUC of 0.735. This shows that a high SNP number is required for higher composite genotype risk scores. However, Janssens et al. used only 40 SNPs. The composite risk score is not equal to the sum of individual SNP scores. Due to the overlapping effect of the risk alleles, we could obtain a higher composite risk score with a higher number of SNPs. However, phenotype risk scores are higher than those of individual SNP scores, i.e. OR is 3.86 for BMI in our study. Thus, small phenotype variables could yield higher scores.
The prediction of an individual’s risk of developing type 2 diabetes is the most anticipated clinical use of genetic information. Prediction values of phenotypic and genotypic characters have been investigated in the Malmö Preventive Project, the Botnia Study (8), the Framingham Offspring Study I (9), the Whitehall II study (10), and the GoDARTS Study (26). These studies examined loci ranging in number from 11 to 20 that were associated with type 2 diabetes. The results of these analyses showed no clear improvement in predictive power when adding the genetic risk score to the established risk prediction models by using phenotypic variables such as age, sex, family history, BMI, fasting glucose level, systolic blood pressure, and lipid profile. Basic demographic, clinical, and laboratory predictors have C-statistics (AUC) ranging from 0.66 in the Rotterdam Study (11) to 0.90 in the Framingham Offspring Study I (9). The C-statistic improves from 0.903 to 0.906 with the addition of a 40-SNP score to the clinical model in the Framingham Offspring Study II (7) and from 0.74 to 0.75 in the larger Malmö Preventive Project (8). In other studies, adding genetic information to phenotype-based risk models did not improve discrimination and showed a maximum increase of only 2% over phenotype in ROC curves (6,10,26). AUC values were equal to or lower than 0.60 for genetic variants alone in these studies
(9–11,26). Therefore, phenotype scores were found to be superior to the scores achieved thus far by using genotype alone.
Genotype-based risk prediction may work better in younger individuals. In the Framingham Offspring II study, the addition of a 40-SNP score to a full clinical model achieved better net reclassification improvement (NRI) among those younger than 50 years old (7). However, the degree of prediction scores obtained from genotype is still below the widely accepted clinical prevention target. The greater contribution of genotype over the prediction value of phenotype for patients at a younger age is expected since phenotype variables are more overt only at middle age or older. The most desirable risk prediction method is one with a higher prediction value at an early age, even in childhood. Therefore, our findings provide an opportunity for risk prediction of type 2 diabetes with high accuracy at an early stage.
A limitation on the use of phenotypic variables is the reduced range of ages and follow-up durations for type 2 diabetes genetic prediction. In previous studies, participants with baseline ages were generally in middle adulthood, and the follow-up period was around 10 years. However, we need a model that can estimate the risk earlier, which should be validated at a young age with a longer prediction time horizon to help achieve early prevention. As noted above, in the Framingham Offspring Study II, the 40-SNP genotype risk score significantly improved NRI in younger participants but not in older ones. Here, we show that genetic risk prediction alone using 798 SNPs could yield higher risk prediction for type 2 diabetes.
Due to the low predictive value of the genetic susceptibility loci of type 2 diabetes so far, alternative GWAS strategies, such as enrichment of genetic effects for improving predictive power (i.e. selecting more severe cases, early onset of disease, and family history of type 2 diabetes), and original GWAS study designs (such as response to an antidiabetic treatment or type 2 diabetes in the presence of extreme obesity) (15,27) have been proposed. Complementary epigenomic approaches such as DNA methylation studies have also been proposed in addition to GWAS (27). However, our strategy of using more SNPs may provide greater risk prediction for type 2 diabetes; therefore, the need for a sophisticated approach to risk prediction could be reviewed. Our approach might be combined with epigenomic, environmental, or other enrichment methods for further insight into type 2 diabetes etiology.
In the future, follow-up studies with a reasonable time period should be designed to evaluate the development of type 2 diabetes using the genotype-based risk prediction value from our study. We were able to calculate individual risk scores using the constants of the present
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study obtained through analysis. Our findings should be validated by comparing the cumulative type 2 diabetes incidence in low- and high-risk groups in a follow-up study. In addition, interethnic differences should be reviewed from the perspective of our results, since some GWAS studies did not mention the sex of the participants (28,29). Furthermore, our prediction strategy could also be tested for treatment success of type 2 diabetes by establishing a pharmacogenetic investigation of a genome-wide approach. In a previous study, it was found that a SNP, rs11212617, at a locus containing the ataxia telangiectasia mutated gene could explain 2.5% of the variance in the metformin response (30). Variance greater than this can probably be explained using the composite SNP score
approach. Translation of the findings of the present study will provide a gateway into personalized preventive and therapeutic medicine.
In conclusion, we found that genotype-based risk prediction could yield higher risk prediction values when a sufficient number of SNPs are used. This could enable early risk prediction for type 2 diabetes. The growing importance of the threshold P-value in GWAS analysis should be reviewed, depending on the investigation field. Our findings open up new horizons for translating GWAS findings into improved care for patients with diabetes. The value of genotype-based risk prediction alone or in combination with phenotypic variables should be further investigated in follow-up studies for validation.
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1
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116
0,87
197,
19E-
040,
329
124
4271
398
GC
6475
4SM
YD3
SET
and
MYN
D d
omai
n co
ntai
ning
3
87rs
3893
111
0,86
554,
40E-
040,
302
286
9279
5G
A
88rs
1550
105
0,87
917,
11E-
040,
444
220
6135
84T
C
89rs
1189
7611
0,83
66,
05E-
040,
161
220
6387
98C
T
90rs
4666
430
0,83
012,
33E-
040,
173
220
6419
40G
A
91rs
9307
600,
8558
8,79
E-05
0,35
52
2066
9817
CT
92rs
4666
438
1,15
67,
02E-
040,
264
220
6740
67A
G
93rs
1109
6680
1,15
9,87
E-04
0,27
02
2067
5712
AT
94rs
3796
064
1,16
5,39
E-04
0,26
02
2070
1799
AG
6434
2H
S1BP
3H
CLS
1 bi
ndin
g pr
otei
n 3
95rs
1016
6174
0,86
853,
97E-
040,
349
220
7024
84A
G64
342
HS1
BP3
HC
LS1
bind
ing
prot
ein
3
96rs
1780
3553
0,87
436,
86E-
040,
356
225
6786
07T
C18
38D
TNB
dyst
robr
evin
, bet
a
97rs
1261
3835
0,87
46,
66E-
040,
356
225
6827
05A
G18
38D
TNB
dyst
robr
evin
, bet
a
App
endi
x. (C
ontin
ued)
.
4
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
98rs
7562
790
1,14
63,
94E-
040,
399
236
5270
59G
T51
232
CRI
M1
cyst
eine
rich
tran
smem
bran
e BM
P re
gula
tor 1
(cho
rdin
-like
)
99rs
2160
367
1,14
83,
09E-
040,
429
236
5351
23G
C51
232
CRI
M1
cyst
eine
rich
tran
smem
bran
e BM
P re
gula
tor 1
(cho
rdin
-like
)
100
rs38
2115
31,
139
6,86
E-04
0,41
72
3660
6626
GT
5123
2C
RIM
1cy
stei
ne ri
ch tr
ansm
embr
ane
BMP
regu
lato
r 1 (c
hord
in-li
ke)
101
rs27
2788
01,
141
5,83
E-04
0,42
92
5240
8156
CT
102
rs17
7307
800,
8557
4,53
E-04
0,23
62
5241
6883
GA
103
rs65
4527
40,
8526
3,46
E-04
0,23
32
5249
7718
CT
104
rs25
5235
60,
8732
3,56
E-04
0,45
92
5250
8248
GA
105
rs12
6228
110,
8602
2,44
E-04
0,30
32
5264
1453
TC
106
rs67
2039
01,
139
6,06
E-04
0,46
72
5265
4578
CT
107
rs13
4302
960,
8517
8,30
E-05
0,31
32
5267
2168
GC
108
rs17
0431
200,
8574
1,70
E-04
0,31
32
5267
9905
GA
109
rs18
4303
21,
138
8,27
E-04
0,39
62
5269
4816
AG
110
rs14
4644
10,
828
2,42
E-04
0,17
02
5315
5170
TC
111
rs75
7510
71,
228
1,94
E-04
0,13
32
5515
9490
GT
112
rs46
7236
70,
8309
2,06
E-04
0,17
62
6025
1920
TC
113
rs17
3297
261,
232,
03E-
040,
129
260
3385
90A
G
114
rs35
9274
1,17
59,
55E-
040,
178
260
3603
85C
G
115
rs17
6621
760,
7373
1,65
E-04
0,05
92
6495
0508
GC
116
rs12
4709
941,
288
3,02
E-04
0,08
22
6752
8010
AC
117
rs11
5976
61,
151
8,91
E-04
0,27
32
7231
7749
TC
2323
3EX
OC
6Bex
ocys
t com
plex
com
pone
nt 6
B
118
rs11
5976
41,
159,
47E-
040,
273
272
3178
74A
T23
233
EXO
C6B
exoc
yst c
ompl
ex co
mpo
nent
6B
119
rs10
2217
691,
158
5,05
E-04
0,27
62
7233
2562
TA
2323
3EX
OC
6Bex
ocys
t com
plex
com
pone
nt 6
B
120
rs21
1883
61,
165
2,46
E-04
0,29
22
9652
6699
CT
121
rs11
1234
061,
147
4,66
E-04
0,36
52
1116
6701
2T
C
122
rs17
7156
880,
8029
2,28
E-04
0,11
32
1150
8955
0G
T57
628
DPP
10di
pept
idyl
-pep
tidas
e 10
(non
-fun
ctio
nal)
123
rs17
7158
670,
7716
2,45
E-04
0,07
82
1150
9685
3C
A57
628
DPP
10di
pept
idyl
-pep
tidas
