title: The association of telomere length and genetic variation in telomere biology genes.
abstract: Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA. mirabellol@mail.nih.gov
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Immaculata
authors.initials: I
authors.lastname: De Vivo
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Jennifer
authors.initials: J
authors.lastname: Prescott
authors.forename: Jason Y Y
authors.initials: JY
authors.lastname: Wong
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000328:Adult; D000368:Aged; D005189:False Positive Reactions; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*