Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes,...

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Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type

1 diabetes, celiac disease and rheumatoid arthritis

Behrooz Z. Alizadeh1,2,*, Gustavo Valdigem1, Marieke J. H. Coenen3, Alexandra

Zhernakova1, Barbara Franke3, Alienke Monsuur1, Piet L. C. M. van Riel4, Pilar Barrera4,

Timothy R. D. J. Radstake4, Bart. O. Roep2, Cisca Wijmenga1,5 and Bobby P.C. Koeleman1,2

1 Complex Genetics Section, Dept. of Medical Genetics, University Medical Center Utrecht,

Utrecht, the Netherlands.

2 Dept. of Immunohematology & Blood Transfusion, Leiden University Medical Center,

Leiden, the Netherlands.

3 Dept. of Anthropogenetics, Radboud University Nijmegen Medical Center, Nijmegen, the

Netherlands.

4 Dept. of Rheumatology and Experimental Rheumatology and Advanced Therapeutics,

Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

5 Dept. of Genetics, University Medical Center Groningen, the Netherlands.

*Correspondence to:

Behrooz Z. Alizadeh, MD, PhD

Complex Genetics Section, Department of Medical Genetics, University Medical Center

Utrecht, PO Box 85060, 3508 AB Utrecht, the Netherlands. Tel: +31-30-2537925, Fax: +31-

30-2538479. E-mail: [email protected]

© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]

HMG Advance Access published July 25, 2007 by guest on February 21, 2016

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ABSTRACT

Background FcgRIIa and FcgRIIIa are potent modulators of the immune system which bind

(auto)antibodies and activate immune cells. The FcgRIIa*A519G and FcgRIIIa* A559C

functional variants have been associated with several immune-related diseases. We studied

FcgRIIa*A519G and FcgRIIIa*A559C SNPs in type 1 diabetes (T1D), celiac disease (CD),

and rheumatoid arthritis (RA) patients and controls, and included a meta-analysis of all recent

studies of FcgRIIIa*A559C and RA.

Method Our cohorts comprised 350 T1D, 519 CD, 639 RA patients and 1,359 controls, who

were genotyped for FcgRIIa*A519G and FcgRIIIa*A559C variants. Regression and EM-

algorithm-based haplotype analyses were used for the data analysis.

Results We found significant differences in genotype frequencies of FcgRIIa between

controls and patients with T1D (P=0.04), CD (P=0.000005) and RA (P=0.04). The

FcgRIIa*519GG genotype showed an increased risk for both T1D (OR=1.51; 95%CI=1.08-

2.12; P=0.015), and CD (OR=1.81, 95%CI=1.35-2.37; P=0.000004), but not for RA. There

was no difference in the frequency of FcgRIIIa*A559C genotypes or allelotypes between

controls with T1D, CD, and RA. We found that FcgRIIa and FcgRIIIa haplotypes frequencies

differed significantly between controls and patients with T1D (P=0.05), and with CD

(P=0.00038), but not with RA patients. Our meta-analysis showed a significant 1.37(1.14-

1.66) fold increased risk of RA for the FcgRIIIa*559CC (158VV) genotype (P=0.001).

Conclusion This is the first report that the FcgRIIa*519GG genotype predisposes to T1D and

CD. We confirmed the FcgRIIIa*559CC genotype is associated to RA. If replicated, our

findings would suggest the FcgRIIa*519G as a common risk factor for auto-immune diseases.

This may have clinical implications with regard to efficacy or safety of antibody-based

immuno-modulator therapies.

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INTRODUCTION

Fc receptors I, II, and III (FcgRI, FcgRII, and FcgRIII) have evolved as crucial immune

response-modulating molecules that participate in reactivity to environmental antigens (1-3).

Eight genes clustered on chromosome 1q21-q24 encode three classes of FcgRs that are

expressed at the cell surface, namely the high-affinity receptor FcgRI (CD64) that binds

monomeric IgG, and FcgRII (CD32) and FcgRIII (CD16) that bind to multivalent IgG.

