The Human Leukocyte Antigen Locus and Susceptibility to Rheumatic Heart Disease in South Asians and Europeans

Abstract

Background. Rheumatic heart disease (RHD) remains an important cause of morbidity and mortality globally. Several reports have linked the disease to the human leukocyte antigen (HLA) locus but with negligible consistency. Methods. We undertook a genome-wide association study (GWAS) of susceptibility to RHD in 1163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1459 Europeans (150 cases; 1309 controls) from the UK Biobank study. For fine-mapping, we used HLA imputation to define classical alleles and amino acid polymorphisms. Results. A single signal situated in the HLA class III region reached genome-wide significance in the South Asians, and replicated in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P=3.48x10-10). While the signal fine-mapped to specific amino acid polymorphisms within HLA-DQB1 and HLA-B, with conditioning, the lead class III variant remained associated with susceptibility (P=3.34x10-4), suggesting an independent effect. Conclusions. A complex HLA signal, likely comprising at least two underlying causal variants, strongly associates with susceptibility to RHD in South Asians and Europeans. Crucially, the involvement of the class III region may partly explain the previous inconsistency, while offering important new insight into pathogenesis.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

“…The MS intrachromosomal model for chromosome 6:p21.32 mapped to the HLA region (chromosome 6:p21.3), which is well characterized in the literature for its dynamic role encoding cell-surface proteins responsible for regulation of the immune system (Dendrou et al, 2018). MS, as well as numerous other conditions including Alzheimer’s disease (AD), type 1 diabetes, and rheumatic heart disease, have been linked to the HLA region (Auckland et al, 2020; Jiang et al, n.d.; R.-C. Lu et al, 2017; Patsopoulos et al, 2013). This highlights the strong genetic effect that combinations of alleles in the HLA region have on disease susceptibility and protection.…”

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals

“…We systematically evaluated 75 candidate genes and loci of interest but found no significant enrichment for genetic associations (Figure 3; eTable 1 in the Supplement). A prior GWAS of 2852 Pacific Islander individuals implicated a variant at the IGH locus on chromosome 14 (rs11846409).…”

“…In RHDGen, this locus replicated ( P < .05/2 independent tests) in admixed African individuals (OR, 1.37; 95% CI, 1.17-1.56; P = 2.38 × 10 −3 ) and in the combined GWAS meta-analysis (OR, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10 −3 ), with a consistent direction of effect to earlier analyses. Pooling these association statistics with those from the Pacific, European, and Indian populations, each risk allele was associated with a 1.2-fold increased risk of disease (OR, 1.23, 95% CI, 1.15-1.31; P = 9.1 × 10 −10 ; Figure 3).…”

“…B, Meta-analysis of associations of previously reported candidate genes and loci in Black African individuals. C, Forest plot for the lead immunoglobulin heavy chain (IGH) variant on chromosome 14 (rs11846409) showing effect size estimates from RHDGen alongside those from previously reported studies . UKB indicates UK Biobank.…”

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†

“…It is also one of the first studies to evaluate the genetic susceptibility of RHD in continental Africans. While other genetic association studies have examined RHD in 4 other populations (Aboriginal Australians, Asians, Europeans, and Oceanians 18 – 20 ), RHDGen is the first to do so in multiple African countries at a large scale. 21 …”