Morgan Ann W, Barrett Jennifer H, Griffiths Bridget, Subramanian Deepak, Robinson Jim I, Keyte Viki H, Ali Manir, Jones Elizabeth A, Old Robert W, Ponchel Frederique, Boylston Arthur W, Situnayake R Deva, Markham Alexander F, Emery Paul, Isaacs John D
Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
Arthritis Res Ther. 2006;8(1):R5. doi: 10.1186/ar1847.
The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.
Fcγ受体在许多免疫和炎症过程的启动及调节中发挥重要作用，并且基因变异体（FCGR）已与多种自身免疫性疾病和感染性疾病相关联。类风湿关节炎（RA）的数据存在矛盾，我们之前证明了FCGR3A与RA之间存在关联。鉴于与FCGR2A、FCGR2B和FCGR3B在分子上的紧密关系，我们检测了这些基因内的其他多态性以及FCGR单倍型，以细化与RA的关联程度。在两个特征明确的英国白种人和北印度/巴基斯坦队列中检测了FCGR2A、FCGR2B和FCGR3B的双等位基因多态性与RA的关联，之前已在这些队列中进行了FCGR3A基因分型。估计了整个FCGR基因座的单倍型频率和连锁不平衡，并进行了无模型分析以确定与RA的关联。随后进行回归分析，考虑到相位不确定性，以确定影响疾病风险的特定单倍型。我们的结果显示，FCGR2A、FCGR2B和FCGR3B与RA无关。与RA易感性关联最强的单倍型是FCGR3A-FCGR3B 158V-NA2单倍型（纯合子与所有基因型相比，优势比为3.18，95%置信区间为1.13-8.92 [P = 0.03]）。在有结节的情况下，这种关联更强（优势比为5.03，95%置信区间为1.44-17.56；P = 0.01）。这种单倍型在北印度/巴基斯坦RA患者中也比在对照个体中更常见，但差异不显著。逻辑回归分析表明，FCGR3A在该基因座上仍然是最显著的基因。与FCGR3A-FCGR3B单倍型关联的增加表明，FCGR3A或FCGR3B内的其他多态性变异，或与该单倍型处于连锁不平衡状态的变异，可能也对疾病发病机制有贡献。