e 10
(non
-fun
ctio
nal)
124
rs67
0579
01,
175
5,21
E-04
0,21
32
1216
0935
8T
A
125
rs17
0107
800,
8116
4,87
E-04
0,11
32
1245
3127
4G
T12
9684
CN
TNA
P5co
ntac
tin a
ssoc
iate
d pr
otei
n-lik
e 5
126
rs17
5757
910,
8652
6,66
E-04
0,28
32
1298
0241
5T
C
127
rs49
5404
50,
8795
9,06
E-04
0,39
02
1336
9534
0A
C34
4148
NC
KA
P5N
CK
-ass
ocia
ted
prot
ein
5
128
rs17
7863
001,
189
9,41
E-04
0,14
92
1402
5387
2C
A
129
rs13
5542
10,
7852
4,95
E-05
0,11
82
1606
2146
4A
G22
925
PLA
2R1
phos
phol
ipas
e A
2 re
cept
or 1
, 180
kDa
130
rs13
5542
00,
7953
1,12
E-04
0,11
92
1606
2151
7T
C22
925
PLA
2R1
phos
phol
ipas
e A
2 re
cept
or 1
, 180
kDa
5
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
131
rs46
6514
60,
8047
5,34
E-05
0,14
72
1606
2432
9A
C22
925
PLA
2R1
phos
phol
ipas
e A
2 re
cept
or 1
, 180
kDa
132
rs16
8447
420,
7949
1,94
E-05
0,14
82
1606
3953
0T
A
133
rs75
7346
90,
7916
1,27
E-05
0,14
92
1606
5397
3G
A
134
rs31
1139
70,
8201
2,58
E-05
0,20
42
1607
5960
9C
T36
94IT
GB6
inte
grin
, bet
a 6
135
rs12
6925
851,
163
4,91
E-04
0,25
42
1607
8908
7G
A
136
rs10
1811
810,
809
4,03
E-07
0,29
02
1607
9565
7T
C
137
rs29
2575
70,
7906
1,71
E-06
0,18
32
1608
0941
5G
A
138
rs13
0234
771,
176
8,11
E-04
0,19
32
1608
2013
3T
C
139
rs12
6925
880,
8511
2,43
E-05
0,43
52
1608
3242
8C
T
140
rs75
7297
00,
8261
5,97
E-06
0,28
12
1608
4490
2A
G59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
141
rs10
2073
10,
8064
2,45
E-07
0,29
32
1608
5230
1G
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
142
rs10
2073
20,
8552
4,42
E-05
0,42
22
1608
5248
5G
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
143
rs12
6925
900,
8606
9,21
E-05
0,41
92
1608
6144
3C
G59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
144
rs12
6925
920,
8126
5,95
E-06
0,22
12
1608
7162
7G
T59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
145
rs99
1715
50,
8574
5,20
E-05
0,45
42
1608
7180
5C
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
146
rs40
7746
30,
807
3,16
E-06
0,21
82
1608
7448
0A
G59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
147
rs75
9373
00,
8053
2,55
E-06
0,21
82
1608
7970
0T
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
148
rs45
8970
50,
806
2,75
E-06
0,21
92
1608
8438
2T
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
149
rs43
8628
00,
8605
7,99
E-05
0,44
92
1608
9104
1A
G59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
150
rs46
6401
30,
8334
6,49
E-06
0,33
12
1608
9241
0G
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
151
rs10
1653
190,
8585
1,41
E-04
0,33
72
1609
0105
1T
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
152
rs45
3815
00,
8508
2,18
E-05
0,45
12
1609
1757
3G
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
153
rs92
8779
50,
8055
2,66
E-06
0,21
82
1609
1803
4C
G59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
154
rs67
1852
60,
7817
2,74
E-07
0,19
72
1609
2242
1T
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
155
rs11
6936
020,
8048
2,29
E-06
0,21
92
1609
3290
4C
T59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
156
rs10
9299
820,
8021
4,55
E-06
0,19
52
1609
4452
3C
T59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
157
rs12
9985
870,
8344
1,19
E-05
0,30
72
1609
5054
1T
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
158
rs75
8710
20,
8384
1,99
E-05
0,30
62
1609
6752
8T
C59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
159
rs46
6432
30,
8711
3,11
E-04
0,42
82
1609
6793
1C
T59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
160
rs13
0093
740,
8469
5,84
E-05
0,30
52
1609
7334
5C
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
161
rs67
4279
90,
8377
2,39
E-04
0,19
82
1610
2570
6C
A59
37RB
MS1
RNA
bin
ding
mot
if, si
ngle
stra
nded
inte
ract
ing
prot
ein
1
162
rs67
5256
91,
154,
89E-
040,
327
216
1182
219
CT
163
rs13
3901
721,
169
1,69
E-04
0,28
72
1612
3384
7C
T
6
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
164
rs12
4732
931,
186,
70E-
050,
287
216
1237
591
CA
165
rs43
8335
11,
172
1,35
E-04
0,28
62
1612
4241
4A
G
166
rs43
6834
31,
198
4,39
E-06
0,35
32
1612
4289
7C
G
167
rs16
8513
821,
211,
55E-
040,
169
216
6621
721
AG
6323
SCN
1Aso
dium
chan
nel,
volta
ge-g
ated
, typ
e I,
alph
a su
buni
t
168
rs14
0210
80,
8632
6,78
E-04
0,25
72
1769
5797
2G
T
169
rs12
1856
281,
207
4,01
E-05
0,21
92
1793
8921
6C
T
170
rs10
1907
410,
8765
5,27
E-04
0,44
32
1793
9611
7T
C
171
rs12
4773
460,
8777
6,60
E-04
0,44
42
1794
4585
5A
G28
5025
CC
DC
141
coile
d-co
il do
mai
n co
ntai
ning
141
172
rs10
1761
471,
138
6,24
E-04
0,46
62
1843
7878
9G
C
173
rs82
6186
0,87
767,
66E-
040,
397
218
4403
897
GA
174
rs23
6920
21,
134
9,11
E-04
0,46
82
1846
9431
0T
C
175
rs12
2328
841,
135
8,70
E-04
0,45
42
1847
0963
0G
C
176
rs15
2621
21,
135
8,54
E-04
0,46
02
1847
1910
2A
G
177
rs10
4976
431,
137
6,98
E-04
0,46
22
1847
6102
7T
C
178
rs13
0109
851,
152,
49E-
040,
458
218
4812
923
AG
179
rs71
9736
1,13
77,
00E-
040,
487
218
4895
389
GA
180
rs42
4127
91,
236
3,06
E-04
0,11
72
1923
1791
1T
C
181
rs67
3908
01,
216
8,61
E-04
0,11
92
1923
2235
2T
G
182
rs46
7542
50,
8212
6,52
E-04
0,12
42
2047
3417
3A
G
183
rs75
8385
20,
8505
4,74
E-04
0,21
42
2047
6613
2T
G
184
rs10
1980
840,
8448
4,67
E-05
0,29
72
2048
5557
6A
G
185
rs64
3525
21,
229
4,89
E-04
0,11
62
2053
6626
1A
G11
7583
PARD
3Bpa
r-3
part
ition
ing
defe
ctiv
e 3
hom
olog
B (C
. ele
gans
)
186
rs10
7504
11,
227,
58E-
040,
119
220
5372
981
AG
1175
83PA
RD3B
par-
3 pa
rtiti
onin
g de
fect
ive
3 ho
mol
og B
(C. e
lega
ns)
187
rs26
6389
11,
267
9,40
E-04
0,07
82
2082
8156
6A
G
188
rs16
8400
041,
298
8,31
E-04
0,06
42
2083
2519
3A
G15
1195
CC
NYL
1cy
clin
Y-li
ke 1
189
rs75
8573
61,
177,
85E-
040,
213
221
4300
694
TG
7958
2SP
AG
16sp
erm
ass
ocia
ted
antig
en 1
6
190
rs46
7305
40,
8649
1,25
E-04
0,48
72
2237
9610
6A
T
191
rs22
0373
30,
8618
8,41
E-05
0,48
42
2238
0134
5A
G
192
rs10
9330
000,
8657
1,37
E-04
0,48
82
2238
0165
4G
A
193
rs96
9494
0,86
371,
07E-
040,
484
222
3803
302
GA
194
rs97
0816
0,86
057,
28E-
050,
481
222
3805
584
GA
195
rs75
9502
91,
218
7,62
E-05
0,16
82
2360
5670
2C
T
196
rs46
6359
61,
203
2,29
E-04
0,16
72
2360
6594
3A
G
7
GÜL et al. / Turk J Med Sci
197
rs46
8559
81,
175
7,98
E-04
0,19
13
3486
93A
C10
752
CH
L1ce
ll ad
hesio
n m
olec
ule
with
hom
olog
y to
L1C
AM
(clo
se
hom
olog
of L
1)
198
rs76
3050
91,
172
8,62
E-04
0,19
53
3491
68G
A10
752
CH
L1ce
ll ad
hesio
n m
olec
ule
with
hom
olog
y to
L1C
AM
(clo
se
hom
olog
of L
1)
199
rs76
4954
41,
243
8,03
E-04
0,09
23
3530
69C
A10
752
CH
L1ce
ll ad
hesio
n m
olec
ule
with
hom
olog
y to
L1C
AM
(clo
se
hom
olog
of L
1)
200
rs64
4292
91,
148
7,55
E-04
0,30
83
5072
993
TC
201
rs67
7317
91,
148
6,47
E-04
0,32
73
5073
759
AT
202
rs11
6117
10,
8322
6,51
E-05
0,22
53
8417
494
CT
1002
8842
8LO
C10
0288
428
unch
arac
teriz
ed L
OC
1002
8842
8
203
rs35
9025
0,83
368,
15E-
050,
221
384
2072
9T
C10
0288
428
LOC
1002
8842
8un
char
acte
rized
LO
C10
0288
428
204
rs35
9024
0,84
342,
13E-
040,
224
384
2126
5G
A10
0288
428
LOC
1002
8842
8un
char
acte
rized
LO
C10
0288
428
205
rs35
9033
0,86
9,99
E-04
0,22
73
8431
789
AG
1002
8842
8LO
C10
0288
428
unch
arac
teriz
ed L
OC
1002
8842
8
206
rs35
9032
0,85
495,
74E-
040,
232
384
3237
9C
T10
0288
428
LOC
1002
8842
8un
char
acte
rized
LO
C10
0288
428
207
rs20
8862
00,
8501
4,58
E-04
0,22
33
8435
932
GT
1002
8842
8LO
C10
0288
428
unch
arac
teriz
ed L
OC
1002
8842
8
208
rs11
7120
161,
206
7,15
E-04
0,13
43
9174
613
GC
9901
SRG
AP3
SLIT
-RO
BO R
ho G
TPas
e ac
tivat
ing
prot
ein
3
209
rs12
1859
780,
8598
3,98
E-04
0,27
23
1106
1367
CG
210
rs21
3050
50,
8432
1,43
E-05
0,36
83
2172
7970
GA
7975
0ZN
F385
Dzi
nc fi
nger
pro
tein
385
D
211
rs48
5834
80,
8554
7,59
E-05
0,35
83
2173
0685
GA
7975
0ZN
F385
Dzi
nc fi
nger
pro
tein
385
D
212
rs48
5835
20,
8526
4,51
E-05
0,37
43
2174
3250
GA
7975
0ZN
F385
Dzi
nc fi
nger
pro
tein
385
D
213
rs98
3082
51,
275
3,53
E-04
0,08
33
3143
1027
AC
214
rs12
4859
141,
207
7,85
E-04
0,13
33
3143
7904
CT
215
rs11
9170
100,
8644
7,17
E-04
0,25
93
5418
1107
AG
5579
9C
AC
NA
2D3
calc
ium
chan
nel,
volta
ge-d
epen
dent
, alp
ha 2
/del
ta su
buni
t 3
216
rs67
9422
90,
8528
2,15
E-04
0,26
03
5418
9989
TG
5579
9C
AC
NA
2D3
calc
ium
chan
nel,
volta
ge-d
epen
dent
, alp
ha 2
/del
ta su
buni
t 3
217
rs13
0616
340,
8717
7,75
E-04
0,30
73
5602
9117
CT
2605
9ER
C2
ELK
S/RA
B6-in
tera
ctin
g/C
AST
fam
ily m
embe
r 2
218
rs10
2173
40,
8224
7,23
E-04
0,12
93
5693
8384
TC
5065
0A
RHG
EF3
Rho
guan
ine
nucl
eotid
e ex
chan
ge fa
ctor
(GEF
) 3
219
rs17
2889
930,
8128
3,12
E-04
0,13
13
5694
0107
GA
5065
0A
RHG
EF3
Rho
guan
ine
nucl
eotid
e ex
chan
ge fa
ctor
(GEF
) 3
220
rs46
2606
70,
8091
2,09
E-04
0,13
53
5696
8071
TC
5065
0A
RHG
EF3
Rho
guan
ine
nucl
eotid
e ex
chan
ge fa
ctor
(GEF
) 3
221
rs10
1550
271,
254
1,60
E-04
0,11
83
6025
9909
TG
2272
FHIT
frag
ile h
istid
ine
tria
d
222
rs17
4000
841,
254
1,46
E-04
0,11
73
6026
1426
TC
2272
FHIT
frag
ile h
istid
ine
tria
d
223
rs11
7071
841,
184
2,12
E-04
0,21
53
6231
6084
TC
224
rs83
1080
0,85
793,
13E-
040,
273
371
5151
91C
G27
086
FOX
P1fo
rkhe
ad b
ox P
1
225
rs83
1081
0,84
931,
91E-
040,
250
371
5152
98A
G27
086
FOX
P1fo
rkhe
ad b
ox P
1
226
rs67
6619
01,
249,
16E-
040,
102
373
8710
82A
T
227
rs29
1475
1,26
16,
23E-
040,
091
373
8835
78C
G
228
rs52
4431
0,86
665,
60E-
040,
296
374
3835
84A
G
App
endi
x. (C
ontin
ued)
.
