Genome-Wide Association Study Identifies Variants in Casein Kinase II ( CSNK2A2 ) to be Associated With Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort

Background— Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. Methods and Results— Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P <10–6 ) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in theCSNK2A2 gene (β=−0.38;P =4.5×10−8 ). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P <10–5 ) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal inCSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P <0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis.Conclusions— By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.