Identification of seven loci affecting mean telomere length and their association with disease

被引：768

作者：

Codd, Veryan ^{[1
,2
]}

Nelson, Christopher P. ^{[1
,2
]}

Albrecht, Eva ^{[3
]}

Mangino, Massimo ^{[4
]}

Deelen, Joris ^{[5
,6
]}

Buxton, Jessica L. ^{[7
]}

Hottenga, Jouke Jan ^{[8
]}

Fischer, Krista ^{[9
]}

Esko, Tonu ^{[9
]}

Surakka, Ida ^{[10
,11
]}

Broer, Linda ^{[6
,12
,13
]}

Nyholt, Dale R. ^{[14
]}

Leach, Irene Mateo ^{[15
]}

Salo, Perttu ^{[11
]}

Hagg, Sara ^{[16
]}

Matthews, Mary K. ^{[1
]}

Palmen, Jutta ^{[17
]}

Norata, Giuseppe D. ^{[18
,19
,20
]}

O'Reilly, Paul F. ^{[21
,22
]}

Saleheen, Danish ^{[23
,24
]}

Amin, Najaf ^{[12
]}

Balmforth, Anthony J. ^{[25
]}

Beekman, Marian ^{[5
,6
]}

de Boer, Rudolf A. ^{[15
]}

Bohringer, Stefan ^{[26
]}

Braund, Peter S. ^{[1
]}

Burton, Paul R. ^{[27
]}

de Craen, Anton J. M. ^{[28
]}

Denniff, Matthew ^{[1
]}

Dong, Yanbin ^{[29
]}

Douroudis, Konstantinos ^{[9
]}

Dubinina, Elena ^{[1
]}

Eriksson, Johan G. ^{[11
,30
,31
,32
]}

Garlaschelli, Katia ^{[19
]}

Guo, Dehuang ^{[29
]}

Hartikainen, Anna-Liisa ^{[33
]}

Henders, Anjali K. ^{[14
]}

Houwing-Duistermaat, Jeanine J. ^{[6
,26
]}

Kananen, Laura ^{[34
,35
]}

Karssen, Lennart C. ^{[12
]}

Kettunen, Johannes ^{[10
,11
]}

Klopp, Norman ^{[36
,37
]}

Lagou, Vasiliki ^{[38
]}

van Leeuwen, Elisabeth M. ^{[12
]}

Madden, Pamela A. ^{[39
]}

Maegi, Reedik ^{[9
]}

Magnusson, Patrik K. E. ^{[16
]}

Mannisto, Satu ^{[11
]}

McCarthy, Mark I. ^{[38
,40
,41
]}

Medland, Sarah E. ^{[14
]}

机构：

[1] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[2] Glenfield Gen Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England

[3] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[4] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[5] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Leiden, Netherlands

[6] Leiden Univ, Med Ctr, Netherlands Consortium Hlth Aging, Leiden, Netherlands

[7] Univ London Imperial Coll Sci Technol & Med, Sect Invest Med, London, England

[8] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[9] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[10] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[11] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki, Finland

[12] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[13] Ctr Med Syst Biol, Leiden, Netherlands

[14] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[15] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[16] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[17] UCL, Inst Cardiovasc Sci, London, England

[18] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy

[19] Bassini Hosp, Ctr Soc Italiana Studio Aterosclerosi, Cinisello Balsamo, Italy

[20] Queen Mary Univ, Barts & London Sch Med & Dent, Blizard Inst, London, England

[21] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England

[22] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Hlth Protect Agcy Ctr Environm & Hlth, London, England

[23] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[24] Ctr Noncommunicable Dis, Karachi, Pakistan

[25] Univ Leeds, Sch Med, Div Epidemiol, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England

[26] Leiden Univ, Med Ctr, Sect Med Stat, Leiden, Netherlands

[27] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England

[28] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands

[29] Georgia Hlth Sci Univ, Georgia Prevent Inst, Augusta, GA USA

[30] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[31] Folkhalsan Res Ctr, Helsinki, Finland

[32] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland

[33] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu, Finland

[34] Univ Helsinki, Biomedicum Helsinki, Res Programs Unit, Helsinki, Finland

[35] Univ Helsinki, Dept Med Genet, Haartman Inst, Helsinki, Finland

[36] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[37] Hannover Med Sch, Hanover Unified Biobank, Hannover, NH, Germany

[38] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[39] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[40] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[41] Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX3 7LJ, England

[42] Wellcome Trust Sanger Inst, Hinxton, England

[43] Univ Helsinki, Dept Med Genet, Helsinki, Finland

[44] Helsinki Univ Hosp, Helsinki, Finland

[45] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[46] Munich Heart Alliance, Munich, Germany

[47] Natl Inst Hlth & Welf, Oulu, Finland

[48] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[49] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[50] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany

来源：

NATURE GENETICS | 2013年 / 45卷 / 04期

关键词：

CANCER; RISK; ATHEROSCLEROSIS; SUSCEPTIBILITY; HUMANS; TERC; DNA;

D O I：

10.1038/ng.2528

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

引用

页码：422 / 427

页数：6

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