Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans

Abstract

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10 -5). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.

HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Arthritis in Black South Africans

“…Approximately 90% of black South Africans with RA carry at least one allele bearing the SE motif (6). Moreover, in a genome wide association study using the Immunochip SNP array, the HLA region showed the strongest association with RA in this population (7). These findings contrast with studies in other populations of African ancestry, where the frequency of the SE in RA is much lower, 42% in African Americans (8) and only 30% in west Africans from the Cameroon (9).…”

“…Four-digit high resolution HLA typing was performed by DNA sequencing of exon 2, using the AlleleSEQR HLA-DRB1 reagent kit and protocol (Atria Genetics, South San Francisco, CA) as previously described (7). The sequences were analyzed using Assign software (Conexio Genomics, Fremantle, Western Australia, Australia), which enables assignment of genotypes based on a library file of HLA-DRB1 alleles (12).…”

Association of anti-peptidyl arginine deiminase antibodies with radiographic severity of rheumatoid arthritis in African Americans

“…Notably, we have recently shown subtle differences in the association of HLA-DRB1 alleles with RA in African Americans [ 15 ]. Furthermore, not all non-MHC region risk loci identified in European or Asian RA populations are shared with RA in persons of African ancestry, further justifying the need for research on African Americans with RA [ 16 ]. The objectives of this study are therefore: to determine the prevalence of serum anti-PAD4 antibodies (including anti-PAD4/PAD3 cross-reactive antibodies) in African Americans with RA; to describe the temporal changes in anti-PAD4 and anti-PAD4/PAD3 cross-reactive antibody titers; and to compare the radiographic score and radiographic progression of anti-PAD4-positive and anti-PAD4/PAD3-positive African-American patients with those of patients lacking these antibodies.…”

Indonesians Human Leukocyte Antigen (HLA) Distributions and Correlations with Global Diseases

“…• Citrullination can also modify peptide cleavage, enabling retention of autoantigens (Hüffmeier et al 2010;Padyukov et al 2011;Scally et al 2013;Negi et al 2013;Govind et al 2014;Koning et al 2015;Stuart et al 2015;Jiang et al 2016;Wei et al 2017;Laufer et al 2019) HLA-DR4 (risk) Associated SNPs: rs3135002-A, rs2647044-A T1D…”