@article {7594, title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.}, journal = {JAMA Oncol}, volume = {3}, year = {2017}, month = {2017 May 01}, pages = {636-651}, abstract = {

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.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2016.5945}, author = {Haycock, Philip C and Burgess, Stephen and Nounu, Aayah and Zheng, Jie and Okoli, George N and Bowden, Jack and Wade, Kaitlin Hazel and Timpson, Nicholas J and Evans, David M and Willeit, Peter and Aviv, Abraham and Gaunt, Tom R and Hemani, Gibran and Mangino, Massimo and Ellis, Hayley Patricia and Kurian, Kathreena M and Pooley, Karen A and Eeles, Rosalind A and Lee, Jeffrey E and Fang, Shenying and Chen, Wei V and Law, Matthew H and Bowdler, Lisa M and Iles, Mark M and Yang, Qiong and Worrall, Bradford B and Markus, Hugh Stephen and Hung, Rayjean J and Amos, Chris I and Spurdle, Amanda B and Thompson, Deborah J and O{\textquoteright}Mara, Tracy A and Wolpin, Brian and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael and Trichopoulou, Antonia and Onland-Moret, N Charlotte and Lund, Eiliv and Duell, Eric J and Canzian, Federico and Severi, Gianluca and Overvad, Kim and Gunter, Marc J and Tumino, Rosario and Svenson, Ulrika and van Rij, Andre and Baas, Annette F and Bown, Matthew J and Samani, Nilesh J and van t{\textquoteright}Hof, Femke N G and Tromp, Gerard and Jones, Gregory T and Kuivaniemi, Helena and Elmore, James R and Johansson, Mattias and Mckay, James and Scelo, Ghislaine and Carreras-Torres, Robert and Gaborieau, Valerie and Brennan, Paul and Bracci, Paige M and Neale, Rachel E and Olson, Sara H and Gallinger, Steven and Li, Donghui and Petersen, Gloria M and Risch, Harvey A and Klein, Alison P and Han, Jiali and Abnet, Christian C and Freedman, Neal D and Taylor, Philip R and Maris, John M and Aben, Katja K and Kiemeney, Lambertus A and Vermeulen, Sita H and Wiencke, John K and Walsh, Kyle M and Wrensch, Margaret and Rice, Terri and Turnbull, Clare and Litchfield, Kevin and Paternoster, Lavinia and Standl, Marie and Abecasis, Goncalo R and SanGiovanni, John Paul and Li, Yong and Mijatovic, Vladan and Sapkota, Yadav and Low, Siew-Kee and Zondervan, Krina T and Montgomery, Grant W and Nyholt, Dale R and van Heel, David A and Hunt, Karen and Arking, Dan E and Ashar, Foram N and Sotoodehnia, Nona and Woo, Daniel and Rosand, Jonathan and Comeau, Mary E and Brown, W Mark and Silverman, Edwin K and Hokanson, John E and Cho, Michael H and Hui, Jennie and Ferreira, Manuel A and Thompson, Philip J and Morrison, Alanna C and Felix, Janine F and Smith, Nicholas L and Christiano, Angela M and Petukhova, Lynn and Betz, Regina C and Fan, Xing and Zhang, Xuejun and Zhu, Caihong and Langefeld, Carl D and Thompson, Susan D and Wang, Feijie and Lin, Xu and Schwartz, David A and Fingerlin, Tasha and Rotter, Jerome I and Cotch, Mary Frances and Jensen, Richard A and Munz, Matthias and Dommisch, Henrik and Schaefer, Arne S and Han, Fang and Ollila, Hanna M and Hillary, Ryan P and Albagha, Omar and Ralston, Stuart H and Zeng, Chenjie and Zheng, Wei and Shu, Xiao-Ou and Reis, Andre and Uebe, Steffen and H{\"u}ffmeier, Ulrike and Kawamura, Yoshiya and Otowa, Takeshi and Sasaki, Tsukasa and Hibberd, Martin Lloyd and