title: Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes, celiac disease and rheumatoid arthritis.
abstract: 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. Our cohorts comprised 350 T1D, 519 CD, 639 RA patients and 1359 controls, who were genotyped for FcgRIIa*A519G and FcgRIIIa*A559C variants. Regression and expectation maximization (EM) algorithm-based haplotype analyses were used for the data analysis. 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 [odds ratio (OR) = 1.51; 95% confidence interval (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 haplotype frequencies differed significantly between controls and patients with T1D (P = 0.05) and with CD (P = 0.00038) but not with RA. Our meta-analysis showed a significant 1.37(95% CI 1.14-1.66)-fold increased risk of RA for the FcgRIIIa*559CC (158VV) genotype (P = 0.001). This is the first report that the FcgRIIa*519GG genotype predisposes to T1D and CD. We confirmed that the FcgRIIIa*559CC genotype is associated with RA. If replicated, our findings would suggest 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.
authors.affiliation: Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. b.z.alizadeh@umcutrecht.nl
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: Gustavo
authors.initials: G
authors.lastname: Valdigem
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Alienke
authors.initials: A
authors.lastname: Monsuur
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000293:Adolescent; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002446:Celiac Disease / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: D017452:Receptors, IgG