Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Ann Rheum Dis. 2013 Mar;72(3):437-44. doi: 10.1136/annrheumdis-2012-201851. Epub 2012 Aug 17.
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064).
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
在先前的遗传关联研究中，Xq28 区域内包含 IRAK1 和 MECP2 的基因已被确定为系统性红斑狼疮 (SLE) 的风险位点。然而，由于 IRAK1 和 MECP2 之间存在很强的连锁不平衡，目前尚不清楚哪个基因受到导致 SLE 风险的潜在因果变异的影响。
我们在 Xq28 上一个包含 IRAK1、MECP2 和七个相邻基因（L1CAM、AVPR2、ARHGAP4、NAA10、RENBP、HCFC1 和 TMEM187）的约 227kb 区域内精细定位了≥136 个 SNPs，这些 SNPs 与来自四个不同祖先群体的 15783 例病例对照受试者的 SLE 进行关联分析。
在欧洲裔美国人、亚洲人和西班牙裔人群中，多个 SNP 与 SLE 存在强关联，p<5×10(-8)，而在具有非洲血统的受试者中存在一致的关联。其中，6 个 SNP 位于 TMEM187-IRAK1-MECP2 区域，该区域包含所有四个祖先群体共有的常见风险单倍型所包含的潜在因果变异。其中，rs1059702 能最好地解释条件测试中的 Xq28 关联信号，并且在跨祖先群体的荟萃分析中表现出最强的 p 值（p(meta)=1.3×10(-27)，OR=1.43），因此被认为是最有可能的因果变异。rs1059702 的风险等位基因导致 IRAK1 中的 S196F 氨基酸取代，并且先前已经显示其在体外增加 NF-κB 活性。我们还发现，SLE 患者和健康对照者中 rs1059702 的纯合风险基因型与 MECP2 的 mRNA 水平降低相关（p=0.0012 和 p=0.0064），但与 IRAK1 无关。
这些数据表明 IRAK1 和 MECP2 均对 SLE 易感性有贡献。
