Human Molecular Genetics Advance Access published online on July 25, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm194
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Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes, celiac disease and rheumatoid arthritis
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: b.z.alizadeh{at}umcutrecht.nl
Received June 7, 2007; Revised July 14, 2007; Accepted July 14, 2007
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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