Abstract 18797: Casein Kinase II (csnk2a2) is Associated With Leucocyte Telomere Shortening and Increased Cardiovascular Disease Risk in Diabetes
The shorter telomere length has been linked to the pathology of cardiovascular disease (CVD) and type 2 diabetes (T2D), and is widely considered as a marker for biological aging. A genome-wide association scan (GWAS) analysis of shorter leucocyte telomere length (LTL) conducted on 1,616 participants from the Sikh Diabetes Study (SDS) identified 338 top independent signals (p<10-4) to be significantly associated with a shorter LTL independent of T2D. Most promising 48 SNPs were further replicated through genotyping in an additional Punjabi Sikh sample (n=2,397). In combined meta-analysis in the Punjabi Sikh populations (n=4,013/1,946 T2D cases), we identified a novel locus in association with LTL at 16q21 represented by an intronic SNP in the CSNK2A2 (p=4.4x10-8). Our findings also revealed an independent association of shorter LTL with T2D and cardio metabolic risk. The mean LTL showed a gradual decline from healthy subjects to individuals with T2D and CHD with respective mean LTL being 2.10 in healthy, 1.95 in T2D, 1.69 in CHD, and 1.59 in T2D+CHD. Interestingly, the telomeric repeat binding factor 1(TRF1) serves as a substrate for CSNK2A2, which phosphorylates and initiates its binding to telomere. CSNK2A2 also interacts with multiple genes and miRNAs in pathway controlling LTL and CVD. To further understand the functional significance of the genetic variation CSNK2A2 and other genes in association with CHD and telomere replication pathway, we analyzed the expression of 84 miRNA in carotid aortic plaque and muscle tissues obtained from CHD patients who had undergone coronary artery bypass graft (CABG) using miScript miRNA Human CVD arrays (Qiagen, Chatsworth, CA). Our initial analysis revealed a significant difference (p<0.05) in expression of miR208 that regulates CSNK2A2. Additionally, expression of miR155 associated with TERF1 and miR1 associated with TERF2 were down-regulated, and expression of miR185/miR27a/miR183- associated with POT1 was elevated in atherosclerotic plaque compared to muscle. Future functional studies may provide clinically important insights on the interplay between genetic variants in CSNK2A2 and other LTL pathway genes and their interaction with miRNA in atherosclerotic tissues for affecting CVD risk in diabetes.
- © 2013 by American Heart Association, Inc.