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

Abstract

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.

Keywords: Africa; Autoantibodies; Ethiopia; Genomes; HLA; Rural; Type 1 diabetes.

Fig. 1

PC analysis. (a) The first two PCs (PCs 1 and 2). (b) The second and third PCs (PCs 2 and 3). These are based on genome-wide genotypes of the Ethiopian (Amhara) participants compared with 1000 Genomes ancestral groups. AFR, African; AMR, Americas. EAS, East Asian. ETP, Ethiopian; EUR, European; SAS, Southeast Asian

Fig. 2

Box and whisker plot showing GRS for type 1 diabetes. The GRS was calculated using 19 established type 1 diabetes-associated SNPs of European background; variants, risk alleles and weights are listed in ESM Table 1 (see the Methods/Statistical analysis section for details). Diabetic patients were compared with control participants: autoantibody-positive cases (AA⁺) (n = 121, vs controls, p = 1.54 × 10⁻⁹), all cases (n = 187, vs controls, p = 1.6 × 10⁻⁷), autoantibody-negative cases (AA⁻) (n = 66, vs controls, p = NS) and control participants (n = 137). The vertical lines denote the maximum and minimum values