Abstract
T1DM results from the interaction of genetic and environmental factors; the classical phenotype has been based largely on people of European background. However, Africa is a continent of enormous genetic diversity and extreme environmental conditions; do these differences have an impact on the T1DM phenotype? A consecutive series of recently diagnosed insulin-dependent diabetic subjects (n=236, ≤35 years) and controls (n=200), were recruited from the ethnic Amhara of rural NW Ethiopia. We assessed their demographic and socio-economic characteristics, measured non-fasting C-peptide, diabetes-associated autoantibodies, and HLA-DRB1 alleles. With genome-wide genotyping we performed principal component analysis (PCA) and a genome-wide association study (GWAS), and calculated a T1DM genetic risk scores (GRS) to compare their genetic background with known European T1DM determinants. Patients presented with low BMI, stunted growth, and were insulin sensitive; only 15.3% had diabetes onset ≤15 years. C-peptide levels were low but not absent (P=0.03). 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 GADA as a single antibody; the prevalence of IA-2A and ZnT8A was low in all age groups. PCA showed that the Amhara genomes falls between those of ancestral European and ancestral African genomes. HLA-DRB1*03:01 and HLA-DRB1*04 were positively associated with diabetes while HLA-DRB1*15 was protective (P<0.0008 for each). The mean T1DM GRS (derived from European data) was higher in patients than controls (P=1.50x10-6). Autoantibody positive patients showed suggestive GWAS significance (P<5x10-6) with SNPs in the MHC region known to explain half of the T1DM heritability in Europeans. Thus, insulin-dependent diabetes in rural Ethiopia does have the immunogenetic characteristics of T1DM. The phenotypic differences between T1DM in rural Ethiopia and the industrialized world could be due, at least in part, to chronic undernourishment. Disclosure E.R. Trimble: None. S.A. Balcha: None. A.G. Demisse: None. D.L. Cousminer: None. R. Mishra: Employee; Self; GlaxoSmithKline plc. B.F. Voight: None. K. Lorenz: None. T. Vartak: None. S.T. Jerram: None. K.M. Hodge: None. S. Schwartz: Advisory Panel; Self; Intarcia Therapeutics, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Salix Pharmaceuticals. A. Holmes: None. A. Gamper: Stock/Shareholder; Self; GlaxoSmithKline plc., Unilever. H.F. Wilson: None. A.J. Williams: None. R.D. Leslie: None. S.F. Grant: None. D.I.W. Phillips: None. Funding American Diabetes Association (1-17-PDF-077 to D.L.C.); Association of Physicians of Great Britain and Ireland; National Institutes of Health (1K99HD099330-01, R01DK085212); Diabetes UK
Published Version
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