FcgRII and FcgRIII have different subclasses. FcgRIIa and FcgRIIIa associate with the

common FcRgamma-chain containing a stimulatory ITAM motif that is also present in the

intracellular tail of FcgRIIa, whereas FcgRIIb contains an inhibitory ITIM motif in the

cytoplasmic domain. FcgRIIa and FcgRIIIa stimulatory receptors are expressed by most

leukocytes, including monocytes, dendritic cells, macrophages, natural killer cells, platelets,

and endothelial cells, and a subpopulation of T-cells whereas FcgRIIb is expressed by B

lymphocytes, macrophages and dendritic cells (FcgRb2) (4). Upon binding of antibodies or

autoantibodies, FcgRIIa and FcgRIIIa activate immune cell functions, including phagocytosis,

and the release of inflammatory mediators, whereas FcgRIIb nullifies cell activation (3, 5).

Thus, FcgRs are part of an important regulatory system in intercepting and digesting

(auto)antibodies, which modulates antibody-mediated cellular cytotoxicity (1, 3, 6, 7).

FcgR isoforms were therefore linked to the pathogenic consequences triggered by

autoantibodies or immune complexes in autoimmune diseases such as rheumatoid arthritis

(RA) and systemic lupus erythematosus (SLE) (1, 3, 7).

FcgRIIa can have either histidine (H131) or arginine (R131) at amino acid position

131 located in the IgG binding site, which is encoded FcgRIIa*A519G SNP (8, 9). The

FcgRIIa*519G allele encodes the H131 high-binding isoform to IgG2, and the FcgRIIa*519A

encodes the low-binding R131 isoform (3, 9). The FcgRIIIa gene expresses two isoforms,

namely V158 (or V176) and F158 (or F176), which differ at amino acid 158 (or 176) in the



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extracellular domain and are encoded by FcgRIIIa*A559C SNP. The FcgRIIIa*559C allele

encodes the high-binding isoform to IgG1 and IgG3 valine isoform (i.e. V158), and the

FcgRIIIa*559A encodes the 158 low-binding phenylalanine isoform (i.e. F158) (10, 11). It is

interesting that several independent genetic studies have linked chromosome 1q22-q24 to RA

and SLE (7, 12-14). However, extensive studies yielded different results on the relationship

between genetic polymorphisms in the FcgR genes, in particular the FcgRIIa and FcgRIIIa

high/low binding polymorphisms, to autoimmune diseases. On the one hand, meta-analyses

have confirmed association of the FcgRIIa*519G variant with susceptibility to SLE

worldwide (1, 15), and an association of FcgRIIIa*559C with SLE nephritis (16) and several

other inflammatory diseases (1, 4, 16-29). On the other hand, the association of these two

genes with RA remains interesting, but inconclusive for FcgRIIIa*559C, whereas no

association was found in multiple sclerosis (22, 25, 27, 30-32).

Like SLE and RA, type 1 diabetes (T1D) and celiac disease (CD) are common

autoimmune diseases, which are characterized clinically by the presence of autoantibodies:

against insulin-producing beta cells in T1D or intestinal mucosal cells in CD (33-37). The

experimental-clinical studies are of great interest and have implied a role for FcgRs in the

efficacy and side-effects of anti-CD3 immuno-modulatory therapy in T1D (30, 38-40).

However, the relevance of the FcgRIIa or FcgRIIIa genes to the pathogenesis of T1D and CD

has not been investigated so far. In this study, we investigated FcgRIIa*A519G and

FcgRIIIa*A559C and their joint effects on susceptibility to T1D, CD and RA, and performed

a meta-analysis on the association between FcgRIIIa*A559C with RA.