8
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
229
rs47
1800
0,87
419,
77E-
040,
312
374
3923
34T
C
230
rs65
5148
30,
8779
9,58
E-04
0,36
43
8756
8689
CT
231
rs98
1514
90,
8716
4,77
E-04
0,36
63
8756
9165
GC
232
rs98
1634
41,
141
5,71
E-04
0,40
83
1151
6278
0C
T25
4887
ZDH
HC
23zi
nc fi
nger
, DH
HC
-typ
e co
ntai
ning
23
233
rs98
4092
51,
342
7,41
E-04
0,05
43
1165
8254
6G
A
234
rs16
8239
341,
162
9,09
E-04
0,22
83
1168
1837
4A
G
235
rs17
2816
121,
208
8,85
E-04
0,12
23
1206
0668
9C
T57
514
ARH
GA
P31
Rho
GTP
ase
activ
atin
g pr
otei
n 31
236
rs11
3220
21,
216
5,93
E-04
0,12
23
1206
3318
1C
G55
254
TMEM
39A
tran
smem
bran
e pr
otei
n 39
A
237
rs43
1412
40,
8663
6,53
E-04
0,27
83
1272
7032
2A
G54
946
SLC
41A
3so
lute
car
rier f
amily
41,
mem
ber 3
238
rs67
9661
00,
8683
7,97
E-04
0,27
83
1272
8060
3A
G54
946
SLC
41A
3so
lute
car
rier f
amily
41,
mem
ber 3
239
rs23
6501
20,
8541
6,97
E-05
0,34
83
1272
9989
4T
A54
946
SLC
41A
3so
lute
car
rier f
amily
41,
mem
ber 3
240
rs11
7154
741,
171
6,46
E-05
0,35
03
1502
8460
5T
G65
96H
LTF
helic
ase-
like
tran
scrip
tion
fact
or
241
rs76
4616
61,
149
4,62
E-04
0,34
53
1503
0710
2A
G
242
rs67
9216
81,
156,
29E-
040,
307
315
0319
263
CT
243
rs12
6959
431,
163
9,81
E-04
0,22
53
1509
8810
7A
T38
9161
AN
KU
B1an
kyrin
repe
at a
nd u
biqu
itin
dom
ain
cont
aini
ng 1
244
rs87
7439
0,88
198,
89E-
040,
497
316
9282
596
CT
2733
3G
OLI
M4
golg
i int
egra
l mem
bran
e pr
otei
n 4
245
rs15
2237
80,
8768
5,13
E-04
0,49
63
1692
8323
1G
A27
333
GO
LIM
4go
lgi i
nteg
ral m
embr
ane
prot
ein
4
246
rs10
4908
090,
842
1,64
E-04
0,22
73
1726
9944
9G
A
247
rs21
3101
70,
8595
7,95
E-04
0,24
23
1727
0025
5C
T
248
rs15
6556
70,
8511
4,30
E-04
0,22
43
1727
0685
5A
T
249
rs14
0200
21,
135
8,86
E-04
0,45
13
1851
2548
8A
G10
057
ABC
C5
ATP-
bind
ing
cass
ette
, sub
-fam
ily C
(CFT
R/M
RP),
mem
ber 5
250
rs93
9338
1,14
44,
01E-
040,
446
318
5186
762
GA
1005
7A
BCC
5AT
P-bi
ndin
g ca
sset
te, s
ub-f
amily
C (C
FTR/
MRP
), m
embe
r 5
251
rs10
9373
301,
144
3,64
E-04
0,47
93
1892
2146
0G
A
252
rs76
1334
00,
8474
7,90
E-04
0,17
93
1892
3342
3C
T
253
rs11
9295
980,
8355
2,93
E-04
0,17
93
1892
3595
8T
C
254
rs10
9386
810,
7794
8,69
E-05
0,09
94
8066
769
AG
8444
8A
BLIM
2ac
tin b
indi
ng L
IM p
rote
in fa
mily
, mem
ber 2
255
rs76
6247
71,
138
6,44
E-04
0,48
24
2384
7568
AG
256
rs11
7267
231,
174
8,07
E-04
0,19
04
2606
5365
TG
257
rs10
0340
331,
209
1,21
E-04
0,17
64
2607
1049
AC
258
rs17
2197
041,
168
9,18
E-04
0,20
04
6173
5051
AG
259
rs13
1508
830,
8059
4,64
E-04
0,10
84
6582
8632
CT
260
rs17
7503
110,
8294
3,36
E-04
0,15
74
6586
6784
GA
9
GÜL et al. / Turk J Med Sci26
1rs
6849
315
1,17
39,
60E-
040,
191
483
7959
01A
T79
966
SCD
5st
earo
yl-C
oA d
esat
uras
e 5
262
rs73
7720
40,
8534
2,29
E-04
0,26
14
8872
7430
CT
263
rs73
7722
50,
8562
3,10
E-04
0,26
24
8872
7547
CT
264
rs46
9384
60,
8494
1,52
E-04
0,26
24
8872
8693
AC
265
rs10
0069
781,
258
3,07
E-05
0,13
64
9689
8971
GA
266
rs76
5712
41,
241
3,38
E-05
0,15
54
9691
4610
CA
267
rs11
9317
521,
268
1,64
E-05
0,13
54
9693
8876
AT
268
rs11
9465
521,
244,
24E-
050,
151
496
9400
53A
C
269
rs17
0245
711,
226
1,09
E-04
0,14
74
9694
2220
GA
270
rs18
3690
01,
173
6,12
E-04
0,20
44
9695
8725
GA
271
rs10
4339
751,
175
6,58
E-04
0,19
54
9696
0072
GA
272
rs18
3689
91,
172
8,21
E-04
0,19
54
9696
6126
AG
273
rs10
0192
641,
173
7,48
E-04
0,20
24
9696
6176
CG
274
rs17
4734
051,
237
1,54
E-04
0,12
64
9697
0645
AT
275
rs13
1075
011,
179,
34E-
040,
194
496
9718
22C
T
276
rs17
0248
261,
215
5,54
E-04
0,12
64
9698
3626
CT
277
rs17
4759
481,
284
3,09
E-05
0,10
94
9700
2780
CG
278
rs12
5015
861,
174
8,91
E-05
0,30
74
1028
6103
5T
C
279
rs12
5050
431,
177
2,15
E-04
0,24
44
1028
7438
5T
C
280
rs17
5082
890,
7895
1,96
E-04
0,10
44
1063
3448
2A
G54
790
TET2
tet m
ethy
lcyt
osin
e di
oxyg
enas
e 2
281
rs12
6446
251,
204
9,67
E-04
0,13
04
1119
3596
2T
C
282
rs13
1365
210,
8591
9,10
E-05
0,39
24
1444
2501
4T
C
283
rs12
5012
000,
8522
2,20
E-04
0,26
64
1551
7060
0C
A
284
rs76
7985
60,
8773
7,03
E-04
0,40
14
1603
1598
8G
C
285
rs76
8367
10,
8794
8,79
E-04
0,40
14
1603
3466
7A
G
286
rs11
9391
060,
8803
9,63
E-04
0,40
24
1603
3591
1T
C
287
rs10
0500
990,
8766
8,45
E-04
0,35
84
1603
4385
7T
G
288
rs14
3462
11,
151
8,80
E-04
0,27
44
1628
6910
5G
C56
884
FSTL
5fo
llist
atin
-like
5
289
rs76
6037
31,
374
9,21
E-06
0,07
74
1629
1503
3T
C56
884
FSTL
5fo
llist
atin
-like
5
290
rs13
1178
691,
193
3,19
E-05
0,26
94
1899
2324
4G
C
291
rs48
6306
91,
202
1,64
E-05
0,26
34
1899
2806
0A
C
292
rs65
5323
21,
188
2,00
E-04
0,20
64
1899
4710
9G
A
293
rs11
9421
381,
175
2,58
E-04
0,23
84
1899
6918
8G
C
App
endi
x. (C
ontin
ued)
.
