Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia

• Published in: Diabetologia Vol. 63; no. 10; pp. 2158 - 2168
• Main Authors: Balcha, Shitaye A., Demisse, Abayneh G., Mishra, Rajashree, Vartak, Tanwi, Cousminer, Diana L., Hodge, Kenyaita M., Voight, Benjamin F., Lorenz, Kim, Schwartz, Stanley, Jerram, Samuel T., Gamper, Arla, Holmes, Alice, Wilson, Hannah F., Williams, Alistair J. K., Grant, Struan F. A., Leslie, R. David, Phillips, David I. W., Trimble, Elisabeth R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2020; Springer Nature B.V
• Subjects: Adolescent; Adult; Age of Onset; Autoantibodies; Autoantibodies - immunology; Autoimmunity; Black People - genetics; C-Peptide - blood; Child; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Drb1 protein; Ethiopia; Female; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotyping; Glutamate decarboxylase; Heritability; Histocompatibility antigen HLA; HLA-DRB1 Chains - genetics; Human Physiology; Humans; Immunogenetics; Immunogenicity; Insulin; Internal Medicine; Major histocompatibility complex; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Peptides; Population studies; Principal Component Analysis; Principal components analysis; Single-nucleotide polymorphism; Young Adult; Zinc Transporter 8 - immunology; Ethiopia; Rural; Autoantibodies; Type 1 diabetes; Africa; Genomes; HLA; Ethiopia
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-020-05229-x

Aims/hypothesis We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations. Methods A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes ( n  = 236, ≤35 years) and control participants ( n  = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants. Results Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16–25 and 26–35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 ( p  = 0.0014) and HLA-DRB1*04 ( p  = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective ( p  < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants ( p  = 1.60 × 10 −7 ). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans. Conclusions/interpretation The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.