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RESULTS

FcgRIIa

Overall, the frequencies of FcgRIIa*A519G genotypes differed significantly between

controls and T1D patients (P=0.04; Table 1). Individuals homozygous for the FcgRIIa*519G

variant (corresponding to the high-binding 131H isoform) were more frequent in T1D patients

(29.01%) than controls (22.65%), yielding a 1.51-fold increased risk for T1D in carriers

(95%CI 1.08–2.12; P=0.015, Table 1). Similarly, we found a significant difference in the

frequency of FcgRIIa*T519G genotypes in controls and CD patients (P=0.000005). CD

patients were also more frequently (32.61%) homozygous for the high-binding FcgRIIa*519G

than controls, leading to a 1.81-fold (1.35–2.37; P=0.000004) increase in risk for CD in

carriers (Table 1). Overall, the frequency of FcgRIIa*A519G genotypes differed significantly

between controls and RA patients (P=0.047; Table 1). RA patients were more frequently

heterozygous for this SNP than controls (54.08% vs. 48.50%), and were less often

homozygous for both A (27.20%) and G (18.72%) alleles than the controls (28.85%, and

22.65%, respectively). When the data was analyzed per chromosome, the high-binding

FcgRIIa*519G allele was significantly more frequent in patients with T1D (frequency 0.52;

P=0.01) and CD (0.55; P=0.000002) than in controls (0.47), yielding an increased risk of 1.24

(0.93-1.55) and 1.39 (1.04-1.74) for T1D and CD, respectively. We found no significant

difference in the frequencies of the FcgRIIa*519G allele in controls and RA patients.

FcgRIIIa

Overall, there was no significant difference of FcgRIIIa*A559C genotypes between controls

and T1D, CD, or RA (Table 1). Also, the frequency of the FcgRIIIa*559C allele did not differ

significantly among the controls and patients with T1D, CD or RA (Table 1).



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Linkage disequilibrium and haplotype analysis

Since the FcgRIIa and FcgRIIIa genes reside close to each other in the same chromosomal

region, we tested whether there was an allelic association between these two genes in our

cohorts (Table 2). We found that FcgRIIa*A519G and FcgRIIIa*A559C were significantly

associated in the controls (P=5.97*10-19), T1D (7.06*10-8), CD (1.70*10-5) and RA patients

(5.30*10-6). To quantify the strength of LD, we calculated the D’ between the two loci (Table

2). The D’ as well as R2 between the FcgRIIa*A519G and FcgRIIIa*A559C variants were

low in our cohorts, indicating that there is a low LD between the studied variants.

Next, we tested whether there was a specific disease-associated FcgRIIa*A519G

_FcgRIII*A559C haplotype for T1D and CD. Overall, we found significant differences in the

frequencies of FcgRIIa*A519G_FcgRIII*A559C haplotypes between controls and T1D

(P=0.03), CD (P=0.00038) but not with RA patients (P=0.58; Table 2). The haplotype specific

risks indicate that it is mainly the FcgRIIa* 519G allele that explains the association of the

FcgRIIa-FcgRIIIa haplotypes to T1D and CD, while there were no differences in the

frequencies of these haplotypes between RA patients and controls (Table 2).

We further fitted the statistical model with interaction terms between FcgRIIa*A519G

and FcgRIIIa*A559C genotypes. We found no significant evidence of interaction between the

two loci in susceptibility to T1D or CD suggesting an FcgRIIIa-independent association of

FcgRIIa*519G variant with T1D and CD.

Meta-analysis of FcgRIIIa genotypes

To further clarify the inconclusive association between FcgRIIIa and RA we conducted a

meta-analysis of 11 studies together with our current data (Fig. 1). The heterogeneity test was

not statistically significant in the analysis of the FcgRIIIa*559CC genotype (P=0.35) whereas

it was significant for the analysis of the FcgRIIIa*559CA genotype (P=0.03). In Caucasians,



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we found that the FcgRIIIa*559CC genotype was associated with a significant, 1.37 (95%CI

1.14 - 1.66; P=0.001) increased risk of RA in carriers (Fig. 1) while the FcgR*559CA

genotype was not associated to RA (P=0.33). We found no association of FcgRIIIa*559CC or

of FcgRIIIa*559CA to RA in Asians (Fig. 1).

DISCUSSION

We demonstrated that the FcgRIIa*519G variant is associated with both T1D and CD. We

found a relatively low LD between FcgRIIa*A519G and FcgRIIIa*A559C, and hence the

FcgRIIa–FcgRIIIa haplotypes showed different frequencies in the healthy controls and T1D or

CD patients that is mainly explained by FcgRIIa*519G, but not between RA patients and

controls. Our meta-analysis showed that FcgRIIIA*559CC genotype is significantly

associated with a mild increase in the risk of RA.

