Salmon J E, Millard S, Schachter L A, Arnett F C, Ginzler E M, Gourley M F, Ramsey-Goldman R, Peterson M G, Kimberly R P
Department of Medicine, Graduate Program in Immunology, The Cornell University Medical College, New York 10021, USA.
J Clin Invest. 1996 Mar 1;97(5):1348-54. doi: 10.1172/JCI118552.
Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.
FcγR的等位基因变体具有不同的吞噬能力，为免疫复合物疾病的遗传性易感性提供了一种机制。人类FcγRIIa有两个共显性表达的等位基因，R131和H131，它们在连接人IgG2的能力上有很大差异。FcγRIIa-H131是唯一能有效识别IgG2的人类FcγR，只有在纯合状态下才会出现最佳的IgG2处理。因此，由于免疫复合物清除在系统性红斑狼疮（SLE）中至关重要，我们假设FcγRIIA基因是SLE，特别是狼疮性肾炎的重要疾病易感性因素。在一项两阶段横断面研究中，我们比较了患有SLE的非裔美国人与非SLE的非裔美国对照中FcγRIIA等位基因的分布。一项对43名SLE患者和39名对照的初步研究表明，FcγRIIA等位基因分布存在偏差，只有9%的SLE患者为FcγRIIa-H131纯合子，而对照为36%（优势比，0.18；95%可信区间，0.05-0.69，P = 0.009）。这在一项对214名SLE患者和100名非SLE对照的多中心研究中得到了证实。FcγRIIA等位基因分布的改变在狼疮性肾炎中最为显著。基因型分布的趋势分析显示，随着狼疮性肾炎可能性的增加，FcγRIIA-H131显著减少（P = 0.0004），这与FcγRIIA-H131基因的保护作用一致。FcγRIIA等位基因分布的偏差表明该基因是对非裔美国人SLE素质具有病理生理重要性的危险因素。
