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

Codd, Veryan; Nelson, Christopher P.; Albrecht, Eva; Mangino, Massimo; Deelen, Joris; Buxton, Jessica L.; Hottenga, Jouke Jan; Fischer, Krista; Esko, Tõnu; Surakka, Ida; Broer, Linda; Nyholt, Dale R.; Leach, Irene Mateo; Salo, Perttu; Hägg, Sara; Matthews, Mary K; Palmen, Jutta; Norata, Giuseppe Danilo; O’Reilly, Paul F.; Saleheen, Danish; Amin, Najaf; Balmforth, Anthony J.; Beekman, Marian; Boer, Rudolf A. de; Böhringer, Stefan; Braund, Peter S.; Burton, Paul R.; Craen, Anton J. M. de; Denniff, Matthew; Dong, Yanbin; Douroudis, Konstantinos; Dubinina, E. E.; Eriksson, Johan G.; Garlaschelli, K.; Guo, Dadong; Hartikainen, Anna-Liisa; Henders, Anjali K.; Houwing-Duistermaat, Jeanine J.; Kananen, Laura; Karssen, Lennart C.; Kettunen, Johannes; Klopp, Norman; Lagou, Vasiliki; Leeuwen, Elisabeth M. van; Madden, Pamela A. F.; Mägi, Reedik; Magnusson, Patrik K. E.; Männistö, Satu; McCarthy, Mark I.; Medland, Sarah E.; Mihailov, Evelin; Montgomery, Grant W.; Oostra, Ben A.; Palotie, Aarno; Peters, Annette; Pollard, Helen Perlstein; Pouta, Anneli; Prokopenko, Inga; Ripatti, Samuli; Salomaa, Veikko; Suchiman, H. Eka D.; Valdes, Ana M.; Verweij, Niek; Viñuela, Ana; Wang, Xiaoling; Wichmann, H‐Erich; Widén, Elisabeth; Willemsen, Gonneke; Wright, Margaret J.; Xia, Kai; Xiao, Xiangjun; Veldhuisen, Dirk J. van; Catapano, Alberico L.; Tobin, Martin D.; Hall, Alistair S.; Blakemore, Alexandra I. F.; Gilst, Wiek H. van; Zhu, Haidong; Erdmann, Jeanette; Reilly, Muredach P; Kathiresan, Sekar; Schunkert, Heribert; Talmud, Philippa J.; Pedersen, Nancy L.; Perola, Markus; Ouwehand, Willem H.; Kaprio, Jaakko; Martin, Nicholas G.; Duijn, Cornelia M. van; Hovatta, Iiris; Gieger, Christian; Metspalu, Andres; Boomsma, Dorret I.; Järvelin, Marjo‐Riitta; Slagboom, P. Eline; Thompson, John R.; Spector, Tim D.; Harst, Pim van der; Samani, Nilesh J.

doi:10.1038/ng.2528

Cited by 804 publications

(999 citation statements)

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“…The effect size of telomere length predicting disease is likely small, so these differences in study design would easily obscure effects. Confidence that telomeres are important to disease pathogenesis is increasing with recent Mendelian randomization studies demonstrating that genetic variants associated with shorter telomeres are associated with cardiovascular, pulmonary, and Alzheimer's diseases (23,24) and a recent meta-analysis that includes prospective associations between telomere length and cardiovascular disease (7). Considering the continued debate, however, there remains a significant need for more prospective, meta-analytic, and Mendelian randomization studies with nationally representative populations with other diseases and mortality as outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Puterman

Gemmill

Karasek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

102

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Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging. cellular aging | telomeres | lifespan adversity | childhood adversity A ging cells play a crucial role in the pathogenesis of noncommunicable diseases, and telomere shortening in cells plays a part of this aging process (1, 2). Telomeres are DNAprotein caps at the ends of chromosomes that protect genetic material from degradation, and their lengths indicate cellular aging (2, 3). Experiments in rodents implicate shortened telomeres and lower activity of telomerase, the enzyme that lengthens telomeres, as causes of mitochondrial and tissue damage associated with disease pathogenesis (4-6).Telomere length is linked cross-sectionally and prospectively with human disease states in many studies. A recent meta-analysis suggests that individuals with observed short leukocyte telomeres are at an ∼80% increased risk of concurrent reports of cardiovascular disease and an ∼40% increased risk of developing cardiovascular disease in the future (7). Other recent meta-analyses support the concurrent associations between short telomeres and diabetes (8) and several cancers (9, 10). Several studies indicate that short telomeres from varied sources, including leukocytes and saliva, are related to early mortality (11-17), including a study with >60,000 adults (18), although null studies also exist (19)(20)(21)(22).Although these studies suggest that telomere length plays a role in disease, they are observational, and studies directly linking genetics...