In our cohorts, homozygosity for the FcgRIIa*519G variant was consistently

associated with T1D and CD, which agrees with the studies that demonstrated homozygosity

for the FcgRIIa*519G variant is consistently associated with other autoimmune disorders (16,

20, 24-26). A meta-analysis of a large number of SLE patients and controls, confirmed the

FcgRIIa*519G variant as a genetic risk factor to SLE (16). Others have found an association

between this SNP and Guillain-Barre syndrome (GB), and RA (1, 4, 17-30).

Our findings also fit with the functional characteristics of this stimulatory variant in

determinations of immune hyper-reactivity, and thus suggest that the FcgRIIa gene is a

predisposing factor for several autoimmune diseases (1, 4, 16-29). This finding seems to be

similar to the associations of CTLA4 and PTPN22 with autoimmunity in general (41).

PTPN22 and CTLA4 are functionally completely different molecules and are involved in the

regulation of T cell function (41). There may be also a point of concern: the effect of FcgRIIa

varies with autoimmune diseases, in the sense that the FcgRIIa*519G variant is associated to



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SLE and GB, and in our study, to CD and T1D, but it shows no consistent association with

multiple sclerosis (MS) or RA (22).Also in our study, the association of FcgRIIa*G to RA

was weaker and not convincing. The association was due to an excess of heterozygosity,

which lacks a plausible biological meaning. In contrast, we detected novel association of

FcgRIIa with CD and T1D with excess of homozygosity, which supports the hypothesis that

FcgRIIa is a crucial determinant of susceptibility to several autoimmune diseases. Thus,

FcgRIIa genotypes may serve as a marker for distinguishing the underlying basic pathologic

heterogeneity in autoimmune diseases.

We could not confirm an association of the FcgRIIIa*A559C genotypes to RA in our

study. Indeed, reports on this association are contradictory. Some have shown an association

of this marker with RA in the English, Indian and Pakistani populations (26, 31, 42), but

several other studies found no association between the FcgRIII*559C variant and RA in

Japanese, Taiwanese, Spanish, Norwegian, Dutch, or Spanish populations (22, 25, 43-45).

However, our meta-analysis confirmed an association of FcgRIIIa*559CC genotypes to RA in

Caucasians. This finding agrees with the results of an earlier pervious meta-analysis that

confirmed the association between FcgRIIIa*559CC and SLE (15). It should be noted that the

latter studies reported a positive association between FcgRIIIa and RA in subgroups of

patients who shared a particular clinical characteristic such as shared anti-GPI positivity (46),

severe in hands RA (25) nodular arthritis (26) or only in men (25), which are indicators of

disease severity. These observations fit with the finding that the FcgRIIIa*559C variant is

associated with lupus nephritis (1), a disease complication, implying that the FcgRIIIa gene

may be involved in the course of autoimmune diseases. This would partly explain the

contradictory findings in RA, including those in the present study. Altogether, and given the

findings of our meta-analysis we concluded that FcgRIIIa is associated to RA in Caucasians,

most likely in those with a severe form of RA.



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Our study focused on the FcgRIIa and FcgRIIIa genes, two activating receptors for

immuno-effector cells. However, there are effective classes of inhibitory FcgRs, such as

FcgRIIb and FcgRIIIb, which were also clustered to chromosome 1q21-q24, often present as

pairs on the cell surface, and associated with several autoimmune diseases (3, 15, 47). The

inhibitory receptors nullify stimulation signals from FcgRIIa and FcgRIIIa. Interestingly,

association between copy number variation of FcgRIIIb and lupus nephritis, SLE and

Wegner’s granulomatosis has been reported (48, 49). The low LD FcgRIIa and FcgRIIIa and

the close proximity of FcgRIIIb to the latter indicates that FcgRIIIb may be an independent

risk locus in this region that warrants further investigation (48). Our risk estimates may

therefore be skewed, due to the modifying effects of “functionally” interacting variants in

neighboring inhibitory FcgRs.

