Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Yokohama, Japan.
PLoS Genet. 2012 Jan;8(1):e1002455. doi: 10.1371/journal.pgen.1002455. Epub 2012 Jan 26.
Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，可导致多器官损伤。尽管最近的全基因组关联研究（GWAS）有助于发现 SLE 易感性基因，但在亚洲人群中进行的研究较少。在这里，我们报告了一项针对 SLE 的 GWAS 研究，共纳入 891 例 SLE 病例和 3384 例对照，以及在日本人群中进行的 1387 例 SLE 病例和 28564 例对照的多阶段复制研究。考虑到表达数量性状基因座（eQTLs）与自身免疫性疾病的遗传风险有关，我们将 eQTL 研究纳入 GWAS 的结果中。我们观察到，与全基因组 SNP 相比（6.9%），在已知的 SLE 易感位点中，cis-eQTL 阳性位点的富集度更高（30.8%）。此外，我们还发现了一个位于 4q21 的 AF4/FMR2 家族成员 1（AFF1）基因的变异与 SLE 易感性之间的新关联（rs340630；P=8.3×10(-9)，优势比=1.21）。rs340630 的风险 A 等位基因对 AFF1 转录本具有 cis-eQTL 效应，可增强表达水平（P<0.05）。由于 AFF1 转录本在外周血 CD4(+)和 CD19(+)淋巴细胞中表达明显上调，AFF1 的上调可能导致这些淋巴细胞异常，从而导致疾病发作。