10
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
294
rs10
1792
41,
164
9,47
E-04
0,22
05
2029
187
AG
295
rs10
4912
230,
8729
4,47
E-04
0,39
55
8843
528
CG
296
rs10
4912
220,
8724
4,18
E-04
0,39
55
8870
497
AG
297
rs39
60,
8796
8,05
E-04
0,42
85
9668
339
CG
298
rs25
3091
30,
7781
1,32
E-04
0,09
45
1163
8455
TC
1501
CTN
ND
2ca
teni
n (c
adhe
rin-a
ssoc
iate
d pr
otei
n), d
elta
2
299
rs48
6604
60,
8759
8,30
E-04
0,35
75
2027
0802
AG
300
rs48
6604
70,
8746
7,19
E-04
0,35
45
2027
0828
CA
301
rs10
0371
150,
8766
8,77
E-04
0,35
55
2027
2670
GA
302
rs81
8052
20,
8719
5,26
E-04
0,35
55
2027
4979
CG
303
rs29
7460
20,
8805
8,66
E-04
0,43
15
2028
6581
CT
304
rs13
1648
860,
8797
7,06
E-04
0,48
45
2030
2871
TG
305
rs29
7459
10,
8784
6,79
E-04
0,43
75
2032
5791
CT
306
rs44
2981
20,
8601
3,48
E-04
0,27
75
2720
9030
CT
307
rs45
1834
50,
8576
2,68
E-04
0,27
75
2722
1661
AG
308
rs45
1054
50,
8557
2,17
E-04
0,27
75
2722
5107
CA
309
rs68
8052
60,
8558
2,22
E-04
0,28
05
2722
7465
TC
310
rs68
9031
00,
8586
2,95
E-04
0,27
85
2722
9330
AG
311
rs21
9921
40,
8431
8,33
E-04
0,16
65
2733
8180
CT
312
rs14
2825
61,
182
4,18
E-04
0,19
85
3830
9217
TG
1335
84EG
FLA
MEG
F-lik
e, fib
rone
ctin
type
III a
nd la
min
in G
dom
ains
313
rs18
3496
71,
228
2,95
E-04
0,12
35
3840
1890
AG
1335
84EG
FLA
MEG
F-lik
e, fib
rone
ctin
type
III a
nd la
min
in G
dom
ains
314
rs43
3638
31,
149
5,91
E-04
0,32
35
3883
1091
AT
315
rs68
8600
10,
879
6,63
E-04
0,48
35
5222
2194
CT
3672
ITG
A1
inte
grin
, alp
ha 1
316
rs68
6682
30,
8769
5,37
E-04
0,48
45
5222
2328
AG
3672
ITG
A1
inte
grin
, alp
ha 1
317
rs68
7128
60,
8781
5,92
E-04
0,47
95
5222
2513
TC
3672
ITG
A1
inte
grin
, alp
ha 1
318
rs19
7939
80,
8801
7,33
E-04
0,47
35
5223
0084
AG
3672
ITG
A1
inte
grin
, alp
ha 1
319
rs16
8860
340,
7589
3,06
E-04
0,06
75
5601
9613
CT
320
rs16
8863
640,
7709
5,91
E-04
0,06
85
5615
8101
GA
4214
MA
P3K
1m
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GÜL et al. / Turk J Med SciA
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GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
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GÜL et al. / Turk J Med Sci39
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14
GÜL et al. / Turk J Med SciA
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(Con
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6231
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7894
3,93
E-05
0,12
78
6320
7496
GC
456
rs42
6811
80,
8079
2,08
E-04
0,12
58
6321
7632
GA
457
rs42
5658
70,
8034
1,06
E-04
0,13
28
6321
8545
TC
15
GÜL et al. / Turk J Med Sci45
8rs
7832
144
0,80
341,
35E-
040,
126
863
2251
35A
G
459
rs10
5043
440,
8093
2,11
E-04
0,12
88
6322
9338
GT
460
rs16
9285
450,
7521
4,81
E-06
0,10
58
6325
6978
GA
461
rs78
3395
80,
8204
1,75
E-04
0,15
28
6327
3320
AG
462
rs16
9286
020,
8151
9,57
E-05
0,15
68
6330
9109
TC
463
rs10
9572
160,
8109
1,14
E-04
0,14
38
6331
9367
TA
464
rs13
2784
230,
8768
5,08
E-04
0,48
88
8778
9535
AC
5471
4C
NG
B3cy
clic
nuc
leot
ide
gate
d ch
anne
l bet
a 3
465
rs24
3686
01,
252
5,49
E-04
0,09
28
1038
1122
5A
G
466
rs25
1475
61,
158
8,04
E-04
0,24
78
1191
5112
4A
G21
31EX
T1ex
osto
sin 1
467
rs11
7770
701,
172
7,54
E-04
0,20
08
1410
1954
1T
G83
696
TRA
PPC
9tr
affick
ing
prot
ein
part
icle
com
plex
9
468
rs10
9603
631,
196
5,55
E-04
0,16
29
1190
703
CT
469
rs13
1933
21,
372,
16E-
040,
055
920
1824
95G
A
470
rs10
8113
301,
228
1,65
E-05
0,20
09
2019
7095
CT
471
rs10
9644
771,
379,
75E-
050,
060
920
2060
63C
T
472
rs10
4650
481,
244
6,32
E-06
0,19
69
2020
8695
AG
473
rs49
7739
51,
474
7,64
E-06
0,05
39
2021
6358
GA
474
rs10
9644
931,
338
2,87
E-04
0,06
19
2022
9840
CT
475
rs10
9644
951,
376,
32E-
050,
064
920
2352
83C
T
476
rs16
9235
211,
438
1,07
E-05
0,05
89
2025
1635
CT
477
rs12
5539
481,
351,
14E-
040,
067
920
2531
86G
A
478
rs70
4195
11,
456
6,41
E-06
0,05
79
2026
5354
GC
479
rs49
7725
11,
371
6,35
E-05
0,06
39
2026
9793
GA
480
rs13
3007
410,
8262
1,41
E-04
0,17
89
2095
3339
CT
5491
4FO
CA
Dfo
cadh
esin
481
rs10
9664
840,
8278
1,74
E-04
0,16
99
2480
2191
GA
482
rs67
6484
1,14
17,
52E-
040,
367
925
9539
89C
A
483
rs17
5596
390,
8709
5,63
E-04
0,33
49
2601
1612
AC
484
rs10
7387
431,
146
4,94
E-04
0,37
19
2602
7974
CT
485
rs51
1545
0,86
983,
28E-
040,
404
978
5010
10C
T15
8471
PRU
NE2
prun
e ho
mol
og 2
(Dro
soph
ila)
486
rs50
6086
0,84
441,
07E-
040,
257
978
5164
28C
G15
8471
PRU
NE2
prun
e ho
mol
og 2
(Dro
soph
ila)
487
rs49
1798
0,86
823,
00E-
040,
401
978
5199
89T
A15
8471
PRU
NE2
prun
e ho
mol
og 2
(Dro
soph
ila)
488
rs22
0988
21,
256
5,06
E-04
0,09
09
8112
7236
AG
489
rs20
1355
71,
206
9,56
E-04
0,13
29
1036
1581
5T
A
490
rs64
7906
70,
8569
3,92
E-04
0,25
79
1036
3538
6A
T
App
endi
x. (C
ontin
ued)
.
16
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
491
rs27
8671
60,
8623
6,66
E-04
0,25
79
1036
3634
2C
T
492
rs14
1564
70,
8643
8,06
E-04
0,25
69
1036
3645
5A
T
493
rs10
7398
160,
8619
6,53
E-04
0,25
19
1036
5629
1C
T
494
rs10
7395
921,
342,
08E-
140,
485
912
3011
433
GA
495
rs10
7601
821,
137
6,75
E-04
0,48
19
1234
5278
2A
G15
3090
DA
B2IP
DA
B2 in
tera
ctin
g pr
otei
n
496
rs74
6835
11,
148,
33E-
040,
369
913
8114
710
TC
1381
51N
AC
C2
NA
CC
fam
ily m
embe
r 2, B
EN a
nd B
TB (P
OZ)
dom
ain
cont
aini
ng
497
rs38
0257
70,
8656
5,18
E-04
0,29
810
1336
1864
CT
5264
PHYH
phyt
anoy
l-CoA
2-h
ydro
xyla
se
498
rs95
6007
1,17
61,
35E-
040,
276
1023
7614
18G
T
499
rs79
2053
51,
147
8,72
E-04
0,30
910
2377
4744
GA
500
rs12
2460
981,
155
4,55
E-04
0,31
210
2378
6957
GA
501
rs11
0135
141,
174
1,12
E-04
0,29
110
2379
9607
AG
502
rs70
8599
91,
141
9,35
E-04
0,34
710
2380
0758
GC
503
rs79
0025
21,
163
1,62
E-04
0,34
010
2380
2398
GA
504
rs64
8228
51,
143
7,67
E-04
0,34
810
2380
8719
TC
505
rs43
3391
41,
156
3,31
E-04
0,32
810
2381
0664
AG
506
rs64
8228
91,
143
7,67
E-04
0,34
710
2381
6469
TC
507
rs12
2446
681,
145
7,84
E-04
0,33
710
2384
1366
GA
508
rs79
1340
11,
154
3,30
E-04
0,34
110
2384
4221
AC
509
rs18
5611
31,
159
2,23
E-04
0,34
110
2384
4775
TC
510
rs98
3990
1,15
72,
63E-
040,
342
1023
8463
88G
A
511
rs11
0135
551,
149
9,25
E-04
0,28
410
2385
8933
AG
512
rs10
7637
900,
8642
9,06
E-04
0,24
410
3083
1361
CG
513
rs11
5939
430,
8722
4,44
E-04
0,37
710
3358
5087
TC
8829
NRP
1ne
urop
ilin
1
514
rs10
4305
410,
8777
7,30
E-04
0,39
510
5649
4253
AG
515
rs26
5864
10,
8287
1,29
E-04
0,18
610
5939
4437
GA
516
rs26
5863
00,
8453
3,09
E-04
0,20
810
5940
9250
AG
517
rs19
3045
00,
8418
1,74
E-04
0,22
110
5941
0701
TG
518
rs29
3958
30,
8453
2,19
E-04
0,22
410
5941
2336
TC
519
rs23
9340
00,
846
2,32
E-04
0,22
510
5941
4510
TG
520
rs19
3045
50,
8507
3,87
E-04
0,22
310
5941
4530
AG
521
rs19
3045
60,
8447
2,03
E-04
0,22
410
5941
4551
AG
522
rs10
7407
250,
8784
9,56
E-04
0,37
110
5946
0061
GA
17
GÜL et al. / Turk J Med Sci52
3rs
1100
6021
0,87
184,
72E-
040,
377
1059
4607
12C
T
524
rs17
5936
50,
8511
3,68
E-04
0,22
610
5949
0502
AG
525
rs39
1593
20,
8544
4,70
E-05
0,40
910
8061
1942
CG
5717
8ZM
IZ1
zinc
fing
er, M
IZ-t
ype
cont
aini
ng 1
526
rs81
0517
0,85
333,
08E-
050,
452
1080
6126
26T
C57
178
ZMIZ
1zi
nc fi
nger
, MIZ
-typ
e co
ntai
ning
1
527
rs12
5717
510,
8533
3,05
E-05
0,45
210
8061
2637
GA
5717
8ZM
IZ1
zinc
fing
er, M
IZ-t
ype
cont
aini
ng 1
528
rs70
3982
0,85
676,
72E-
050,
395
1080
6127
27G
A57
178
ZMIZ
1zi
nc fi
nger
, MIZ
-typ
e co
ntai
ning
1
529
rs11
5538
401,
323
7,27
E-04
0,05
410
8226
8160
CT
8161
9TS
PAN
14te
tras
pani
n 14
530
rs17
4151
120,
837
7,52
E-04
0,15
610
9919
4781
AG
5101
3EX
OSC
1ex
osom
e co
mpo
nent
1
531
rs11
1918
410,
8746
3,97
E-04
0,50
010
1056
2960
1C
T
532
rs71
0092
00,
8741
3,81
E-04
0,48
810
1056
3096
8T
C
533
rs10
8839
420,
8699
2,30
E-04
0,48
610
1056
4137
6C
T79
991
OBF
C1
olig
onuc
leot
ide/
olig
osac
char
ide-
bind
ing
fold
cont
aini
ng 1
534
rs12
7658
780,
8699
2,30
E-04
0,48
610
1056
5961
2C
T79
991
OBF
C1
olig
onuc
leot
ide/
olig
osac
char
ide-
bind
ing
fold
cont
aini
ng 1
535
rs14
2150
31,
164
7,37
E-04
0,22
710
1074
8509
0G
A
536
rs21
1199
51,
169,
82E-
040,
226
1010
7497
352
GA
537
rs10
7870
191,
146
9,79
E-04
0,30
610
1090
5080
8T
G
538
rs28
0461
11,
245
4,64
E-04
0,10
710
1138
3746
2C
T
539
rs28
0461
41,
235
7,72
E-04
0,10
710
1138
4183
1C
T
540
rs40
7472
01,
156
1,30
E-04
0,47
610
1147
3848
7T
C69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
541
rs79
0169
51,
288,
18E-
100,
328
1011
4744
078
CT
6934
TCF7
L2tr
ansc
riptio
n fa
ctor
7-li
ke 2
(T-c
ell s
peci
fic, H
MG
-box
)
542
rs45
0656
51,
278
9,48
E-10
0,33
110
1147
4603
1T
A69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
543
rs41
3267
01,
282
6,53
E-10
0,33
110
1147
5776
1A
G69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
544
rs65
8520
11,
144
3,96
E-04
0,45
910
1147
5877
3A
G69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
545
rs10
7874
721,
155
1,38
E-04
0,47
410
1147
7128
7C
A69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
546
rs12
2433
261,
292
6,12
E-10
0,29
510
1147
7880
5C
T69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
547
rs70
7703
91,
157
1,35
E-04
0,46
710
1147
7906
7C
T69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
548
rs11
1962
051,
173,
49E-
050,
473
1011
4797
037
CG
6934
TCF7
L2tr
ansc
riptio
n fa
ctor
7-li
ke 2
(T-c
ell s
peci
fic, H
MG
-box
)
549
rs10
8854
091,
172
2,71
E-05
0,47
210
1147
9806
2C
T69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
550
rs12
2553
721,
292
4,37
E-10
0,30
210
1147
9889
2T
G69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
551
rs11
1962
081,
173
2,40
E-05
0,47
210
1148
0130
6C
T69
34TC
F7L2
tran
scrip
tion
fact
or 7
-like
2 (T
-cel
l spe
cific
, HM
G-b
ox)
552
rs10
5100
040,
8647
1,97
E-04
0,37
310
1162
1456
9A
G39
83A
BLIM
1ac
tin b
indi
ng L
IM p
rote
in 1
553
rs24
8359
30,
7592
4,89
E-04
0,06
210
1163
5969
6G
A39
83A
BLIM
1ac
tin b
indi
ng L
IM p
rote
in 1
554
rs10
9117
90,
7741
1,03
E-04
0,09
210
1165
5625
8A
G
555
rs24
2092
80,
8735
4,36
E-04
0,40
810
1231
4346
2G
A
App
endi
x. (C
ontin
ued)
.
