title: Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.
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.
  
  
  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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authors.lastname: Saxena
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authors.lastname: Codd
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authors.lastname: Brackett
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authors.lastname: Mirabello
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authors.lastname: Kraft
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
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authors.lastname: Stowell
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authors.lastname: Ralhan
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authors.initials: GS
authors.lastname: Wander
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authors.lastname: Salpea
authors.forename: Jian
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authors.lastname: Gu
authors.forename: Xifeng
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authors.lastname: Wu
authors.forename: Massimo
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authors.lastname: Mangino
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Immaculata
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authors.lastname: De Vivo
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Sharon A
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authors.lastname: Sanghera
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D047390:Casein Kinase II / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007194:India; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D012067:Religion; D016615:Telomere / Q000378:metabolism*; D055815:Young Adult
chemical_list: D047390:Casein Kinase II
keywords: cardiovascular diseases; diabetes mellitus, type 2; genome-wide association study; telomere length