HLA Class II Genotyping of African American Type 1 Diabetic Patients Reveals Associations Unique to African Haplotypes

Abstract

HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date. Cases were from Children’s Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]). Controls were from the T1DGC and from newborn bloodspot cards. The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans. Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes. Notably, the African-specific “DR3” haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01-DQB1*02:01. Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g. The heterozygous DR4/DR9 genotype, containing the African-derived “DR9” haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations. Disease risk assessment for African Americans differs greatly from risk assessment in European populations. This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened.

Immunogenetics of type 1 diabetes: A comprehensive review

“…The combination of DQA1*05:01 and DQB1*03:02 has not been observed encoded in cis but has been hypothesized to confer very high T1D risk [34]. The other transencoded combination, DQA1:03:01 and DQB1*02:01, is encoded in cis on some haplotypes, particularly in African Americans, and appears to increase risk for T1D on all haplotypes on which it is found [36]. Of note, DQB1*02:01 can only be distinguished from DQB1*02:02 by a polymorphism in exon 3 which does not contribute to the peptide binding groove.…”

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

“…Reported associations between HLA class II haplotypes (DRB1-DQA1-DQB1) and risk of developing T1D are summarized from the literature in Supplemental Table 2 (25,26), and donors were categorized based on whether they carried T1D-protective or T1D-susceptible HLA class II haplotypes (Supplemental Table 3). As expected, the majority of T1D donors possessed at least one of the T1D risk HLA haplotypes, while the majority of controls possessed at least one protective allele (25,26). Despite this enrichment of susceptible HLA donors in T1D subjects, two controls were determined to also carry T1D risk-associated HLA (nPOD 6174 and 6254).…”

Diagnostic Dilemma: Clinical and Histological Abnormalities in a Hispanic Patient With Diabetes

“…The HLA region provides the highest contribution to genetic risk for type 1 diabetes (2). Although the HLA profile observed for this patient is not known to be associated with either risk or protection (2,3), there has been a recent rise in type 1 diabetes incidence among patients with HLA considered to confer lower risk for developing the disease (4). The absence of type 1 diabetes-associated autoantibodies (i.e., glutamic acid decarboxylase, insulinoma-associated protein 2, zinc transporter 8) at the time of study may be attributable to autoantibody loss over time; the absence altogether has been reported in type 1 diabetes in a mere 10% of cases at diagnosis (5).…”