18
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
556
rs13
2232
80,
8817
9,04
E-04
0,46
610
1239
1109
4C
G10
579
TAC
C2
tran
sfor
min
g, a
cidi
c coi
led-
coil
cont
aini
ng p
rote
in 2
557
rs12
4124
851,
163
6,93
E-04
0,23
410
1317
3159
0T
G
558
rs70
7582
50,
7641
1,83
E-04
0,07
510
1337
2097
9T
C
559
rs11
8272
961,
187
3,63
E-04
0,18
611
3334
236
CT
560
rs71
0412
81,
232
9,03
E-04
0,10
611
4697
321
TC
561
rs93
5951
0,82
762,
12E-
040,
166
1159
1814
5T
G
562
rs27
2366
30,
8763
4,90
E-04
0,46
611
6440
086
CA
1061
2TR
IM3
trip
artit
e m
otif
cont
aini
ng 3
563
rs23
0349
30,
8762
5,63
E-04
0,47
411
6455
791
AG
2364
7A
RFIP
2A
DP-
ribos
ylat
ion
fact
or in
tera
ctin
g pr
otei
n 2
564
rs42
7710
30,
7731
7,73
E-05
0,09
711
8345
806
CT
565
rs18
8182
00,
8518
1,09
E-04
0,29
211
1375
7134
GC
566
rs23
5104
41,
169
6,83
E-05
0,36
311
1553
5033
AG
567
rs71
1707
70,
8411
4,65
E-04
0,18
211
1951
0993
CT
8979
7N
AV2
neur
on n
avig
ator
2
568
rs32
9526
1,13
77,
56E-
040,
438
1129
4587
29T
G
569
rs29
2646
10,
8703
7,80
E-04
0,30
311
3420
8169
CT
2584
1A
BTB2
anky
rin re
peat
and
BTB
(PO
Z) d
omai
n co
ntai
ning
2
570
rs29
5752
30,
8663
5,25
E-04
0,30
311
3420
8431
GA
2584
1A
BTB2
anky
rin re
peat
and
BTB
(PO
Z) d
omai
n co
ntai
ning
2
571
rs29
2646
30,
8694
7,23
E-04
0,30
211
3420
8964
GT
2584
1A
BTB2
anky
rin re
peat
and
BTB
(PO
Z) d
omai
n co
ntai
ning
2
572
rs29
5594
90,
863
3,64
E-04
0,30
411
3421
0651
AT
2584
1A
BTB2
anky
rin re
peat
and
BTB
(PO
Z) d
omai
n co
ntai
ning
2
573
rs71
1570
21,
175
9,69
E-05
0,29
111
6178
7955
TA
574
rs11
6033
831,
174
9,99
E-05
0,29
111
6179
4159
AG
4250
SCG
B2A
2se
cret
oglo
bin,
fam
ily 2
A, m
embe
r 2
575
rs17
7095
521,
245
1,59
E-04
0,11
711
6179
7095
GA
4250
SCG
B2A
2se
cret
oglo
bin,
fam
ily 2
A, m
embe
r 2
576
rs11
2285
060,
8812
8,60
E-04
0,45
811
6864
5758
AG
577
rs64
4961
0,88
249,
73E-
040,
473
1178
3704
68T
C26
011
OD
Z4od
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hom
olog
4 (D
roso
phila
)
578
rs10
7933
500,
8643
1,17
E-04
0,48
311
7837
2163
TC
2601
1O
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odd
Oz/
ten-
m h
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(Dro
soph
ila)
579
rs10
7513
010,
8623
9,09
E-05
0,48
511
7837
2286
GC
2601
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ten-
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soph
ila)
580
rs11
2376
750,
8708
2,56
E-04
0,49
011
7837
5191
CT
2601
1O
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odd
Oz/
ten-
m h
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(Dro
soph
ila)
581
rs17
3108
751,
207
7,14
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0,13
011
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2113
CG
582
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2324
291,
347
3,79
E-04
0,05
211
8039
7567
TA
583
rs11
2353
021,
215,
02E-
040,
135
1187
1325
74A
T
584
rs17
1508
521,
263
3,74
E-04
0,08
911
8720
2808
AG
585
rs17
8335
791,
258
5,03
E-04
0,08
711
8720
3798
CT
586
rs17
1508
821,
267
2,10
E-04
0,09
511
8721
9070
CT
587
rs96
6647
91,
202
3,35
E-04
0,16
011
8725
0138
GA
588
rs71
2125
21,
206
2,52
E-04
0,16
311
8725
6116
CT
19
GÜL et al. / Turk J Med Sci58
9rs
1939
168
1,17
7,65
E-04
0,21
211
8728
8340
AG
590
rs71
0186
51,
174
3,13
E-04
0,23
111
8757
7209
AG
591
rs11
0188
161,
225
8,87
E-05
0,16
011
8757
9357
CT
592
rs79
3788
21,
225
8,26
E-05
0,15
711
8757
9997
GA
593
rs41
2205
70,
8374
6,05
E-04
0,16
511
8761
9967
AG
594
rs11
0200
930,
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4,36
E-04
0,24
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9226
7291
TC
1201
14FA
T3FA
T tu
mor
supp
ress
or h
omol
og 3
(Dro
soph
ila)
595
rs17
1342
781,
246
6,85
E-04
0,09
411
9910
6275
GC
5394
2C
NTN
5co
ntac
tin 5
596
rs45
5971
71,
253
7,39
E-04
0,08
711
1126
5630
9A
G
597
rs16
0022
30,
8376
4,84
E-04
0,16
511
1267
9825
9T
C
598
rs39
3579
40,
7246
4,41
E-05
0,06
311
1278
9588
7G
A21
13ET
S1v-
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ryth
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sis v
irus E
26 o
ncog
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hom
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vian
)
599
rs39
3579
50,
7216
3,45
E-05
0,06
411
1278
9600
1C
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S1v-
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ryth
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sis v
irus E
26 o
ncog
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hom
olog
1 (a
vian
)
600
rs39
3579
60,
7476
2,56
E-04
0,06
111
1278
9613
7A
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S1v-
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ryth
robl
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sis v
irus E
26 o
ncog
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hom
olog
1 (a
vian
)
601
rs49
3734
20,
7488
2,31
E-04
0,06
311
1279
0351
9G
T21
13ET
S1v-
ets e
ryth
robl
asto
sis v
irus E
26 o
ncog
ene
hom
olog
1 (a
vian
)
602
rs43
3443
0,87
246,
98E-
040,
334
1113
0876
412
AG
5086
3N
TMne
urot
rimin
603
rs18
7019
90,
8733
3,73
E-04
0,44
412
6564
99A
G
604
rs10
8494
640,
8563
6,59
E-05
0,39
112
6594
13A
C
605
rs28
8747
40,
8693
2,37
E-04
0,47
112
6663
92C
T
606
rs10
8489
580,
8312
2,51
E-04
0,17
412
3901
365
TC
607
rs10
8490
401,
147
3,01
E-04
0,49
812
4312
167
CT
5710
3C
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f5ch
rom
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e 12
ope
n re
adin
g fr
ame
5
608
rs17
7004
060,
864
1,81
E-04
0,37
812
4332
859
CT
5710
3C
12or
f5ch
rom
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e 12
ope
n re
adin
g fr
ame
5
609
rs10
8490
450,
862
1,57
E-04
0,36
812
4337
744
AG
5710
3C
12or
f5ch
rom
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e 12
ope
n re
adin
g fr
ame
5
610
rs71
3539
00,
8718
3,18
E-04
0,44
412
2148
9968
TC
7991
2PY
ROX
D1
pyrid
ine
nucl
eotid
e-di
sulp
hide
oxi
dore
duct
ase
dom
ain
1
611
rs11
6109
420,
8747
4,42
E-04
0,44
312
2149
2898
GA
7991
2PY
ROX
D1
pyrid
ine
nucl
eotid
e-di
sulp
hide
oxi
dore
duct
ase
dom
ain
1
612
rs10
8418
431,
176
2,20
E-04
0,24
912
2158
3158
TC
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
613
rs10
4921
181,
165
9,48
E-04
0,21
512
2158
3225
TC
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
614
rs64
8723
61,
175,
34E-
040,
227
1221
5911
83G
A29
98G
YS2
glyc
ogen
synt
hase
2 (l
iver
)
615
rs10
8418
481,
163
8,61
E-04
0,22
612
2160
0821
AG
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
616
rs11
0461
161,
164
8,22
E-04
0,22
612
2160
0886
GC
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
617
rs10
7708
361,
166,
93E-
040,
248
1221
6080
08A
G29
98G
YS2
glyc
ogen
synt
hase
2 (l
iver
)
618
rs10
8418
501,
161
6,69
E-04
0,24
812
2160
8123
GA
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
619
rs11
0461
221,
159
7,69
E-04
0,25
012
2160
8288
TC
2998
GYS
2gl
ycog
en sy
ntha
se 2
(liv
er)
620
rs10
7837
600,
8774
9,15
E-04
0,35
812
5426
2230
AG
621
rs47
5917
30,
877
8,81
E-04
0,35
712
5428
7453
AG
App
endi
x. (C
ontin
ued)
.
