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.

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.

OBJECTIVE -To examine the association between adiponectin, a known predictor of diabetes in Pima Indians, and markers of inflammation and endothelial function in nondiabetic subjects and to assess whether these markers predict later diabetes in a case-control study within a longitudinal health study in Pima Indians.RESEARCH DESIGN AND METHODS -Participants with normal glucose tolerance at baseline were selected. Case subjects (who later developed type 2 diabetes), and control subjects (n ϭ 71 pairs) were matched for BMI, age, and sex. Adiponectin, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-␣, phospholipase A2 (sPLA2), soluble E-selectin (SE-selectin), soluble intracellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor (vWF) were measured in baseline samples.RESULTS -Adiponectin was negatively correlated with CRP (r ϭ Ϫ0.25, P Ͻ 0.05), IL-6 (r ϭ Ϫ0.20, P Ͻ 0.05), sPLA2 (r ϭ Ϫ0.22, P Ͻ 0.05), and SE-selectin (r ϭ Ϫ0.20, P Ͻ 0.05). CRP and IL-6 did not predict diabetes. Only vWF predicted the development of diabetes (incidence rate ratio 0.67 for a 1-SD difference, 95% CI 0.41-1.00, P ϭ 0.05), but this was not significant after adjustment for age, glucose, HbA 1c , waist circumference, and fasting insulin (hazard rate ratio 0.73, 95% CI 0.46 -1.16, P ϭ 0.18).CONCLUSIONS -Adiponectin is negatively correlated with markers of inflammation in vivo. In case and control subjects matched for BMI, with the exception of vWF, none of the inflammatory markers predicted diabetes. Adiponectin may be the link between adiposity, inflammation, and type 2 diabetes. Diabetes Care 26:1745-1751, 2003C hronic inflammation has been postulated to play a role in the pathogenesis of type 2 diabetes (1). Crosssectional studies have shown that obesity and insulin resistance are associated with higher levels of markers of inflammation and endothelial function (2-6). Recent prospective studies have shown a relationship between various inflammatory markers, specifically sialic acid, orosomucoid, C-reactive protein (CRP), and interleukin (IL)-6, and the risk of developing type 2 diabetes (7-10). In the Pima Indians of Arizona, elevations in serum immunoglobulins and white blood cell count (WBC) have also been found to predict diabetes (11,12). Adiponectin is a 244 amino acid adipose-specific protein (13) that has been shown to downregulate inflammatory responses in vitro (14,15), but it also improves glucose tolerance and insulin resistance in mouse models of diabetes (16). Adiponectin is related to insulin resistance and adiposity in humans (17,18). Recently, we have shown in the subjects of this report that adiponectin is protective against later development of diabetes (19).We hypothesized that adiponectin might underpin relationships of markers of inflammation, endothelial dysfunction, and obesity and later risk of type 2 diabetes. Therefore, in the same nested case control study mentioned above (19), we examined the relationship of adiponectin to a variety of markers of inflamm...