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.
References
[1]
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460.
[2]
von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends in Biochemical Sciences 27: 339–344.
[3]
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.
[4]
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.
[5]
Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, et al. (2007) Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol 165: 14–21.
[6]
Takubo K, Izumiyama-Shimomura N, Honma N, Sawabe M, Arai T, et al. (2002) Telomere lengths are characteristic in each human individual. ExpGerontol 37: 523–531.
[7]
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.
[8]
Slagboom PE, Droog S, Boomsma DI (1994) Genetic determination of telomere size in humans: a twin study of three age groups. Am J HumGenet 55: 876–882.
[9]
Njajou OT, Cawthon RM, Damcott CM, Wu SH, Ott S, et al. (2007) Telomere length is paternally inherited and is associated with parental lifespan. ProcNatlAcadSciUSA 104: 12135–12139.
[10]
Jeanclos E, Schork NJ, Kyvik KO, Kimura M, Skurnick JH, et al. (2000) Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial. Hypertension 36: 195–200.
[11]
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.
[12]
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.
[13]
Vasa-Nicotera M, Brouilette S, Mangino M, Thompson JR, Braund P, et al. (2005) Mapping of a Major Locus that Determines Telomere Length in Humans. The American Journal of Human Genetics 76: 147–151.
[14]
Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, et al. (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42: 197–199.
[15]
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.
[16]
Prescott J, Kraft P, Chasman DI, Savage SA, Mirabello L, et al. (2011) Genome-wide association study of relative telomere length. PLoSOne 6: e19635.
[17]
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.
[18]
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.
[19]
Mirabello L, Yu K, Kraft P, De Vivo I, Hunter DJ, et al. (2010) The association of telomere length and genetic variation in telomere biology genes. Hum Mutat 31: 1050–1058.
[20]
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.
[21]
Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, et al. (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8: 416–424.
[22]
Vera E, Canela A, Fraga MF, Esteller M, Blasco MA (2008) Epigenetic regulation of telomeres in human cancer. Oncogene 27: 6817–6833.
[23]
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.
[24]
Blasco MA (2007) The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8: 299–309.
[25]
Grewal SI, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301: 798–802.
[26]
Stancheva I (2005) Caught in conspiracy: cooperation between DNA methylation and histone H3K9 methylation in the establishment and maintenance of heterochromatin. BiochemCell Biol 83: 385–395.
[27]
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.
[28]
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.
Shinkai Y, Tachibana M (2011) H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev 25: 781–788.
[31]
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.
[32]
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.
[33]
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.
[34]
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.
[35]
Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, et al. (2006) Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. EnvironHealth Perspect 114: 1547–1552.
[36]
Harmon DL, Shields DC, Woodside JV, McMaster D, Yarnell JW, et al. (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. GenetEpidemiol 17: 298–309.
[37]
Jin G, Huang J, Hu Z, Dai J, Tang R, et al. (2010) Genetic variants in one-carbon metabolism-related genes contribute to NSCLC prognosis in a Chinese population. Cancer 116: 5700–5709.
[38]
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.
[39]
Paul L, Cattaneo M, D’Angelo A, Sampietro F, Fermo I, et al. (2009) Telomere Length in Peripheral Blood Mononuclear Cells Is Associated with Folate Status in Men. The Journal of Nutrition.
[40]
Motoyama N, Naka K (2004) DNA damage tumor suppressor genes and genomic instability. Current Opinion in Genetics & Development 14: 11–16.
[41]
von Zglinicki T, Saretzki G, Ladhoff J, d’Adda di Fagagna F, Jackson SP (2005) Human cell senescence as a DNA damage response. Mechanisms of Ageing and Development 126: 111–117.
[42]
Sunyaev S, Ramensky V, Koch I, Lathe W III, Kondrashov AS, et al. (2001) Prediction of deleterious human alleles. Human Molecular Genetics 10: 591–597.
[43]
Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: 3812–3814.
[44]
Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. NatRevMolCell Biol 6: 838–849.
[45]
Weinberg CR, Shore DL, Umbach DM, Sandler DP (2007) Using Risk-based Sampling to Enrich Cohorts for Endpoints, Genes, and Exposures. American Journal of Epidemiology 166: 447–455.
[46]
Cawthon RM (2009) Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Research 37: e21.
[47]
Xu Z, Taylor JA (2009) SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res 37: W600–W605.
[48]
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.