We have tested FcgRIIa*A519G and FcgRIIIa*A559C alleles on the basis of prior

evidence of previous reported association in other autoimmune diseases. Thus, multiple

testing may not be applicable to our study. Nevertheless, significant association would still

remain for the CD study when a conservative six-fold Bonferroni correction for multiple-

hypothesis testing is used.

It has been shown that the efficacy and compliance to the immunomodulatory

monoclonal antibody against CD3 (anti-CD3 Ab) therapy differs according to imuunoglobolin

FcgRIIa, and FcgRIIIa isoforms due to variation in the encoding genes (39, 40, 50, 51), while

the non-FcR binding anti-CD3 is less immunogenic than FcR-binding forms (52-54).

Furthermore it has been shown that FcgRs variations influences the release of cytokines,

which may underlie the occurrence of side-effects after initiation of anti-CD3 mAb (54). On

the basis of these observations, several studies investigated the role variations in the FcgRIIa,

FcgRIIIa genes in the efficacy of anti-CD3 therapy in different immune diseases, and they

found conflicting and non-consistent results (55-57). Therefore, our findings may further



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delineate that the disease risk genotype of FcgRIIa may modify the efficacy of anti-CD3 Ab

oriented therapies, a hypothesis which remains to be tested.

In conclusion, this is the first report of homozygosity for FcgRIIa*519G as a

predisposing factor to T1D and CD but not to RA. Our novel findings need to be replicated by

others. We also found that homozygosity for FcgRIIIa*559C was associated to RA in the

meta-analysis. Our findings provide basic insight into the possible mechanism of AIDs and

may well have clinical implications with respect to the efficacy, and side-effects, of immuno-

modulator interventions, such as anti-CD3 therapy.

MATERIALS AND METHODS

Study populations

Type 1 Diabetes. Patients were retrieved from the Kolibri T1D cohort that includes 350

Dutch patients with juvenile onset T1D (median 8.7 yrs, range 1-17 yrs). The cohort was

collected consecutively after diagnosis by pediatricians in the Southwestern part of the

Netherlands between 1995 and 1999. The diagnosis was made according to International

Society of Pediatric and Adolescent Diabetes (ISPAD) and WHO criteria.

Celiac Disease. Patients were included from cohorts of Dutch CD patients that included

children and adults. All the 519 CD patients have been diagnosed according to the revised

ESPGHAN criteria (58). More than 90% of the patients were HLA-DQ2 positive. The

patients’ initial biopsy specimens were retrieved and all showed a Marsh III lesion on re-

evaluation by experienced pathologists.

Rheumatoid Arthritis. The characteristics of patients with RA have been described

elsewhere (59). In brief, the RA patients included in our study were recruited from an ongoing

early-RA inception study that was started in 1985 at the Department of Rheumatology,

Radboud University Nijmegen Medical Centre (RUNMC) in the Netherlands. All the patients



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were diagnosed according to the American College of Rheumatology criteria for RA (60), had

a disease duration of less than one year, and had no prior use of disease-modifying anti-

rheumatic drugs or biological agents before presentation. All patients in the early-RA

inception cohort are regularly monitored for disease phenotype, severity, and outcome. In

total, 639 Dutch patients with RA were included in our study.

The T1D, CD and RA patients were also born in the Netherlands and had at least three out of

four grandparents also born in the Netherlands.

Control subjects. A total of 1,359 unrelated Dutch individuals were selected for being born

in the Netherlands and had at least three out of four grandparents also born in the Netherlands.

All the patients and controls gave their informed consent and the medical ethical

committee of the University Medical Center Utrecht or the Radboud University Nijmegen

Medical Centre approved this study.

Genotyping

We genotyped our study cohorts for the FcgRIIa* A519G SNP (rs1801274), and the

FcgRIIIa*A559C SNP (rs396991). The genotyping of FcgRIIa*A519G SNP was successful

for 1,324 controls, 324 T1D patients, 509 CD patients, and 625 RA patients, while the

genotyping for FcgRIIIa* A559C succeeded in 1,326 controls, 319 T1D patients, 510 CD, and

601 RA patients. Participants’ genotypes for both the FcgRIIa*A519G and FcgRIIIa*A559C

variants were available for 1,290 controls, 314 T1D patients, 503 CD patients and 587 RA

patients. Genotype frequencies of FcgRIIa* A519G and FcgRIIIa* A559C variants were in

Hardy-Weinberg proportions in controls.