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Section: Discussionmentioning

confidence: 99%

“…They showed that common sequence variants of seven genes that directly regulate telomere maintenance, summed as a genetic risk score, significantly increase risks for cardiovascular, pulmonary (23), and Alzheimer's diseases (24).…”

mentioning

confidence: 99%

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Puterman

Gemmill

Karasek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

141

102

View full text Add to dashboard Cite

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“…Moreover polymorphic variants in both TERT and TERC have been consistently associated with telomere length measured in leukocytes (LTL), 35,36 which in turn is a putative What's new? A critical element of cancer cell immortality is the maintenance of telomere length, a process that is influenced in part by genetic variations in telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC).…”

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confidence: 99%

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Campa

Martino

Várkonyi

et al. 2014

Intl Journal of Cancer

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Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.

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“…In humans, Mendelian singlegene mutations that directly compromise telomere maintenance cause premature mortality and onset of a spectrum of diseases overlapping with the age-related diseases common in the population (4). In addition, genome-wide association studies show that certain combinations of SNPs at genetic loci encoding known telomere-maintenance factors are associated with increased relative risks for pulmonary and coronary diseases (5). Shorter telomere length (TL) in white blood cells is linked and, in some cases, anticipates aging-related morbidity and mortality from conditions with immune system involvement, such as infectious diseases, cancer, and cardiovascular diseases, as well as risk factors, including hypertension, diabetes, obesity, and smoking (6-9).…”

mentioning

confidence: 99%

Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources

Zalli

Carvalho

Lin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

113

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Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. The combination of shorter telomeres with high telomerase activity (TA) may be indicative of active cell stress. We hypothesized that older individuals characterized by shorter telomeres with high TA in unstimulated leukocytes would show signs of high allostatic load and low levels of protective psychosocial resources. We studied 333 healthy men and women aged 54-76 y who underwent laboratory testing in which we measured cardiovascular, neuroendocrine, and inflammatory responses to standardized mental stress tasks. The tasks elicited prompt increases in blood pressure (BP), heart rate, cortisol, and mediators of inflammation and reductions in heart rate variability, returning toward baseline levels following stress. However, men having shorter telomeres with high TA showed blunted poststress recovery in systolic BP, heart rate variability, and monocyte chemoattractant protein-1, together with reduced responsivity in diastolic BP, heart rate, and cortisol, in comparison to men with longer telomeres or men with shorter telomeres and low TA. Shorter telomeres with high TA were also associated with reduced social support, lower optimism, higher hostility, and greater early life adversity. These effects were independent of age, socioeconomic status, and body mass index. We did not observe differences among older women. Our findings suggest that active cell stress is associated with impaired physiological stress responses and impoverished psychosocial resources, reflecting an integration of cellular, systemic, and psychological stress processes potentially relevant to health in older men. cellular senescence | allostasis | psychological distress T elomeres are nucleoprotein structures composed of tandem hexanucleotide repeats of the sequence TTAGGG that cap the ends of eukaryotic chromosomes, protecting them from end-to-end fusion and degradation during cell division. Human telomeric DNA naturally shortens with age during somatic cell divisions and as a result of oxidative attack (1, 2). At critical shortness, telomeres exhibit impaired function, leading to genomic instability, apoptosis, and cell senescence, often with altered transcriptional programming and mitochondrial dysfunction (1). Telomere attrition represents one of the hallmarks of aging (3). In humans, Mendelian singlegene mutations that directly compromise telomere maintenance cause premature mortality and onset of a spectrum of diseases overlapping with the age-related diseases common in the population (4). In addition, genome-wide association studies show that certain combinations of SNPs at genetic loci encoding known telomere-maintenance factors are associated with increased relative risks for pulmonary and coronary diseases (5). Shorter telomere length (TL) in white blood cells is linked and, in some cases, anticipates aging-related morbidity and mortality from conditions with immune system involvement, such as infectious disease...

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

Cited by 804 publications

References 52 publications

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources

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