Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.

Circ Cardiovasc Genet
Authors
Keywords
Abstract

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 (P10(-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 the CSNK2A2 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 (P10(-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 in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P0.001). 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.

Year of Publication
2014
Journal
Circ Cardiovasc Genet
Volume
7
Issue
3
Pages
287-95
Date Published
2014 Jun
ISSN
1942-3268
URL
DOI
10.1161/CIRCGENETICS.113.000412
PubMed ID
24795349
PubMed Central ID
PMC4106467
Links
Grant list
RG/08/008/25291 / British Heart Foundation / United Kingdom
PG08/008 / British Heart Foundation / United Kingdom
R01 DK082766 / DK / NIDDK NIH HHS / United States
R01DK082766 / DK / NIDDK NIH HHS / United States
K01 TW006087 / TW / FIC NIH HHS / United States