The Taqman(R) SNP genotyping assays for PCR were supplied by Applied Biosystems

(Nieuwerkerk a/d Ijssel, the Netherlands) for FcgRIIa*A519G (ABI assay identification

number C__9077561_20), or for FcgRIIIa*A559C (C_25815666_10).



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Meta-analysis. We searched Medline for all publications relating to association studies

using the combinations of quarries of “FcgRIIa*A519G”, “FcgRIIIa*A559C”, “IIIA”, “IIA”,

“RA”, “Rheumatoid”, “Arthritis”, “FcgR”, “FcgammaRIIIA”, “FcgammaRIIA” and checked

the references from retrieved publications for additional studies. We identified 14 articles: two

performed analysis in 2 different ethnic populations i.e. Caucasians and Indians (26, 27), of

which each analysis was treated as a separate entity in the meta-analysis. One study provided

family-based association study(44); and one study presented data only for patients (61). These

studies were not included in our meta-analysis. All the studies used the same diagnostic

criteria for RA and patients were diagnosed according to the American College of

Rheumatology criteria (60). In total we included 11 studies in our meta-analysis, of which 8

were conducted in Caucasian populations (25-27, 42, 45, 62, 63) including two analysis in

Indians (26, 27), and three in Asians (22, 30, 43). In total the meta-analysis covered

chromosomes from 3341 patients and 4161 controls.

Data analyses

Genotype and allele frequencies were calculated by direct counting. Hardy-Weinberg

equilibrium was checked by using GenePOP software. First the data was analyzed overall by

genotypes. Chi-squared tests were used to compare frequencies. Regression analysis was used

to first estimate genotypic main-effect odds ratios (OR) and the corresponding 95%

confidence intervals (95% CI), and then the main effect of the risk allele of the two SNPs and

the interaction effect OR (95% CI) between variants of the FcgRIIa*A519G and

FcgRIIIa*A559C SNPs. Coefficient (D’) and corresponding 95% confidence bound of pair-

wise linkage disequilibrium as well as r-Squared (r2) between FcgRIIa*A519G and

FcgRIIIa*A559C using the LD plot module implemented in the Haploview software, version

3.2. We tested for allelic association between these SNPs independently in the controls, T1D,

CD, and RA patients using an expectation maximization (EM) algorithm as described



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elsewhere (64). A two-tailed p-value < 0.05 was considered statistically significant. Data

analysis was performed using UNPHASED (65, 66), and STATA statistical software, version

8.0 for MS Windows.

Meta-analysis. For each study the frequency of FcgRIIIa genotypes were derived from

counting method in patients and controls. In all the studies, allele frequencies were consistent

with Hardy-Weinberg Equilibrium. In addition to the total group, we classified the studies into

Caucasians and Asian. The effect of the FcgRIIIa*A559C genotypes were assessed by

comparing the frequency of the FcgRIIIa*559AC and FcgRIIIa*559CC genotype versus the

FcgRIIIa*559AA genotype in patients and controls. We used funnel plots to examine

publication bias of reported associations. The study of Milicic et al.(2002) had a very skewed

frequency for the FcgRIIIa* 559CC genotype that led to this study being an oulier. We

excluded this study from the analysis. To accommodate the effect of different ethnic

backgrounds on the association between FcgRIIIa*559AC and RA, heterogeneity between

studies was tested using the Chi-squared test, and the confidence interval for the odds ratio

was estimated using a random effect model. We included only FcgRIIIa*A559C in the meta-

analysis; since there were not enough data on the association of FcgRIIa*A519G variant and

RA. The meta-analysis was conducted using the Cochrane Review Manager, version 4.1.2.

