Thabet M M, Huizinga T W J, Marques R B, Stoeken-Rijsbergen G, Bakker A M, Kurreeman F A, White S J, Toes R E M, van der Helm-van Mil A H M
Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
Ann Rheum Dis. 2009 Nov;68(11):1775-80. doi: 10.1136/ard.2008.099309. Epub 2008 Nov 19.
Fcgamma receptors (FcgammaRs) are potent immune modulators. FcgammaR genes encompass a complex region, polymorphic by both single nucleotide polymorphisms (SNPs) and copy number variation (CNV). The heterogeneity of rheumatoid arthritis (RA) combined with the genetic complexity of FcgammaR genes may be the cause of inconsistent findings in previous RA studies on FcgammaR SNPs. There is increasing evidence that anti-citrullinated peptide antibody (ACPA)-positive RA and ACPA-negative RA have a different genetic background.
To investigate whether FcgammaRIIIA 158V/F SNP associates differently with ACPA-positive and ACPA-negative RA and to assess if the FcgammaRIIIA gene CNV affects the association of the FcgammaRIIIA 158V/F SNP with RA and whether the FcgammaRIIIA gene CNV confers risk for RA.
945 patients with RA and 388 healthy controls, all Dutch-Caucasians, were included in the study. FcgammaRIIIA 158V/F SNP was genotyped using Sequenom. CNV of the FcgammaRIIIA gene was determined in 456 patients with RA and 285 controls using multiplex ligation-dependent probe amplification. Associations between genotypes and RA were analysed, stratifying for the presence/absence of ACPA and CNV.
In all patients with RA the FcgammaRIIIA 158V/F SNP was not associated with RA. In ACPA-positive RA (n = 358), the VV genotype was more prevalent in cases than in controls (18.4% vs 13.2%, OR = 1.5, p = 0.05). After stratification for CNV the VV genotype was associated with RA in general (n = 426) (OR = 1.6, 95% CI 0.97 to 2.6, p = 0.05) and with ACPA-positive RA (n = 135) (OR = 2.1, 95% CI 1.2 to 3.8, p = 0.009) but not with ACPA-negative RA. The distribution of CNV was not significantly different between patients with RA and controls.
The FcgammaRIIIA 158 VV genotype confers risk for ACPA-positive RA; this association increased slightly after correction for CNV of the FcgammaRIIIA gene. CNV itself is not associated with RA susceptibility.
Fcγ受体（FcγRs）是强大的免疫调节剂。FcγR基因包含一个复杂区域，通过单核苷酸多态性（SNP）和拷贝数变异（CNV）表现出多态性。类风湿关节炎（RA）的异质性与FcγR基因的遗传复杂性相结合，可能是先前关于FcγR SNP的RA研究结果不一致的原因。越来越多的证据表明，抗瓜氨酸化肽抗体（ACPA）阳性的RA和ACPA阴性的RA具有不同的遗传背景。
研究FcγRIIIA 158V/F SNP与ACPA阳性和ACPA阴性RA的关联是否不同，并评估FcγRIIIA基因CNV是否影响FcγRIIIA 158V/F SNP与RA的关联，以及FcγRIIIA基因CNV是否赋予RA发病风险。
本研究纳入了945例RA患者和388名健康对照，均为荷兰白种人。使用Sequenom对FcγRIIIA 158V/F SNP进行基因分型。使用多重连接依赖探针扩增技术在456例RA患者和285名对照中测定FcγRIIIA基因的CNV。分析基因型与RA之间的关联，并根据ACPA和CNV是否存在进行分层。
在所有RA患者中，FcγRIIIA 158V/F SNP与RA无关联。在ACPA阳性的RA患者（n = 358）中，VV基因型在病例组中的比例高于对照组（18.4%对13.2%，OR = 1.5，p = 0.05）。在根据CNV分层后，VV基因型总体上与RA（n = 426）相关（OR = 1.6，95% CI 0.97至2.6，p = 0.05），与ACPA阳性的RA（n = 135）相关（OR = 2.1，95% CI 1.2至3.8，p = 0.009），但与ACPA阴性的RA无关。RA患者和对照组之间CNV的分布无显著差异。
FcγRIIIA 158 VV基因型赋予ACPA阳性RA发病风险；在对FcγRIIIA基因的CNV进行校正后，这种关联略有增加。CNV本身与RA易感性无关。
