HLA class II gene associations in African American Type 1 diabetes reveal a protective HLA‐DRB1*03 haplotype

Abstract

AimsOwing to strong linkage disequilibrium between markers, pinpointing disease associations within genetic regions is difficult in European ancestral populations, most notably the very strong association of the HLA-DRB1*03-DQA1*05:01-DQB1*02:01 haplotype with Type 1 diabetes risk, which is assumed to be because of a combination of HLA-DRB1 and HLA-DQB1. In contrast, populations of African ancestry have greater haplotype diversity, offering the possibility of narrowing down regions and strengthening support for a particular gene in a region being causal. We aimed to study the human leukocyte antigen (HLA) region in African American Type 1 diabetes.MethodsTwo hundred and twenty-seven African American patients with Type 1 diabetes and 471 African American control subjects were tested for association at the HLA class II genes, HLA-DRB1, HLA-DQA1, HLA-DQB1 and 5147 single nucleotide polymorphisms across the major histocompatibility complex region using logistic regression models. Population admixture was accounted for with principal components analysis.ResultsSingle nucleotide polymorphism marker associations were explained by the HLA associations, with the major peak over the class II loci. The HLA association overall was extremely strong, as expected for Type 1 diabetes, even in African Americans in whom diabetes diagnosis is heterogeneous. In addition, there were unique features: the HLA-DRB1*03 haplotype was split into HLA-DRB1*03:01, which confers greatest susceptibility in these samples (odds ratio 3.17, 95% CI 1.72–5.83) and HLA-DRB1*03:02, an allele rarely observed in Europeans, which confers the greatest protection in these African American samples (odds ratio 0.22, 95% CI 0.09–0.55).ConclusionsThe unique diversity of the African HLA region we have uncovered supports a specific and major role for HLA-DRB1 in HLA-DRB1*03 haplotype-associated Type 1 diabetes risk.

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

“…Furthermore, associations for T1D are stronger at HLA class II ( HLA-DRB1 , -DQA1 , and - DQB1 ) than HLA class I regions in Europeans [33]–[34], [38]–[41] (http://www.t1dbase.org). In African Americans, T1D individuals showed both shared and unique risk and protective HLA class II haplotypes as compared to European T1D individuals [42]–[43]. More importantly, these individuals also showed substantially stronger associations at HLA class II ( P <1×10 −25 ) than class I regions ( P <1×10 −5 ) [42], which is in contradiction with our finding of stronger associations at HLA class I than class II regions in T2D individuals ( HLA - B , Figure S4).…”

“…In African Americans, T1D individuals showed both shared and unique risk and protective HLA class II haplotypes as compared to European T1D individuals [42]–[43]. More importantly, these individuals also showed substantially stronger associations at HLA class II ( P <1×10 −25 ) than class I regions ( P <1×10 −5 ) [42], which is in contradiction with our finding of stronger associations at HLA class I than class II regions in T2D individuals ( HLA - B , Figure S4). The observed HLA-B association may be due to LD with nearby causal gene(s) since there is long range LD in this region.…”

Immunogenetics of type 1 diabetes: A comprehensive review

“…However, a closely-related version of DR7, DRB1*07:01-DQA1*03:01-DQB1*02:02, found in African populations, is not protective for T1D but is, in fact, predisposing for T1D [36,68,69]. Similarly, an African-Specific DR3, DRB1*03:02-DQA1*04:01-DQB1*04:02, has the opposite T1D susceptibility effect (protection) to that of the common, predisposing DR3 haplotype, DRB1*03:01-DQA1*05:01-DQB1*02:01, seen in most other populations [36,70]. The opposite effects of European and African DR3 and DR7 haplotypes are illustrated in Table 5.…”

Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans

“…The differences in peptide binding affinities of the DR3 proteins encoded by *03:01 and *03:02 alleles may explain the observed differences in disease associations for these alleles. In African Americans, *03:02 confers protection against type I diabetes, whereas *03:01 increases risk (48). DRB1*03:01 is a strong risk factor for systemic erythematous lupus in whites (49), but neither *03:01 nor *03:02 confers risk for systemic erythematous lupus in African Americans (50).…”