Abstract
Aims/hypothesisWe 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.MethodsA 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.ResultsPatients 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/interpretationThe 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.
Highlights
Type 1 diabetes is poorly characterised in many low- and middle-income countries of sub-Saharan Africa; there has been uncertainty about whether its pathogenesis is similar to the classic form of the disease found in industrialised countries
Striking phenotypic differences from the classic form of type 1 diabetes have been reported from several locations in sub-Saharan Africa; these include a low incidence in the pre-pubertal years with an age-specific peak in the third decade [1, 2], strong associations with low socioeconomic status [3], skewing of sex ratios with male predominance in some settings [4] and reported low autoantibody prevalence, suggesting a diminished role for autoimmune mechanisms in its aetiology compared with classic type 1 diabetes [5,6,7]
10−6) (ESM Table 3); no type 2 diabetes-associated loci achieved significance (ESM Table 4). This detailed study of consecutive, unselected, newly diagnosed patients in an impoverished, mainly rural population in sub-Saharan Africa shows that the majority have low C
Summary
Type 1 diabetes is poorly characterised in many low- and middle-income countries of sub-Saharan Africa; there has been uncertainty about whether its pathogenesis is similar to the classic form of the disease found in industrialised countries. The widespread experience of undernutrition in some areas of sub-Saharan Africa, taken in conjunction with the low levels of islet-cell autoimmunity in many historic reports from Africa [5,6,7], has raised the possibility that insulin-dependent diabetes in these populations may have a nutritional origin. Those with the lowest BMIs (15–16 kg/m2) were said to have ‘protein-deficient pancreatic diabetes’ [19], a type of malnutrition-related diabetes which has since been removed from WHO classifications. There is agreement that environmental factors are important, it is not easy to prove their aetiological significance in type 1 diabetes, probably because genetic factors are stable and environmental factors change with time
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