20
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
622
rs10
7477
580,
8779
9,48
E-04
0,36
912
5428
7594
TC
623
rs47
5918
60,
8419
5,66
E-04
0,17
612
5435
0346
AG
624
rs11
6145
060,
8544
7,92
E-04
0,21
112
5610
1942
CT
625
rs39
1652
90,
8284
3,60
E-04
0,15
312
6272
1863
GA
5752
2SR
GA
P1SL
IT-R
OBO
Rho
GTP
ase
activ
atin
g pr
otei
n 1
626
rs71
3261
71,
136
9,37
E-04
0,39
212
6348
2244
AG
627
rs10
8782
111,
143
5,35
E-04
0,39
612
6348
6189
CT
628
rs38
5160
81,
137
9,35
E-04
0,38
112
6349
5765
GA
629
rs99
8314
1,14
35,
49E-
040,
392
1263
5066
34G
A23
329
TBC
1D30
TBC
1 do
mai
n fa
mily
, mem
ber 3
0
630
rs12
7555
60,
8717
6,98
E-04
0,32
412
7449
6341
AG
631
rs99
8137
0,87
496,
75E-
040,
401
1277
4860
27C
G
632
rs12
5826
341,
292
9,45
E-04
0,06
612
8038
5922
TC
8499
PPFI
A2
prot
ein
tyro
sine
phos
phat
ase,
rece
ptor
type
, f p
olyp
eptid
e (P
TPRF
), in
tera
ctin
g pr
otei
n (li
prin
), al
pha
2
633
rs12
8159
880,
7707
1,70
E-04
0,08
312
8218
3441
TC
634
rs11
1156
630,
7634
9,08
E-05
0,08
412
8218
4765
GA
635
rs12
5784
180,
7861
4,98
E-04
0,08
312
9508
1078
AG
636
rs73
0081
51,
301
2,15
E-04
0,07
612
1004
8614
4C
A
637
rs12
5806
321,
205
9,75
E-04
0,13
112
1004
8679
2C
T
638
rs85
5287
0,83
296,
57E-
040,
146
1210
1470
239
AT
639
rs75
3479
0,83
163,
25E-
040,
163
1210
1482
692
GA
640
rs10
8608
770,
8429
6,74
E-04
0,17
312
1014
8369
5A
G
641
rs49
6467
11,
145
6,62
E-04
0,34
912
1072
2782
4G
C12
40C
MK
LR1
chem
okin
e-lik
e re
cept
or 1
642
rs10
4004
101,
228
9,70
E-04
0,10
012
1096
7788
2A
G
643
rs11
0675
870,
863
7,45
E-04
0,25
912
1143
3810
7C
T
644
rs12
3133
390,
7823
9,90
E-04
0,07
012
1198
7087
6A
G
645
rs11
0577
650,
8408
8,20
E-04
0,16
112
1237
5938
2C
T
646
rs10
7731
820,
8758
6,21
E-04
0,39
312
1246
8631
2G
T11
4795
TMEM
132B
tran
smem
bran
e pr
otei
n 13
2B
647
rs20
5801
20,
879
7,02
E-04
0,46
212
1246
9336
2G
A11
4795
TMEM
132B
tran
smem
bran
e pr
otei
n 13
2B
648
rs97
9589
0,86
864,
55E-
040,
337
1212
4693
655
TC
1147
95TM
EM13
2Btr
ansm
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ane
prot
ein
132B
649
rs38
0315
20,
8741
4,00
E-04
0,45
412
1247
0114
8G
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4795
TMEM
132B
tran
smem
bran
e pr
otei
n 13
2B
650
rs38
2538
10,
861
6,46
E-04
0,25
312
1247
0281
6T
C11
4795
TMEM
132B
tran
smem
bran
e pr
otei
n 13
2B
651
rs10
8469
411,
142
4,56
E-04
0,48
312
1247
2039
2T
C
652
rs10
7731
871,
135
7,97
E-04
0,48
412
1247
2408
8G
A
653
rs10
8469
551,
134
8,82
E-04
0,48
712
1247
6271
1T
C
21
GÜL et al. / Turk J Med Sci65
4rs
1084
6980
1,14
34,
13E-
040,
486
1212
4857
508
TG
655
rs73
1337
10,
8751
9,86
E-04
0,31
912
1248
6103
6A
G
656
rs79
5441
50,
8642
2,46
E-04
0,34
312
1248
6213
4T
C
657
rs91
7334
0,86
752,
41E-
040,
395
1212
4864
111
GA
658
rs64
8901
90,
8632
1,47
E-04
0,39
312
1248
6683
5A
G
659
rs64
8902
00,
8582
5,91
E-05
0,44
512
1248
6695
6C
T
660
rs64
8902
10,
8455
1,63
E-05
0,40
112
1248
7205
3T
G
661
rs79
7804
51,
193
5,76
E-04
0,15
912
1248
7374
3T
C
662
rs11
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188
7,00
E-04
0,16
212
1248
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7T
A
663
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6103
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1,61
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0,44
112
1248
9465
8T
G
664
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0583
711,
197
3,66
E-05
0,24
812
1248
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2A
G
665
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7337
0,85
858,
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050,
393
1212
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032
TC
666
rs11
0585
740,
866
1,44
E-04
0,47
712
1252
5656
9T
C
667
rs10
8471
140,
8648
1,24
E-04
0,48
612
1252
5683
1G
A
668
rs10
7732
450,
8667
1,55
E-04
0,48
612
1252
5705
8A
C
669
rs10
7732
470,
8625
9,24
E-05
0,48
412
1252
6077
9C
T
670
rs10
7442
430,
8624
9,12
E-05
0,48
412
1252
6086
0A
G
671
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90,
8677
1,78
E-04
0,48
312
1252
6411
4G
A
672
rs10
7732
570,
8732
5,11
E-04
0,37
812
1252
9248
3G
A
673
rs20
1048
41,
168
1,36
E-04
0,30
912
1262
9837
8C
G
674
rs10
8479
191,
192
5,42
E-04
0,16
412
1287
0693
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C12
1256
TMEM
132D
tran
smem
bran
e pr
otei
n 13
2D
675
rs45
2876
0,88
19,
55E-
040,
416
1212
9326
198
GT
676
rs17
3571
430,
7415
1,37
E-04
0,06
313
2250
4391
CT
677
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9305
1,17
98,
55E-
040,
175
1326
0378
76T
G10
810
WA
SF3
WA
S pr
otei
n fa
mily
, mem
ber 3
678
rs18
8881
00,
8314
9,95
E-04
0,14
213
3044
2238
TG
1220
46TE
X26
test
is ex
pres
sed
26
679
rs20
2696
00,
8286
8,28
E-04
0,13
913
3045
8544
CT
680
rs42
5850
21,
145,
87E-
040,
456
1348
4617
01A
G22
862
FND
C3A
fibro
nect
in ty
pe II
I dom
ain
cont
aini
ng 3
A
681
rs95
6814
31,
148
2,88
E-04
0,45
613
4846
8631
AT
2286
2FN
DC
3Afib
rone
ctin
type
III d
omai
n co
ntai
ning
3A
682
rs49
4279
60,
8653
4,10
E-04
0,31
113
4848
4019
TC
2286
2FN
DC
3Afib
rone
ctin
type
III d
omai
n co
ntai
ning
3A
683
rs93
1642
80,
8733
9,53
E-04
0,31
113
4852
6552
AG
2286
2FN
DC
3Afib
rone
ctin
type
III d
omai
n co
ntai
ning
3A
684
rs14
0782
70,
8688
6,17
E-04
0,30
813
4860
8987
CT
2286
2FN
DC
3Afib
rone
ctin
type
III d
omai
n co
ntai
ning
3A
685
rs19
8380
50,
8704
7,21
E-04
0,31
013
4860
9971
CT
2286
2FN
DC
3Afib
rone
ctin
type
III d
omai
n co
ntai
ning
3A
686
rs95
9124
60,
8627
3,72
E-04
0,30
613
4870
4899
TC
App
endi
x. (C
ontin
ued)
.
22
GÜL et al. / Turk J Med SciA
ppen
dix.
(Con
tinue
d).
687
rs10
1334
70,
8592
2,95
E-04
0,28
413
4870
8882
TG
688
rs95
7120
81,
222,
03E-
040,
149
1363
8766
87C
T
689
rs79
9121
01,
188
9,62
E-06
0,39
513
9954
9906
GA
5095
PCC
Apr
opio
nyl C
oA c
arbo
xyla
se, a
lpha
pol
ypep
tide
690
rs91
6048
1,13
89,
35E-
040,
379
1421
8607
60A
C
691
rs37
5148
81,
169,
91E-
040,
224
1422
3739
34A
G12
2704
MRP
L52
mito
chon
dria
l rib
osom
al p
rote
in L
52
692
rs42
4964
1,14
73,
33E-
040,
425
1430
0555
54A
G
693
rs10
1355
621,
186
5,23
E-04
0,18
214
3219
8399
TC
9472
AK
AP6
A k
inas
e (P
RKA
) anc
hor p
rote
in 6
694
rs65
7164
70,
7866
2,51
E-04
0,09
314
3383
6835
GA
695
rs19
9819
31,
145,
78E-
040,
456
1438
7605
07T
G
696
rs28
5025
091,
142
4,79
E-04
0,45
714
3876
1768
CT
697
rs13
8775
41,
143
4,85
E-04
0,42
114
6234
1315
CT
2713
3KC
NH
5po
tass
ium
vol
tage
-gat
ed ch
anne
l, su
bfam
ily H
(eag
-rel
ated
), m
embe
r 5
698
rs48
9938
40,
887,
61E-
040,
455
1470
6957
09T
A
699
rs10
4838
371,
205
1,07
E-04
0,19
314
7151
9244
GA
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
700
rs71
5620
01,
176
2,48
E-04
0,24
114
7152
7435
CA
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
701
rs12
8847
771,
177
2,35
E-04
0,24
014
7153
0913
TC
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
702
rs12
8852
581,
197
1,58
E-04
0,19
714
7153
1051
AG
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
703
rs22
8342
21,
184
1,44
E-04
0,23
914
7153
1955
CT
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
704
rs22
8338
10,
805
5,34
E-07
0,25
514
7197
8830
GA
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
705
rs10
4838
450,
846
3,15
E-05
0,34
214
7198
4874
GC
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
706
rs15
4868
70,
8381
5,46
E-05
0,24
814
7202
8222
AG
9628
RGS6
regu
lato
r of G
-pro
tein
sign
alin
g 6
707
rs17
1199
800,
8615
2,01
E-04
0,33
314
7225
3994
AT
8110
DPF
3D
4, zi
nc a
nd d
oubl
e PH
D fi
nger
s, fa
mily
3
708
rs74
0974
0,86
482,
76E-
040,
338
1472
2578
27G
A81
10D
PF3
D4,
zinc
and
dou
ble
PHD
fing
ers,
fam
ily 3
709
rs42
4364
20,
863
2,33
E-04
0,33
514
7225
8454
CG
8110
DPF
3D
4, zi
nc a
nd d
oubl
e PH
D fi
nger
s, fa
mily
3
710
rs17
8084
670,
8227
7,61
E-04
0,12
114
7623
9145
AG
711
rs11
1592
270,
8498
8,86
E-04
0,18
614
7626
9385
AT
712
rs17
1092
211,
164
9,72
E-04
0,21
414
7897
9872
TC
9369
NRX
N3
neur
exin
3
713
rs71
4401
11,
165
8,36
E-04
0,21
614
7901
0136
TG
9369
NRX
N3
neur
exin
3
714
rs71
5362
50,
8089