Davila, Sonia and Xie, Gang and Siminovitch, Katherine and Bei, Jin-Xin and Zeng, Yi-Xin and F{\"o}rsti, Asta and Chen, Bowang and Landi, Stefano and Franke, Andre and Fischer, Annegret and Ellinghaus, David and Flores, Carlos and Noth, Imre and Ma, Shwu-Fan and Foo, Jia Nee and Liu, Jianjun and Kim, Jong-Won and Cox, David G and Delattre, Olivier and Mirabeau, Olivier and Skibola, Christine F and Tang, Clara S and Garcia-Barcelo, Merce and Chang, Kai-Ping and Su, Wen-Hui and Chang, Yu-Sun and Martin, Nicholas G and Gordon, Scott and Wade, Tracey D and Lee, Chaeyoung and Kubo, Michiaki and Cha, Pei-Chieng and Nakamura, Yusuke and Levy, Daniel and Kimura, Masayuki and Hwang, Shih-Jen and Hunt, Steven and Spector, Tim and Soranzo, Nicole and Manichaikul, Ani W and Barr, R Graham and Kahali, Bratati and Speliotes, Elizabeth and Yerges-Armstrong, Laura M and Cheng, Ching-Yu and Jonas, Jost B and Wong, Tien Yin and Fogh, Isabella and Lin, Kuang and Powell, John F and Rice, Kenneth and Relton, Caroline L and Martin, Richard M and Davey Smith, George} } @article {7664, title = {Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.}, journal = {Lancet}, volume = {391}, year = {2018}, month = {2018 04 14}, pages = {1513-1523}, abstract = {

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12{\textperiodcentered}5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5{\textperiodcentered}6 years [5th-95th percentile 1{\textperiodcentered}04-13{\textperiodcentered}5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5{\textperiodcentered}4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1{\textperiodcentered}14, 95\% CI, 1{\textperiodcentered}10-1{\textperiodcentered}17), coronary disease excluding myocardial infarction (1{\textperiodcentered}06, 1{\textperiodcentered}00-1{\textperiodcentered}11), heart failure (1{\textperiodcentered}09, 1{\textperiodcentered}03-1{\textperiodcentered}15), fatal hypertensive disease (1{\textperiodcentered}24, 1{\textperiodcentered}15-1{\textperiodcentered}33); and fatal aortic aneurysm (1{\textperiodcentered}15, 1{\textperiodcentered}03-1{\textperiodcentered}28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0{\textperiodcentered}94, 0{\textperiodcentered}91-0{\textperiodcentered}97). In comparison to those who reported drinking >0-<=100 g per week, those who reported drinking >100-<=200 g per week, >200-<=350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

}, issn = {1474-547X}, doi = {10.1016/S0140-6736(18)30134-X}, author = {Wood, Angela M and Kaptoge, Stephen and Butterworth, Adam S and Willeit, Peter and Warnakula, Samantha and Bolton, Thomas and Paige, Ellie and Paul, Dirk S and Sweeting, Michael and Burgess, Stephen and Bell, Steven and Astle, William and Stevens, David and Koulman, Albert and Selmer, Randi M and Verschuren, W M Monique and Sato, Shinichi and Nj{\o}lstad, Inger and Woodward, Mark and Salomaa, Veikko and Nordestgaard, B{\o}rge G and Yeap, Bu B and Fletcher, Astrid and Melander, Olle and Kuller, Lewis H and Balkau, Beverley and Marmot, Michael and Koenig, Wolfgang and Casiglia, Edoardo and Cooper, Cyrus and Arndt, Volker and Franco, Oscar H and Wennberg, Patrik and Gallacher, John and de la C{\'a}mara, Agustin G{\'o}mez and V{\"o}lzke, Henry and Dahm, Christina