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

aging

cancer

cardiovascular

genetics

senescence

telomere length

Authors: Richa R. Saxena, Andrew A. Bjonnes, Jennifer J. Prescott, Patrick P. Dib, Praveen P. Natt, Jacqueline J. Lane, Megan M. Lerner, Jackie A JA. Cooper, Yuanqing Y. Ye, Ka Wah KW. Li, Cécilia G CG. Maubaret, Veryan V. Codd, Daniel D. Brackett, Lisa L. Mirabello, Peter P. Kraft, Colin P CP. Dinney, Donald D. Stowell, Marvin M. Peyton, Sarju S. Ralhan, Gurpreet S GS. Wander, Narinder K NK. Mehra, Klelia D KD. Salpea, Jian J. Gu, Xifeng X. Wu, Massimo M. Mangino, David J DJ. Hunter, Immaculata I. De Vivo, Steve E SE. Humphries, Nilesh J NJ. Samani, Tim D TD. Spector, Sharon A SA. Savage, Dharambir K DK. Sanghera
Published: 05/03/2014, Circulation. Cardiovascular genetics

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 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 (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 in CSNK2A2 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.

© 2014 American Heart Association, Inc.
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