3,27
E-04
0,12
314
7911
9015
AG
9369
NRX
N3
neur
exin
3
715
rs71
5459
90,
815
4,68
E-04
0,12
614
7911
9562
CG
9369
NRX
N3
neur
exin
3
716
rs17
7640
960,
8089
3,01
E-04
0,12
514
7912
0259
TG
9369
NRX
N3
neur
exin
3
717
rs19
0092
0,85
331,
40E-
040,
299
1479
1212
36C
A93
69N
RXN
3ne
urex
in 3
718
rs32
7465
0,86
371,
07E-
040,
494
1480
2997
93C
T14
5508
CEP
128
cent
roso
mal
pro
tein
128
kDa
23
GÜL et al. / Turk J Med Sci71
9rs
2556
611
0,86
461,
19E-
040,
495
1480
4159
19A
G14
5508
CEP
128
cent
roso
mal
pro
tein
128
kDa
720
rs12
0503
420,
8686
2,07
E-04
0,49
214
8043
8617
TC
1455
08C
EP12
8ce
ntro
som
al p
rote
in 1
28kD
a
721
rs28
8803
20,
8678
1,77
E-04
0,50
014
8043
9264
CT
1455
08C
EP12
8ce
ntro
som
al p
rote
in 1
28kD
a
722
rs11
6251
990,
8741
3,73
E-04
0,49
814
8044
2498
AG
1455
08C
EP12
8ce
ntro
som
al p
rote
in 1
28kD
a
723
rs65
7460
80,
8742
3,77
E-04
0,50
014
8044
4575
AC
1455
08C
EP12
8ce
ntro
som
al p
rote
in 1
28kD
a
724
rs10
4447
450,
8628
1,00
E-04
0,47
014
8789
1057
GT
725
rs11
8489
571,
244
7,53
E-04
0,09
614
9473
1600
CG
7978
9C
LMN
calm
in (c
alpo
nin-
like,
tran
smem
bran
e)
726
rs12
9072
781,
149
2,60
E-04
0,45
115
3176
0469
AG
6263
RYR3
ryan
odin
e re
cept
or 3
727
rs12
5925
421,
141
5,00
E-04
0,45
615
3177
3110
AG
6263
RYR3
ryan
odin
e re
cept
or 3
728
rs16
9625
420,
7151
4,52
E-05
0,05
715
3418
9070
AT
729
rs71
7095
51,
194
1,32
E-04
0,20
915
4444
4884
CA
730
rs71
8060
01,
201
5,53
E-04
0,15
115
5085
7433
AG
3175
ON
ECU
T1on
e cu
t hom
eobo
x 1
731
rs10
5186
941,
225
1,58
E-04
0,14
215
5085
9965
AC
3175
ON
ECU
T1on
e cu
t hom
eobo
x 1
732
rs24
5652
61,
215
2,77
E-04
0,14
515
5087
6734
CT
733
rs10
5191
070,
8559
3,93
E-05
0,48
115
5911
4168
GC
6095
RORA
RAR-
rela
ted
orph
an re
cept
or A
734
rs64
9430
70,
8769
6,36
E-04
0,41
315
6018
1982
GC
735
rs10
0835
870,
8756
5,60
E-04
0,41
315
6018
5825
TC
736
rs80
3024
00,
8632
7,29
E-04
0,25
915
6018
6856
TC
737
rs14
3695
50,
8659
8,85
E-04
0,26
315
6019
1674
TC
738
rs10
0836
390,
836
1,78
E-04
0,19
315
6836
8811
AG
739
rs11
0721
560,
8357
1,82
E-04
0,19
115
6836
9472
AT
740
rs20
5932
21,
246
5,21
E-04
0,10
615
6879
2114
CA
5507
5U
AC
Auv
eal a
utoa
ntig
en w
ith co
iled-
coil
dom
ains
and
ank
yrin
repe
ats
741
rs10
5189
211,
242
6,24
E-04
0,10
515
6879
3963
TC
5507
5U
AC
Auv
eal a
utoa
ntig
en w
ith co
iled-
coil
dom
ains
and
ank
yrin
repe
ats
742
rs71
7797
01,
242
6,51
E-04
0,10
415
6883
2308
GA
5507
5U
AC
Auv
eal a
utoa
ntig
en w
ith co
iled-
coil
dom
ains
and
ank
yrin
repe
ats
743
rs64
9508
11,
139
6,53
E-04
0,43
515
7190
3355
GT
744
rs22
9027
11,
152
3,43
E-04
0,35
815
8324
8639
CA
9154
SLC
28A
1so
lute
car
rier f
amily
28
(sod
ium
-cou
pled
nuc
leos
ide
tran
spor
ter)
, mem
ber 1
745
rs11
6295
421,
154
1,99
E-04
0,47
215
8789
9758
CG
746
rs11
6362
100,
8803
8,33
E-04
0,43
415
8941
5484
CT
747
rs21
3165
90,
8711
2,84
E-04
0,47
515
9892
5810
TG
748
rs11
2472
260,
8731
3,46
E-04
0,46
815
9893
8486
CT
5518
0LI
NS
lines
hom
olog
(Dro
soph
ila)
749
rs80
3368
90,
8736
4,08
E-04
0,43
415
9895
1820
GC
5518
0LI
NS
lines
hom
olog
(Dro
soph
ila)
750
rs71
8084
40,
8721
3,11
E-04
0,47
315
9895
3582
TC
5518
0LI
NS
lines
hom
olog
(Dro
soph
ila)
App
endi
x. (C
ontin
ued)
.
24
GÜL et al. / Turk J Med Sci75
1rs
8055
183
1,18
35,
50E-
040,
187
1691
9237
TC
6478
8LM
F1lip
ase
mat
urat
ion
fact
or 1
752
rs80
4393
51,
181
6,16
E-04
0,18
316
6306
727
GA
753
rs12
5972
191,
183
3,83
E-04
0,19
516
6310
627
AC
754
rs80
6297
51,
191
1,86
E-04
0,20
016
6311
714
TA
755
rs80
9684
1,20
33,
94E-
050,
227
1663
2243
5A
G
756
rs24
9301
1,20
91,
61E-
040,
165
1693
7740
8T
A
757
rs17
1125
1,28
33,
43E-
050,
110
1634
6184
68T
C
758
rs21
6944
0,87
185,
42E-
040,
356
1658
7988
50A
G
759
rs80
6342
41,
176
5,47
E-04
0,20
816
7842
4987
TC
760
rs39
2488
91,
202
2,83
E-04
0,17
216
7842
6000
CA
761
rs80
6204
71,
366
2,18
E-04
0,05
216
7845
7228
GT
762
rs11
6482
950,
8258
6,97
E-04
0,13
416
8743
2022
TG
2588
GA
LNS
gala
ctos
amin
e (N
-ace
tyl)-
6-su
lfate
sulfa
tase
763
rs16
9648
900,
7752
4,36
E-05
0,10
617
2456
7546
CT
764
rs11
6521
970,
8246
3,46
E-04
0,15
017
2847
8690
CA
40A
SIC
2ac
id-s
ensin
g (p
roto
n-ga
ted)
ion
chan
nel 2
765
rs22
8768
1,14
39,
15E-
040,
333
1739
5474
19G
T10
014
HD
AC
5hi
ston
e de
acet
ylas
e 5
766
rs19
6839
31,
146
7,52
E-04
0,32
017
4991
9431
AG
767
rs49
6881
60,
8764
6,27
E-04
0,39
817
6420
0570
GA
768
rs11
6569
691,
198
5,35
E-04
0,15
017
6982
2772
TC
6444
6D
NA
I2dy
nein
, axo
nem
al, i
nter
med
iate
chai
n 2
769
rs80
7679
41,
142
4,76
E-04
0,46
117
7417
2864
AC
770
rs65
0123
81,
145,
87E-
040,
460
1774
1813
34T
C
771
rs10
5126
171,
133
9,67
E-04
0,48
717
7420
5146
CG
9267
CY
TH1
cyto
hesin
1
772
rs15
3179
71,
152,
27E-
040,
488
1774
3337
63T
C57
602
USP
36ub
iqui
tin sp
ecifi
c pep
tidas
e 36
773
rs76
7300
1,14
29,
45E-
040,
328
1898
3023
0A
G11
031
RAB3
1RA
B31,
mem
ber R
AS
onco
gene
fam
ily
774
rs47
1999
1,16
2,01
E-04
0,32
918
9834
729
GA
1103
1RA
B31
RAB3
1, m
embe
r RA
S on
coge
ne fa
mily
775
rs55
5935
1,15
32,
39E-
040,
387
1898
3530
7T
C11
031
RAB3
1RA
B31,
mem
ber R
AS
onco
gene
fam
ily
776
rs57
5420
1,13
68,
21E-
040,
421
1898
3837
1A
C11
031
RAB3
1RA
B31,
mem
ber R
AS
onco
gene
fam
ily
777
rs68
8248
1,15
52,
85E-
040,
342
1898
3861
3C
T11
031
RAB3
1RA
B31,
mem
ber R
AS
onco
gene
fam
ily
778
rs50
8816
1,15
12,
54E-
040,
393
1898
3962
0T
C11
031
RAB3
1RA
B31,
mem
ber R
AS
onco
gene
fam
ily
779
rs22
9983
61,
167
1,90
E-04
0,28
718
9840
212
AG
1103
1RA
B31
RAB3
1, m
embe
r RA
S on
coge
ne fa
mily
780
rs55
9655
1,20
22,
26E-
040,
173
1810
0551
23T
C
781
rs37
3736
11,
159
3,64
E-04
0,29
518
1282
1324
CT
5771
PTPN
2pr
otei
n ty
rosin
e ph
osph
atas
e, no
n-re
cept
or ty
pe 2
782
rs99
4701
10,
8569
4,90
E-04
0,24
918
1867
4407
AG
783
rs65
0732
30,
8509
2,93
E-04
0,24
418
1868
0676
GC
App
endi
x. (C
ontin
ued)
.
25
GÜL et al. / Turk J Med Sci78
4rs
3911
557
0,84
82,
06E-
040,
246
1818
7265
61T
C
785
rs48
0013
80,
8482
2,15
E-04
0,24
518
1876
8295
GA
5932
RBBP
8re
tinob
last
oma
bind
ing
prot
ein
8
786
rs93
0426
10,
8586
8,68
E-04
0,22
518
1886
0594
TC
5932
RBBP
8re
tinob
last
oma
bind
ing
prot
ein
8
787
rs65
0745
70,
8393
9,33
E-05
0,25
018
1888
0434
TC
788
rs20
5601
51,
134
8,99
E-04
0,49
218
3216
4600
GT
8020
6FH
OD
3fo
rmin
hom
olog
y 2
dom
ain
cont
aini
ng 3
789
rs16
9737
560,
7505
6,68
E-04
0,05
518
3661
7062
GA
790
rs72
3486
41,
174
1,57
E-04
0,28
118
5588
5837
TC
791
rs19
4286
71,
188,
71E-
050,
285
1855
8872
50A
G
792
rs11
6643
271,
173
6,36
E-05
0,34
818
5589
0603
CT
793
rs80
9152
41,
195,
56E-
050,
267
1855
9029
40C
T
794
rs15
3995
21,
176
1,73
E-04
0,26
618
5591
7492
GA
795
rs99
6695
11,
148
6,16
E-04
0,33
518
5592
6275
AG
796
rs65
6715
71,
159
2,35
E-04
0,34
018
5594
1205
GT
797
rs19
4288
01,
169
1,02
E-04
0,33
918
5594
4189
TC
798
rs72
3562
61,
162
1,92
E-04
0,33
818
5594
9677
TG
799
rs17
7823
131,
161
7,07
E-04
0,25
318
5600
2077
CT
800
rs47
6828
1,16
83,
76E-
040,
258
1856
0035
67C
T
801
rs99
4740
31,
151
4,18
E-04
0,34
918
5602
0730
TC
802
rs63
9407
1,15
33,
44E-
040,
352
1856
0211
59G
A
803
rs61
9662
1,15
3,05
E-04
0,39
818
5603
5531
AG
804
rs60
7104
1,14
18,
97E-
040,
355
1856
0425
73G
C
805
rs55
7416
1,14
85,
53E-
040,
347
1856
0460
39G
A
806
rs99
5566
61,
152
5,20
E-04
0,33
618
5606
3765
AG
807
rs14
2152
11,
139
9,78
E-04
0,34
818
6023
6486
AG
808
rs47
0443
1,15
85,
80E-
040,
267
1872
8329
68A
G41
55M
BPm
yelin
bas
ic p
rote
in
809
rs48
0525
81,
169
8,10
E-04
0,21
119
3276
3882
AG
810
rs72
5268
91,
173
6,56
E-04
0,20
219
3308
0647
TC
811
rs10
1720
71,
176
8,08
E-04
0,18
319
3905
7327
AG
812
rs72
5121
51,
173
2,09
E-04
0,25
919
3909
9587
GA
813
rs10
4092
991,
166
9,10
E-04
0,20
819
4101
6164
GA
4868
NPH
S1ne
phro
sis 1
, con
geni
tal,
Finn
ish ty
pe (n
ephr
in)
814
rs41
3329
470,
8161
4,90
E-04
0,12
719
5539
1757
CT
815
rs28
7640
91,
141
7,11
E-04
0,36
720
1541
5075
AG
1407
33M
AC
ROD
2M
AC
RO d
omai
n co
ntai
ning
2
816
rs37
4647
60,
8168
9,10
E-04
0,10
920
3637
3583
GA
671
BPI
bact
eric
idal
/per
mea
bilit
y-in
crea
sing
prot
ein
App
endi
x. (C
ontin
ued)
.
