Genome-Wide Association Study Identifies Variants in Casein Kinase II ( CSNK2A2 ) to be Associated With Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort
Andrew Bjonnes
Jennifer Prescott
Patrick Dib
Praveen Natt
Jacqueline Lane
Megan Lerner
Jackie A. Cooper
Yuanqing Ye
Ka Wah Li
Cécilia G. Maubaret
Veryan Codd
Daniel Brackett
Lisa Mirabello
Peter Kraft
Colin P. Dinney
Donald Stowell
Marvin Peyton
Sarju Ralhan
Gurpreet S. Wander
Narinder K. Mehra
Klelia D. Salpea
Jian Gu
Xifeng Wu
Massimo Mangino
David J. Hunter
Immaculata De Vivo
Steve E. Humphries
Nilesh J. Samani
Timothy D Spector
Sharon A. Savage
Dharambir K. Sanghera
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.
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Shaun Purcell, Benjamin Neale, Kathe Todd-Brown et al.
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Nalini Srinivas, Sivaramakrishna Rachakonda · 2020
- Published
- Jun 01, 2014
- Vol/Issue
- 7(3)
- Pages
- 287-295
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