Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus
Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus
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DOI：
10.1002/art.10438
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发表时间：
2002-08-01
影响因子：
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通讯作者：
Kimberly, RP
中科院分区：
文献类型：
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作者：
Edberg, JC;Langefeld, CD;Kimberly, RP
Objective.尽管在病例对照研究中，人Fc γ受体IIA型和IIIA型（分别为Fc γ RIIA和Fc γ RIIIA）的低亲和力等位基因多态性与系统性红斑狼疮（SLE）相关，但这些基因对SLE易感性的相对贡献尚未得到解决。我们采用等位基因特异性聚合酶链反应和基因组DNA直接测序分析了126个SLE多发家系中Fc γ RIIA、Fc γ RIIIA和Fc γ RIIIB等位基因的分布，并在病例对照复制研究中分析了Fc γ RIIA和Fc γ RIIIA。统计学检验显示单核苷酸多态性与SLE之间存在关联。我们在Fc γ RIIIA（单点非参数连锁[NPL] 1.8，P = 0.038;多点NPL 2.7，P = 0.004）和Fc γ RIIA（单点NPL 2.0，P = 0.021;多点NPL 2.6，P = 0.006）位点发现了连锁的证据，但在Fc γ RIIIB位点没有发现。以家族为基础的关联性检验表明，Fc γ RIIIA位点低亲和力F176等位基因的传递增加（传递不平衡检验的比值比[OR] 2.18，P = 0.0005，系谱不平衡检验[PDT]的比值比[OR] 2.18，P = 0.002），但几乎没有证据表明Fc γ RIIA位点等位基因的优先传递（PDT的比值比[OR] 2.18，P = 0.089）。按种族分层显示，在非裔美国人血统和欧裔美国人血统的家庭中，相关的Fc γ RIIIA等位基因优先传递。尽管这些基因之间存在显着的连锁不平衡，但扩展Fc γ受体簇的2-和3-位点单倍型分析并未显示出任何超出单独Fc γ RIIIA观察到的显着关联。在438例SLE患者和219例对照的大型病例对照重复研究中，Fc γ RIIIA提供了Fc γ R-SLE相关性的最强证据（相加模型：VN 176 vs V/F 176 OR 1.51，VN 176 vs F/F 176 OR 1.98，P = 0.007）。据我们所知，这些数据首次证明了Fc γ RIIIA与SLE之间的联系以及基于家族和病例对照的关联。这些数据提供了遗传学证据，支持Fc γ RIIIA基因的生理学相关单核苷酸多态性在这种复杂遗传疾病的病理生理学中的作用。
Objective. Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved.Methods. We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE.Results. We found evidence for linkage at both the FcgammaRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcgammaRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcgammaRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcgammaRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcgammaRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcgammaRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcgamma receptor cluster did not reveal any significant association beyond that observed with FcgammaRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcgammaRIIIA provided the strongest evidence of an FcyR-SLE association (additive model: VN 176 versus V/F 176 OR 1.51, VN 176 versus F/F 176 OR 1.98, P = 0.007).Conclusion. To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcgammaRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcgammaRIIIA gene in the pathophysiology of this complex genetic disease.