Diabetes in Asian Indians-How much is preventable? Ten-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES-142).

We sought to evaluate the contribution of various modifiable risk factors to the partial population attributable risk (PARp) for diabetes in an Asian Indian population. Of a cohort of 3589 individuals, representative of Chennai, India, followed up after a period of ten years, we analyzed data from 1376 individuals who were free of diabetes at baseline. A diet risk score was computed incorporating intake of refined cereals, fruits and vegetables, dairy products, and monounsaturated fatty acid. Abdominal obesity was found to contribute the most to incident diabetes [Relative Risk (RR) 1.63(95%CI 1.21-2.20)]; (PARp 41.1% (95%CI 28.1-52.6)]. The risk for diabetes increased with increasing quartiles of the diet risk score [highest quartile RR 2.14(95% CI 1.26-3.63)] and time spent viewing television [(RR 1.84(95%CI 1.36-2.49] and sitting [(RR 2.09(95%CI 1.42-3.05)]. The combination of five risk factors (obesity, physical inactivity, unfavorable diet risk score, hypertriglyceridemia and low HDL cholesterol) could explain 80.7% of all incident diabetes (95%CI 53.8-92.7). Modifying these easily identifiable risk factors could therefore prevent the majority of cases of incident diabetes in the Asian Indian population. Translation of these findings into public health practice will go a long way in arresting the progress of the diabetes epidemic in this region.

Forkhead box C2 promoter variant c.-512C>T is associated with increased susceptibility to chronic venous diseases.

Chronic venous disease (CVD) is one of the most prevalent yet underrated disorders worldwide. High heritability estimates of CVD indicate prominent genetic components in its etiology and pathology. Mutations in human forkhead box C2 (FoxC2) gene are strongly associated with valve failure in saphenous and deep veins of lower extremities. We explored the association of genetic variants of FoxC2 as well as FoxC2 mRNA and protein expression levels with CVD of lower limbs. We systematically sequenced the single coding exon, 5' and 3' flanking regions of FoxC2 gene in 754 study subjects which includes 382 patients with CVD and 372 healthy subjects. Four novel and three reported polymorphisms were identified in our cohort. Three variants in 5' flanking region and one in 3' flanking region of FoxC2 gene were significantly associated with CVD risk. FoxC2 mRNA in vein tissues from 22 patients was 4±1.42 fold increased compared to saphenous veins from 20 normal subjects (p<0.01). FoxC2 protein was also significantly upregulated in varicose veins compared to control samples. The c.-512C>T (rs34221221: C>T) variant which is located in the FoxC2 putative promoter region was further analyzed. Functional analysis of c.-512C>T revealed increased mRNA and protein expression in patients with homozygous TT genotype compared to heterozygous CT and wild CC genotypes. Luciferase assay indicated higher transcriptional activity of mutant compared to wild genotype of this variant. These findings suggested that c.-512C>T variant of FoxC2 was strongly associated with susceptibility to CVD and also that this variant resulted in FoxC2 overexpression. To obtain a mechanistic insight into the role of upregulated FoxC2 in varicosities, we overexpressed FoxC2 in venous endothelial cells and observed elevated expression of arterial markers Dll4 and Hey2 and downregulation of venous marker COUP-TFII. Our study indicates altered FoxC2-Notch signaling in saphenous vein wall remodeling in patients with varicose veins.