Division of Human Genetics, School of Pathology and National Health Laboratory Services, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2000, South Africa.
Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa.
Hum Mol Genet. 2022 Dec 16;31(24):4286-4294. doi: 10.1093/hmg/ddac178.
The complex pathogenesis of rheumatoid arthritis (RA) is not fully understood, with few studies exploring the genomic contribution to RA in patients from Africa. We report a genome-wide association study (GWAS) of South-Eastern Bantu-Speaking South Africans (SEBSSAs) with seropositive RA (n = 531) and population controls (n = 2653). Association testing was performed using PLINK (logistic regression assuming an additive model) with sex, age, smoking and the first three principal components as covariates. The strong association with the Human Leukocyte Antigen (HLA) region, indexed by rs602457 (near HLA-DRB1), was replicated. An additional independent signal in the HLA region represented by the lead SNP rs2523593 (near the HLA-B gene; Conditional P-value = 6.4 × 10-10) was detected. Although none of the non-HLA signals reached genome-wide significance (P < 5 × 10-8), 17 genomic regions showed suggestive association (P < 5 × 10-6). The GWAS replicated two known non-HLA associations with MMEL1 (rs2843401) and ANKRD55 (rs7731626) at a threshold of P < 5 × 10-3 providing, for the first time, evidence for replication of non-HLA signals for RA in sub-Saharan African populations. Meta-analysis with summary statistics from an African-American cohort (CLEAR study) replicated three additional non-HLA signals (rs11571302, rs2558210 and rs2422345 around KRT18P39-NPM1P33, CTLA4-ICOS and AL645568.1, respectively). Analysis based on genomic regions (200 kb windows) further replicated previously reported non-HLA signals around PADI4, CD28 and LIMK1. Although allele frequencies were overall strongly correlated between the SEBSSA and the CLEAR cohort, we observed some differences in effect size estimates for associated loci. The study highlights the need for conducting larger association studies across diverse African populations to inform precision medicine-based approaches for RA in Africa.
类风湿关节炎（RA）的复杂发病机制尚未完全阐明，很少有研究探讨非洲患者的基因组对 RA 的贡献。我们报告了一项针对东南班图语南非人（SEBSSA）血清阳性 RA（n=531）和人群对照（n=2653）的全基因组关联研究（GWAS）。使用 PLINK（假设加性模型的逻辑回归）进行关联测试，性别、年龄、吸烟和前三个主成分作为协变量。与人类白细胞抗原（HLA）区域的强关联，由 rs602457（靠近 HLA-DRB1）表示，得到了复制。在 HLA 区域中检测到一个由领先 SNP rs2523593（靠近 HLA-B 基因；条件 P 值=6.4×10-10）表示的额外独立信号。尽管没有一个非 HLA 信号达到全基因组显著性（P<5×10-8），但 17 个基因组区域显示出提示性关联（P<5×10-6）。GWAS 复制了与 MMEL1（rs2843401）和 ANKRD55（rs7731626）的两个已知非 HLA 关联，在 P<5×10-3 的阈值下提供了撒哈拉以南非洲人群中 RA 非 HLA 信号复制的首次证据。与来自非裔美国人队列（CLEAR 研究）的汇总统计数据进行的荟萃分析复制了另外三个非 HLA 信号（rs11571302、rs2558210 和 rs2422345，分别位于 KRT18P39-NPM1P33、CTLA4-ICOS 和 AL645568.1 附近）。基于基因组区域（200 kb 窗口）的分析进一步复制了先前报道的 PADI4、CD28 和 LIMK1 周围的非 HLA 信号。尽管等位基因频率在 SEBSSA 和 CLEAR 队列之间总体上高度相关，但我们观察到与相关基因座相关的效应大小估计值存在一些差异。该研究强调需要在不同的非洲人群中进行更大规模的关联研究，以为非洲的 RA 提供基于精准医学的方法。