ACKNOWLEDGMENTS

This study was supported by grants from the Dutch Diabetes Research Foundation (97.137),

the Netherlands Organization for Health Research and Development (ZonMW), and Novo

Nordisk A/S. Collection and genotyping of controls was part of a celiac disease project

supported by grants from the Netherlands Organization for Scientific Research (NWO grants

902-22-094 and 912-02-028), the Dutch Digestive Diseases Foundation (grants 97-44 and 03-

06) and the Celiac Disease Consortium, an innovative cluster approved by the Netherlands



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Genomics Initiative and partially funded by the Dutch government (grant BSIK03009). We

thank Eric Strengman for technical assistance, Harry van Someren as database manager and

Jackie Senior for critically reading the manuscript.

Conflict of Interests statement. None

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LEGENDS FOR TABLES

Table 1.

The association of the functional FcgammaRIIaA519G and FcgammaRIIIaT559G variants to

type 1 diabetes, celiac disease and rheumatoid arthritis

Table 2.

LD between FcgammaRIIa*A519G_FcgammaRIIIa*A559C and their joint association to type

1 diabetes (T1D), celiac disease (CD) and rheumatoid arthritis (RA)

Figure 1,

A meta-analysis of the frequency of FcgammaR*559CC and FcgammaR*559CA genotypes

compared to that of FcgammaR*559AA in RA patients versus controls. OR represents odds

ratio with 95 percent confidence interval estimated using random model (Random). n1

represents number of subjects with CC genotypes; N1, number of sum of subjects with CC

and AA genotypes, n2, number of subjects with CA genotype, and N2 represents sum of the

number of subjects CA and AA genotypes. Vertical grey line serves reference line for no

association i.e. OR=1.



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Cohorts A. Controls B. Type 1 diabetes C. Celiac disease D. Rheumatoid Arthritis

SNPs

Number

(%)

Number

(%)*1OR (95% C.I.)

Number

(%)*2OR (95% C.I.)

Number

(%)*3OR (95% C.I.)

FcgammaRIIa*A519G N=1324 N=324 N=509 N=625

Non-carrier (A/A) 382 (28.85) 079 (24.38) 1.00# 118 (23.20) 1.00# 170 (27.20) 1.00#

Heterozygote (A/G) 642 (48.50) 151 (46.60) 1.13 (0.84-1.53) 225 (44.20) 1.14 (0.88-1.47) 338 (54.08) 1.18 (0.94-1.46)

Homozygote (G/G) 300 (22.65) 94 (29.01) 1.51 (1.08-2.12)*4 158 (32.61) 1.81 (1.35-2.37)*5 117 (18.72) 0.86 (0.65-1.13)

Allele G§ 1242 (0.47) 339 (0.52)*6 1.24 (0.93-1.55) 557 (0.55)*7 1.37 (1.18-1.58)*7 572 (0.46) 0.95 (0.71-1.42)

FcgammaRIIIa*A559C N=1326 N=319 N=510 N=601

Non-carrier (A/A) 533 (40.2) 131 (41.1) 1.00# 209 (41.0) 1.00# 221 (36.8) 1.00#

Heterozygote(A/C) 604 (45.6) 132 (41.4) 1.21 (0.85-1.72). 238 (46.8) 0.87 (0.62–1.20) 290 (48.3) 1.15 (0.85-1.54)

Homozygote (C/C) 189 (14.3) 56 (17.6) 1.92 (0.70–1.91) 63 (12.4) 1.05 (0.85–1.31) 90 (15.1) 1.16 (0.94-1.43)

Allele C§ 982 (0.37) 248 (0.38) 1.06 (0.89-1.27) 375 (0.36) 0.96 (0.83-1.20) 470 (0.39) 1.09 (0.95-1.26)

N. number of subjects; §Numbers represent the number of chromosomes with the specified alleles (i.e. G or C) and figures within the brackets

represent the relative frequencies. Significance: Overall genotype test (cases were compared to controls) *1 PFcgammaRIIA=0.04, *2

PFcgammaRIIA=0.000005, *3 PFcgammaRIIA=0.04. Homozygotes compared to reference: *4 P=0.015, *5 P=0.000004. Allotype compared to reference:

*6 P=0.01, *7 P=0.000002. # reference.

