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Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.
Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.
Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.
Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.
Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.
Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.
Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).
Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGerm-Line Mutation10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aNeoplasms10aPolymorphism, Single Nucleotide10aRisk Assessment10aTelomere10aTelomere Homeostasis1 aTelomeres Mendelian Randomization Collaboration1 aHaycock, Philip, C1 aBurgess, Stephen1 aNounu, Aayah1 aZheng, Jie1 aOkoli, George, N1 aBowden, Jack1 aWade, Kaitlin, Hazel1 aTimpson, Nicholas, J1 aEvans, David, M1 aWilleit, Peter1 aAviv, Abraham1 aGaunt, Tom, R1 aHemani, Gibran1 aMangino, Massimo1 aEllis, Hayley, Patricia1 aKurian, Kathreena, M1 aPooley, Karen, A1 aEeles, Rosalind, A1 aLee, Jeffrey, E1 aFang, Shenying1 aChen, Wei, V1 aLaw, Matthew, H1 aBowdler, Lisa, M1 aIles, Mark, M1 aYang, Qiong1 aWorrall, Bradford, B1 aMarkus, Hugh, Stephen1 aHung, Rayjean, J1 aAmos, Chris, I1 aSpurdle, Amanda, B1 aThompson, Deborah, J1 aO'Mara, Tracy, A1 aWolpin, Brian1 aAmundadottir, Laufey1 aStolzenberg-Solomon, Rachael1 aTrichopoulou, Antonia1 aOnland-Moret, Charlotte, N1 aLund, Eil1 aDuell, Eric, J1 aCanzian, Federico1 aSeveri, Gianluca1 aOvervad, Kim1 aGunter, Marc, J1 aTumino, Rosario1 aSvenson, Ulrika1 avan Rij, Andre1 aBaas, Annette, F1 aBown, Matthew, J1 aSamani, Nilesh, J1 avan t'Hof, Femke, N G1 aTromp, Gerard1 aJones, Gregory, T1 aKuivaniemi, Helena1 aElmore, James, R1 aJohansson, Mattias1 aMckay, James1 aScelo, Ghislaine1 aCarreras-Torres, Robert1 aGaborieau, Valerie1 aBrennan, Paul1 aBracci, Paige, M1 aNeale, Rachel, E1 aOlson, Sara, H1 aGallinger, Steven1 aLi, Donghui1 aPetersen, Gloria, M1 aRisch, Harvey, A1 aKlein, Alison, P1 aHan, Jiali1 aAbnet, Christian, C1 aFreedman, Neal, D1 aTaylor, Philip, R1 aMaris, John, M1 aAben, Katja, K1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aWiencke, John, K1 aWalsh, Kyle, M1 aWrensch, Margaret1 aRice, Terri1 aTurnbull, Clare1 aLitchfield, Kevin1 aPaternoster, Lavinia1 aStandl, Marie1 aAbecasis, Goncalo, R1 aSanGiovanni, John, Paul1 aLi, Yong1 aMijatovic, Vladan1 aSapkota, Yadav1 aLow, Siew-Kee1 aZondervan, Krina, T1 aMontgomery, Grant, W1 aNyholt, Dale, R1 avan Heel, David, A1 aHunt, Karen1 aArking, Dan, E1 aAshar, Foram, N1 aSotoodehnia, Nona1 aWoo, Daniel1 aRosand, Jonathan1 aComeau, Mary, E1 aBrown, Mark1 aSilverman, Edwin, K1 aHokanson, John, E1 aCho, Michael, H1 aHui, Jennie1 aFerreira, Manuel, A1 aThompson, Philip, J1 aMorrison, Alanna, C1 aFelix, Janine, F1 aSmith, Nicholas, L1 aChristiano, Angela, M1 aPetukhova, Lynn1 aBetz, Regina, C1 aFan, Xing1 aZhang, Xuejun1 aZhu, Caihong1 aLangefeld, Carl, D1 aThompson, Susan, D1 aWang, Feijie1 aLin, Xu1 aSchwartz, David, A1 aFingerlin, Tasha1 aRotter, Jerome, I1 aCotch, Mary, Frances1 aJensen, Richard, A1 aMunz, Matthias1 aDommisch, Henrik1 aSchaefer, Arne, S1 aHan, Fang1 aOllila, Hanna, M1 aHillary, Ryan, P1 aAlbagha, Omar1 aRalston, Stuart, H1 aZeng, Chenjie1 aZheng, Wei1 aShu, Xiao-Ou1 aReis, Andre1 aUebe, Steffen1 aHüffmeier, Ulrike1 aKawamura, Yoshiya1 aOtowa, Takeshi1 aSasaki, Tsukasa1 aHibberd, Martin, Lloyd1 aDavila, Sonia1 aXie, Gang1 aSiminovitch, Katherine1 aBei, Jin-Xin1 aZeng, Yi-Xin1 aFörsti, Asta1 aChen, Bowang1 aLandi, Stefano1 aFranke, Andre1 aFischer, Annegret1 aEllinghaus, David1 aFlores, Carlos1 aNoth, Imre1 aMa, Shwu-Fan1 aFoo, Jia, Nee1 aLiu, Jianjun1 aKim, Jong-Won1 aCox, David, G1 aDelattre, Olivier1 aMirabeau, Olivier1 aSkibola, Christine, F1 aTang, Clara, S1 aGarcia-Barcelo, Merce1 aChang, Kai-Ping1 aSu, Wen-Hui1 aChang, Yu-Sun1 aMartin, Nicholas, G1 aGordon, Scott1 aWade, Tracey, D1 aLee, Chaeyoung1 aKubo, Michiaki1 aCha, Pei-Chieng1 aNakamura, Yusuke1 aLevy, Daniel1 aKimura, Masayuki1 aHwang, Shih-Jen1 aHunt, Steven1 aSpector, Tim1 aSoranzo, Nicole1 aManichaikul, Ani, W1 aBarr, Graham1 aKahali, Bratati1 aSpeliotes, Elizabeth1 aYerges-Armstrong, Laura, M1 aCheng, Ching-Yu1 aJonas, Jost, B1 aWong, Tien, Yin1 aFogh, Isabella1 aLin, Kuang1 aPowell, John, F1 aRice, Kenneth1 aRelton, Caroline, L1 aMartin, Richard, M1 aSmith, George, Davey uhttps://chs-nhlbi.org/node/7594