Background The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. Methods In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage. Results There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24). Conclusions Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m 2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone. Diabetes 49:2208-2211, 2000 T ype 2 diabetes has strong genetic and environmental risk factors. Previous studies have shown greater transmission of type 2 diabetes to offspring from mothers than from fathers (1-3), and a significantly higher prevalence of diabetes in offspring of women with diabetes during pregnancy than in offspring of nondiabetic and prediabetic women (2). Intrauterine exposure to diabetes is also associated with a higher prevalence of impaired glucose tolerance in adolescence (4) and with an excess of obesity, especially during the first 20 years of life (5-7). Nevertheless, the effects of intrauterine exposure to diabetes may be confounded by genetic factors. For example, women who develop diabetes at an earlier age might carry more diabetes-susceptibility genes than those who develop diabetes later. Hence, they might transmit greater genetic susceptibility to their offspring.The Pima Indians of Arizona have the world's highest incidence and prevalence of type 2 diabetes (8,9). Both genetic and environmental risk factors contribute to the high rate of diabetes in the Pimas. In Pima Indian children aged 5-19 years, the strongest single risk factor for type 2 diabetes was exposure to diabetes in utero (10). To determine the role of intrauterine diabetic environment, which is in addition to genetic transmission of susceptibility, a sibship study was designed to compare the prevalence of type 2 diabetes and the BMI in Pima Indian siblings born before and after their mother was diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODSData were taken from the longitudinal ...

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Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Objective-To determine the prevalence of diabetes in relation to birth weight in Pima Indians.Design-Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years.Setting-Gila River Indian community, Arizona.

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.

The combination of insulin resistance, dyslipidemia, hypertension, and obesity has been described as a "metabolic syndrome" that is a strong determinant of type 2 diabetes. Factor analysis was used to identify components of this syndrome in 1,918 Pima Indians. Prospective analyses were conducted to evaluate associations of identified factors with incidence of diabetes. Factor analysis identified 4 factors that accounted for 79% of the variance in the original 10 variables. Each of these factors reflected a proposed component of the metabolic syndrome: insulinemia, body size, blood pressure, and lipid metabolism. Among 890 originally nondiabetic participants with follow-up data, 144 developed diabetes in a median follow-up of 4.1 years. The insulinemia factor was strongly associated with diabetes incidence (incidence rate ratio [IRR] for a 1-SD difference in factor scores ‫؍‬ 1.81, P < 0.01). The body size and lipids factors also significantly predicted diabetes (IRR 1.52 and 1.37, respectively, P < 0.01 for both), whereas the blood pressure factor did not (IRR 1.11, P ‫؍‬ 0.20). Identification of four unique factors with different associations with incidence of diabetes suggests that the correlations among these variables reflect distinct metabolic processes, about which substantial information may be lost in the attempt to combine them into a single entity. Diabetes 51:3120 -3127, 2002 T ype 2 diabetes and cardiovascular disease have many risk factors in common, and many of these risk factors are highly correlated with one another (1-3). The relationships among these risk factors may be attributable to a small number of physiological phenomena, perhaps even a single phenomenon. The combination of hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, glucose intolerance, and obesity, particularly central obesity, has been termed the "metabolic syndrome." It has been proposed that this syndrome is a powerful determinant of diabetes and cardiovascular disease (3-6). There are few prospective data, however, on the extent to which this syndrome or its constituent components predict incidence of type 2 diabetes.Factor analysis is a mathematical technique by which a large number of correlated variables can be reduced to fewer "factors" that represent distinct attributes that account for a large proportion of the variance in the original variables. Thus, factor analysis is well suited for identifying components of the metabolic syndrome, and several analyses have been undertaken for this purpose (7-26). Prospective epidemiological studies of factor "scores" from these analyses can further determine relations between components of the metabolic syndrome and incidence of diabetes. In the present study, factor analysis is used to identify components of the metabolic syndrome in Pima Indians, an American Indian population with a high prevalence of type 2 diabetes and obesity (27,28), and relations of these components to incidence of diabetes are examined. RESEARCH DESIGN AND METHODSParticipants and measurements...

Objective-To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications ofnon-insulin dependent diabetes mellitus.Design-Cross sectional and longitudinal analysis of the relation between complications and concomitant results ofthe three tests.Setting-Gila River Indian Community, Arizona. Subjects-Pima Indians (cross sectional, n=960), aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination.Main outcome measures-Development of retinopathy and nephropathy.Results-Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12 0-26 7 and 3 9-4*2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12*6mmol/l; fasting plasma glucose concentration 9-3 mmol/l; glycated haemoglobin (HbAlc) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development ofretinopathy (P < 0.0001) and nephropathy (P<0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P< 0 05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases ofeither complication.Conclusions-These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis ofdiabetes.