C and Dale, Caroline E and Bergmann, Manuela M and Crespo, Carlos J and van der Schouw, Yvonne T and Kaaks, Rudolf and Simons, Leon A and Lagiou, Pagona and Schoufour, Josje D and Boer, Jolanda M A and Key, Timothy J and Rodriguez, Beatriz and Moreno-Iribas, Conchi and Davidson, Karina W and Taylor, James O and Sacerdote, Carlotta and Wallace, Robert B and Quiros, J Ramon and Tumino, Rosario and Blazer, Dan G and Linneberg, Allan and Daimon, Makoto and Panico, Salvatore and Howard, Barbara and Skeie, Guri and Strandberg, Timo and Weiderpass, Elisabete and Nietert, Paul J and Psaty, Bruce M and Kromhout, Daan and Salamanca-Fernandez, Elena and Kiechl, Stefan and Krumholz, Harlan M and Grioni, Sara and Palli, Domenico and Huerta, Jos{\'e} M and Price, Jackie and Sundstr{\"o}m, Johan and Arriola, Larraitz and Arima, Hisatomi and Travis, Ruth C and Panagiotakos, Demosthenes B and Karakatsani, Anna and Trichopoulou, Antonia and K{\"u}hn, Tilman and Grobbee, Diederick E and Barrett-Connor, Elizabeth and van Schoor, Natasja and Boeing, Heiner and Overvad, Kim and Kauhanen, Jussi and Wareham, Nick and Langenberg, Claudia and Forouhi, Nita and Wennberg, Maria and Despr{\'e}s, Jean-Pierre and Cushman, Mary and Cooper, Jackie A and Rodriguez, Carlos J and Sakurai, Masaru and Shaw, Jonathan E and Knuiman, Matthew and Voortman, Trudy and Meisinger, Christa and Tj{\o}nneland, Anne and Brenner, Hermann and Palmieri, Luigi and Dallongeville, Jean and Brunner, Eric J and Assmann, Gerd and Trevisan, Maurizio and Gillum, Richard F and Ford, Ian and Sattar, Naveed and Lazo, Mariana and Thompson, Simon G and Ferrari, Pietro and Leon, David A and Smith, George Davey and Peto, Richard and Jackson, Rod and Banks, Emily and Di Angelantonio, Emanuele and Danesh, John} } @article {8507, title = {Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.}, journal = {Circulation}, volume = {140}, year = {2019}, month = {2019 08 20}, pages = {645-657}, abstract = {

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67\% women, 35\% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.039357}, author = {Agha, Golareh and Mendelson, Michael M and Ward-Caviness, Cavin K and Joehanes, Roby and Huan, Tianxiao and Gondalia, Rahul and Salfati, Elias and Brody, Jennifer A and Fiorito, Giovanni and Bressler, Jan and Chen, Brian H and Ligthart, Symen and Guarrera, Simonetta and Colicino, Elena and Just, Allan C and Wahl, Simone and Gieger, Christian and Vandiver, Amy R and Tanaka, Toshiko and Hernandez, Dena G and Pilling, Luke C and Singleton, Andrew B and Sacerdote, Carlotta and Krogh, Vittorio and Panico, Salvatore and Tumino, Rosario and Li, Yun and Zhang, Guosheng and Stewart, James D and Floyd, James S and Wiggins, Kerri L and Rotter, Jerome I and Multhaup, Michael and Bakulski, Kelly and Horvath, Steven and Tsao, Philip S and Absher, Devin M and Vokonas, Pantel and Hirschhorn, Joel and Fallin, M Daniele and Liu, Chunyu and Bandinelli, Stefania and Boerwinkle, Eric and Dehghan, Abbas and Schwartz, Joel D and Psaty, Bruce M and Feinberg, Andrew P and Hou, Lifang and Ferrucci, Luigi and Sotoodehnia, Nona and Matullo, Giuseppe and Peters, Annette and Fornage, Myriam and Assimes, Themistocles L and Whitsel, Eric A and Levy, Daniel and Baccarelli, Andrea A} }