The incidence of fatal coronary heart disease (CHD) was determined in a population of Pima Indians from the Gila River Indian Community in Arizona. Between 1975 and 1984, 394 deaths occurred among 4,828 subjects aged 5 years or older, and 199 of these occurred in the 1,093 persons with non-insulin-dependent diabetes. Only 28 deaths were attributed to CHD; all occurred among the 689 diabetic persons 45 years of age or older. No CHD deaths occurred among the 419 nondiabetic subjects 45 years of age or older. The rate of fatal CHD among the diabetic subjects was higher in men than in women and increased with advancing age and duration of diabetes. A higher incidence of fatal CHD was associated with proteinuria, renal insufficiency, medial arterial calcification, diabetic retinopathy, insulin therapy, and an abnormal electrocardiogram. In Pima Indians aged 50-79 years, the incidence of fatal CHD was less than half that found in the Framingham population after controlling for age, sex, and diabetes (incidence rate ratio, 0.4; 95% confidence interval, 0.2-0.7). Factors protecting Pima Indians from fatal CHD may include racial heritage, low serum concentrations of total and low density lipoprotein cholesterol, and rarity of heavy smoking. Among the diabetic subjects, mortality from diabetic renal disease, which shows many of the same risk factors, may selectively compete and remove those at risk for fatal CHD. This would not, however, explain the lack of fatal CHD among the nondiabetic subjects. Fatal CHD shares many of the risk factors associated with the specific microvascular complications of diabetes, and diabetes and its associated attributes are the major predictors of fatal CHD in this population. (Circulation 1990;81:987-995) A therosclerotic coronary heart disease (CHD) occurs more frequently in persons with diabetes mellitus than in those without it1,2 and is the most common underlying cause of death in diabetic adults in the United States.2 Although the Pima Indians of the Gila River Indian Community in Arizona have the world's highest reported prevalence of non-insulin-dependent diabetes,3 they have a low frequency of clinically apparent myocardial infarction4 and a low prevalence of electrocardiographic (ECG) and necropsy-proven CHD.4-6 In the present study, the incidence of CHD as an underlying cause of death was determined in the Pima Indians with and without non-insulindependent diabetes. Risk factors for CHD death were identified, and the incidence of fatal CHD was compared with that of the primarily caucasian population participating in the Framingham study.7Methods A longitudinal study of diabetes and its complications has been conducted in the Gila River Indian

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Type 2, non-insulin-dependent diabetes mellitus accounts for 60% of the end-stage renal disease attributed to diabetes in the United States, yet little is known about glomerular function or the development of renal disease in this type of diabetes. The Diabetic Renal Disease Study (DRDS) is a longitudinal study designed to elucidate the natural history of renal disease and to characterize glomerular function throughout the course of renal disease in type 2, non-insulin-dependent diabetes mellitus. The study is being conducted among the Pima Indians from the Gila River Indian Community in Arizona because they experience a very high rate of type 2 diabetes mellitus, which often develops at a young age and which is frequently associated with the development of renal disease. Glomerular filtration rate, renal plasma flow, albumin and IgG excretion, level of vasoactive hormones, retinal damage, and glomerular capillary permeability to dextrans of different sizes will be assessed at regular intervals over 48 months in six groups of subjects representing a range of glucose tolerance from normal to diabetes, and among the diabetic subjects, a range of proteinuria from normal to overt diabetic nephropathy. The DRDS is designed to provide new information on the functional determinants of renal disease in type 2, non-insulin-dependent diabetes mellitus and will serve as the basis for designing intervention strategies.

A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), which is the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p≤x10-8 and fold change ±2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by in silico functional data, and replication where possible, include; AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals, has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.