Telomere length, a biomarker of aging and age-related diseases, exhibits wide variation between individuals. Common genetic variation may explain some of the individual differences in telomere length. To date, however, only a few genetic variants have been identified in the previous genome-wide association studies. As emerging data suggest epigenetic regulation of telomere length, we investigated 72 single nucleotide polymorphisms (SNPs) in 46 genes that involve DNA and histone methylation as well as telomerase and telomere-binding proteins and DNA damage response. Genotyping and quantification of telomere length were performed in blood samples from 989 non-Hispanic white participants of the Sister Study, a prospective cohort of women aged 35–74 years. The association of each SNP with logarithmically-transformed relative telomere length was estimated using multivariate linear regression. Six SNPs were associated with relative telomere length in blood cells with p-values<0.05 (uncorrected for multiple comparisons). The minor alleles of BHMT rs3733890 G>A (p = 0.041), MTRR rs2966952 C>T (p = 0.002) and EHMT2 rs558702 G>A (p = 0.008) were associated with shorter telomeres, while minor alleles of ATM rs1801516 G>A (p = 0.031), MTR rs1805087 A>G (p = 0.038) and PRMT8 rs12299470 G>A (p = 0.019) were associated with longer telomeres. Five of these SNPs are located in genes coding for proteins involved in DNA and histone methylation. Our results are consistent with recent findings that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. Larger studies with greater coverage of the genes implicated in DNA methylation and histone modifications are warranted to replicate these findings.
Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, et al. (2006) Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 5: 325–330.
Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, et al. (2007) Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. The Lancet 369: 107–114.
Hunt SC, Chen W, Gardner JP, Kimura M, Srinivasan SR, et al. (2008) Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell 7: 451–458.
Andrew T, Aviv A, Falchi M, Surdulescu GL, Gardner JP, et al. (2006) Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J HumGenet 78: 480–486.
Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, et al. (2009) Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proceedings of the National Academy of Sciences 107: 1710–1717.
Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, et al. (2010) Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proceedings of the National Academy of Sciences 107: 9293–9298.
Mangino M, Brouilette S, Braund P, Tirmizi N, Vasa-Nicotera M, et al. (2008) A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans. Human Molecular Genetics 17: 2518–2523.
Mangino M, Richards JB, Soranzo N, Zhai G, Aviv A, et al. (2009) A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. Journal of Medical Genetics 46: 451–454.
Garcia-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA (2004) Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. NatGenet 36: 94–99.
Kim S, Sandler DP, Carswell G, De Roo LA, Parks CG, et al. (2011) Telomere length in peripheral blood and breast cancer risk in a prospective case-cohort analysis: results from the Sister Study. Cancer Causes and Control 22: 1061–1066.
Lee J, Sayegh J, Daniel J, Clarke S, Bedford MT (2005) PRMT8, a New Membrane-bound Tissue-specific Member of the Protein Arginine Methyltransferase Family. Journal of Biological Chemistry 280: 32890–32896.
Najbauer J, Johnson BA, Young AL, Aswad DW (1993) Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. The Journal of biological chemistry 268: 10501–10509.
Selhub J, Miller JW (1992) The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. AmJ ClinNutr 55: 131–138.
Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, et al. (2003) Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease. Atherosclerosis 167: 205–214.
Li F, Feng Q, Lee C, Wang S, Pelleymounter LL, et al. (2008) Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization. MolGenetMetab 94: 326–335.
Mostowska A, Hozyasz KK, Biedziak B, Misiak J, Jagodzinski PP (2010) Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts. EurJ Oral Sci 118: 325–332.
Simarro M, Gimenez-Cassina A, Kedersha N, Lazaro JB, Adelmant GO, et al. (2010) Fast kinase domain-containing protein 3 is a mitochondrial protein essential for cellular respiration. BiochemBiophysResCommun 401: 440–446.
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, et al. (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39: 870–874.