A genome-wide association study for rheumatoid arthritis replicates previous HLA and non-HLA associations in a cohort from South Africa

• Published in: Human molecular genetics Vol. 31; no. 24; pp. 4286 - 4294
• Main Authors: Mathebula, Evans M, Sengupta, Dhriti, Govind, Nimmisha, Laufer, Vincent A, Bridges, Jr, S Louis, Tikly, Mohammed, Ramsay, Michèle, Choudhury, Ananyo
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 16.12.2022
• Subjects: Arthritis, Rheumatoid - genetics; Association Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; HLA Antigens - genetics; HLA-DRB1 Chains - genetics; Humans; Lim Kinases - genetics; Polymorphism, Single Nucleotide; South Africa; South Africa
• ISSN: 0964-6906; 1460-2083
• 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.