26
GÜL et al. / Turk J Med Sci81
7rs
6103
249
0,83
257,
24E-
040,
147
2041
3993
50C
T
818
rs60
7305
50,
8728
7,12
E-04
0,33
820
4140
6604
GA
819
rs16
9852
850,
8374
7,84
E-04
0,15
320
4144
8057
TC
820
rs61
0371
61,
157
3,05
E-04
0,32
720
4243
3044
CA
3172
HN
F4A
hepa
tocy
te n
ucle
ar fa
ctor
4, a
lpha
821
rs60
6343
81,
183
3,04
E-04
0,20
420
4787
4575
TC
2331
5SL
C9A
8so
lute
car
rier f
amily
9, s
ubfa
mily
A (N
HE8
, cat
ion
prot
on
antip
orte
r 8),
mem
ber 8
822
rs67
6035
1,18
62,
26E-
040,
205
2047
9163
99G
A23
315
SLC
9A8
solu
te c
arrie
r fam
ily 9
, sub
fam
ily A
(NH
E8, c
atio
n pr
oton
an
tipor
ter 8
), m
embe
r 8
823
rs48
7096
1,21
75,
20E-
040,
128
2047
9326
66G
C23
315
SLC
9A8
solu
te c
arrie
r fam
ily 9
, sub
fam
ily A
(NH
E8, c
atio
n pr
oton
an
tipor
ter 8
), m
embe
r 8
824
rs18
8355
31,
193
6,38
E-05
0,24
020
4800
7523
TC
825
rs60
2017
81,
168
9,91
E-04
0,20
020
4803
7347
CT
6615
SNA
I1sn
ail h
omol
og 1
(Dro
soph
ila)
826
rs22
571,
158
3,47
E-04
0,30
620
5124
5861
GC
1285
53TS
HZ2
teas
hirt
zinc
fing
er h
omeo
box
2
827
rs60
9813
81,
214
7,76
E-04
0,11
920
5270
1411
TC
5581
6D
OK
5do
ckin
g pr
otei
n 5
828
rs14
6805
61,
154
3,96
E-04
0,33
320
5439
9395
CG
6790
AURK
Aau
rora
kin
ase
A
829
rs60
6192
10,
8584
6,35
E-05
0,43
220
5996
6907
CT
830
rs60
8956
80,
8517
2,69
E-05
0,42
520
5996
7110
AG
831
rs20
3799
41,
226
8,93
E-04
0,10
521
1588
0541
AC
832
rs28
2375
91,
245
2,57
E-04
0,11
121
1666
7957
CG
3888
15LI
NC
0047
8lo
ng in
terg
enic
non
-pro
tein
codi
ng R
NA
478
833
rs91
5856
1,24
3,59
E-04
0,11
121
1666
8120
AG
3888
15LI
NC
0047
8lo
ng in
terg
enic
non
-pro
tein
codi
ng R
NA
478
834
rs16
6757
01,
254
1,42
E-04
0,11
221
1666
8591
GA
3888
15LI
NC
0047
8lo
ng in
terg
enic
non
-pro
tein
codi
ng R
NA
478
835
rs38
0220
1,25
2,02
E-04
0,10
921
1666
8953
AG
3888
15LI
NC
0047
8lo
ng in
terg
enic
non
-pro
tein
codi
ng R
NA
478
836
rs36
9347
1,25
31,
44E-
040,
115
2116
6696
62G
A38
8815
LIN
C00
478
long
inte
rgen
ic n
on-p
rote
in co
ding
RN
A 4
78
837
rs15
8046
1,22
4,29
E-04
0,13
221
1831
6684
CT
1405
78C
HO
DL
chon
drol
ectin
838
rs28
2623
90,
8685
5,02
E-04
0,32
621
2070
9622
TG
839
rs99
8042
70,
873
6,81
E-04
0,34
621
2070
9933
AG
840
rs28
2624
20,
8687
5,09
E-04
0,32
621
2071
3322
TC
841
rs19
8505
30,
8615
2,27
E-04
0,32
821
2071
3786
GA
842
rs28
2624
40,
8668
3,54
E-04
0,34
021
2071
6906
GC
843
rs10
2925
80,
8229
5,69
E-04
0,13
621
2671
0675
CA
844
rs28
3105
41,
167
5,52
E-04
0,23
921
2795
4865
AG
845
rs18
8843
31,
139
8,63
E-04
0,38
621
2795
4964
TC
846
rs28
3185
41,
162
3,31
E-04
0,28
321
2878
2159
TC
847
rs28
3186
31,
159
2,21
E-04
0,34
721
2878
8692
TC
App
endi
x. (C
ontin
ued)
.
27
GÜL et al. / Turk J Med Sci84
8rs
1999
318
1,14
89,
33E-
040,
284
2128
8178
20C
A
849
rs99
7537
11,
215
9,45
E-04
0,11
421
2881
7851
TC
850
rs11
7010
351,
246
5,68
E-06
0,18
621
3716
2840
AG
3141
HLC
Sho
loca
rbox
ylas
e sy
nthe
tase
(bio
tin-(
prop
riony
l-CoA
-ca
rbox
ylas
e (A
TP-h
ydro
lysin
g)) l
igas
e)
851
rs81
3253
81,
229
2,21
E-05
0,18
321
3719
7902
AG
3141
HLC
Sho
loca
rbox
ylas
e sy
nthe
tase
(bio
tin-(
prop
riony
l-CoA
-ca
rbox
ylas
e (A
TP-h
ydro
lysin
g)) l
igas
e)
852
rs28
3553
01,
237
1,20
E-05
0,18
221
3719
9189
CT
3141
HLC
Sho
loca
rbox
ylas
e sy
nthe
tase
(bio
tin-(
prop
riony
l-CoA
-ca
rbox
ylas
e (A
TP-h
ydro
lysin
g)) l
igas
e)
853
rs28
4581
21,
204
1,09
E-04
0,18
921
3722
0194
TC
3141
HLC
Sho
loca
rbox
ylas
e sy
nthe
tase
(bio
tin-(
prop
riony
l-CoA
-ca
rbox
ylas
e (A
TP-h
ydro
lysin
g)) l
igas
e)
854
rs81
2723
61,
143
8,21
E-04
0,35
321
3727
1007
TC
3141
HLC
Sho
loca
rbox
ylas
e sy
nthe
tase
(bio
tin-(
prop
riony
l-CoA
-ca
rbox
ylas
e (A
TP-h
ydro
lysin
g)) l
igas
e)
855
rs22
0161
0,81
499,
16E-
040,
109
2142
4223
62C
G89
766
UM
OD
L1ur
omod
ulin
-like
1
856
rs99
8145
90,
823
2,92
E-04
0,14
821
4268
1878
GC
6469
9TM
PRSS
3tr
ansm
embr
ane
prot
ease
, ser
ine
3
857
rs24
0116
30,
8312
4,02
E-04
0,15
422
1651
1078
CT
2378
6BC
L2L1
3BC
L2-li
ke 1
3 (a
popt
osis
faci
litat
or)
858
rs25
8710
30,
8412
8,87
E-04
0,15
622
1652
8454
TC
2378
6BC
L2L1
3BC
L2-li
ke 1
3 (a
popt
osis
faci
litat
or)
859
rs71
3999
0,84
141,
07E-
050,
376
2246
2107
76A
G
860
rs60
0822
61,
189
3,71
E-04
0,18
422
4624
3314
CT
861
rs11
0908
061,
299,
95E-
040,
065
2246
7771
60A
C
862
rs12
0094
341,
181
2,51
E-04
0,32
423
1287
5922
AG
863
rs59
7978
41,
169
5,82
E-04
0,32
923
1287
6296
CA
864
rs17
2775
031,
182
8,38
E-04
0,23
923
5683
3086
GA
5506
43LO
C55
0643
unch
arac
teriz
ed L
OC
5506
43
865
rs59
1479
91,
189
5,27
E-04
0,23
923
5684
0879
CT
5506
43LO
C55
0643
unch
arac
teriz
ed L
OC
5506
43
866
rs59
1480
71,
192
4,32
E-04
0,24
023
5686
7944
GT
867
rs59
6081
11,
191
4,95
E-04
0,23
923
5687
0079
GA
868
rs19
3097
81,
197
3,48
E-04
0,24
123
5692
7132
TC
869
rs11
0915
981,
187
6,06
E-04
0,24
023
5692
7696
GT
870
rs59
1485
21,
186
9,99
E-04
0,21
423
5694
8766
CT
871
rs43
7957
21,
184
6,85
E-04
0,24
323
5696
8844
GA
872
rs45
5784
11,
193
2,75
E-04
0,27
423
5738
3907
GT
1585
84FA
AH
2fa
tty a
cid
amid
e hy
drol
ase
2
App
endi
x. (C
ontin
ued)
.
28
GÜL et al. / Turk J Med Sci
873
rs10
8556
220,
8459
5,73
E-04
0,26
723
8590
2249
GC
1171
54D
AC
H2
dach
shun
d ho
mol
og 2
(Dro
soph
ila)
874
rs59
4272
91,
216
9,40
E-04
0,15
523
1081
8127
9A
G
875
rs59
4275
21,
227,
71E-
040,
155
2310
8209
528
GA
876
rs66
4295
81,
215
9,84
E-04
0,15
423
1082
4927
1G
A
877
rs48
2560
31,
206
8,05
E-04
0,17
723
1177
2789
5C
G
878
rs24
9562
21,
215
5,13
E-04
0,17
623
1177
3702
0G
T
879
rs24
9562
61,
219
4,27
E-04
0,17
423
1177
4294
6T
C
880
rs22
5617
31,
204
9,46
E-04
0,17
423
1177
7361
7C
T35
97IL
13RA
1in
terle
ukin
13
rece
ptor
, alp
ha 1
881
rs29
9705
21,
213
6,24
E-04
0,17
823
1178
0054
8G
A35
97IL
13RA
1in
terle
ukin
13
rece
ptor
, alp
ha 1
882
rs59
6594
70,
8593
5,27
E-04
0,40
823
1447
7723
3C
T
883
rs59
1962
30,
865,
09E-
040,
411
2314
4779
048
CG
884
rs12
8625
910,
8637
7,72
E-04
0,40
623
1448
0178
2G
T
885
rs12
8611
850,
8554
3,44
E-04
0,40
323
1448
0195
2G
C
886
rs59
6595
50,
8593
4,87
E-04
0,40
623
1448
0758
8A
T
App
endi
x. (C
ontin
ued)
.