by guest on February 21, 2016 http://hmg.oxfordjournals.org/ Downloaded from


26

Controls

(N=2396)

T1D

(N=628)

CD

(N=924)

RA

(N=1196)

FcgRIIa

*A519G

FcgIIIa

*A559C N (freq.) N (freq.) OR (95%CI) N (freq.) OR (95%CI) N (freq.) OR (95%CI)

A A 790 (0.31) 141 (0.22) 1.00# 227 (0.25) 1.00# 338 (0.28) 1.00#

A C 582 (0.23) 155 (0.25) 1.19 (0.89–1.49) 188 (0.20) 0.89 (0.67-1.33) 312 (0.26) 1.05 (0.75-1,25)

G A 836 (0.32) 248 (0.39) 1.36 (1.03-1.71) 368 (0.40) 1.22 (0.92-1.53) 391 (0.33) 0.92 (0.69-1.38)

G C 370 (0.14) 84 (0.13) 1.43 (1.07-1.79) 139 (0.15) 1.49 (1.12-1.87) 155 (0.13) 1.10 (0.83-1.38)

Overall statistics for disease association:

chi2 value (df); p value. 8.88 (3), P=0.03 19.94 (3); 0.00017 1.93 (3); 0.59

Analysis of LD between the variants

D’ (95% confidence

bound);

R-squared

0.33 (0.27-0.43);0.06 0.21 (0.12-0.30); 0.08 0.28 (0.17-0.37); 0.03

N: presents the number of chromosomes included in the analysis; D’ coefficient of pair-wise linkage disequilibrium; LR: likelihood ratio; df: degree of

freedom; LD: linkage disequilibrium.

0.28 (0.17-0.37); 0.04



27

FcγRIIIA*559CA vs. AA FcγRIIIA*559CC vs. AA

1817/3608

261/752

077/173

149/354

091/179

1201/2276

056/122

058/098

025/061

364/720

063/120

188/353

051/095

085/155

290/511

045/102

Controlsn2 / N2

317/70675/464080/471Total

Asians170/325033/121046/201Chen _Taiwan (43)

046/105010/050008/067Mprgan _India (26)

042/093023/089023/089Akres _USA (63)

1456/2856366/1442377/1784Total

132/277028/233026/171Kyogoku _Japan (23)

059/150014/110008/099Matsumoto _Japan (30)

596/1128090/311189/728This Study _Dutch

161/329026/09633/201Kastbom _Sweden (25)

032/075017/061014/057 Brun _Norway (62)

214/386048/213034/206Milicic _UK (27)

048/113021/078011/076Morgan _UK (26)

1518/2982441/1906457/2255Total

035/079002/038014/044Milicic _India (27)

241/505116/472056/320Morgan _UK (42)

076/122015/072020/066Nieto_Spanish (45)

Caucasians

Patientsn2 / N2

Patientsn1 / N1

Controlsn1 / N1Studies

FcγRIIIA*559CA vs. AA FcγRIIIA*559CC vs. AA

1817/3608

261/752

077/173

149/354

091/179

1201/2276

056/122

058/098

025/061

364/720

063/120

188/353

051/095

085/155

290/511

045/102

Controlsn2 / N2

317/70675/464080/471Total

Asians170/325033/121046/201Chen _Taiwan (43)

046/105010/050008/067Mprgan _India (26)

042/093023/089023/089Akres _USA (63)

1456/2856366/1442377/1784Total

132/277028/233026/171Kyogoku _Japan (23)

059/150014/110008/099Matsumoto _Japan (30)

596/1128090/311189/728This Study _Dutch

161/329026/09633/201Kastbom _Sweden (25)

032/075017/061014/057 Brun _Norway (62)

214/386048/213034/206Milicic _UK (27)

048/113021/078011/076Morgan _UK (26)

1518/2982441/1906457/2255Total

035/079002/038014/044Milicic _India (27)

241/505116/472056/320Morgan _UK (42)

076/122015/072020/066Nieto_Spanish (45)

Caucasians

Patientsn2 / N2

Patientsn1 / N1

Controlsn1 / N1Studies

*P=0.001

Not included



Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes,...

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