@article {1171, title = {Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.}, journal = {Stat Med}, volume = {29}, year = {2010}, month = {2010 May 30}, pages = {1298-311}, abstract = {

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

}, keywords = {Bayes Theorem, Biostatistics, C-Reactive Protein, Fibrinogen, Genetic Markers, Humans, Meta-Analysis as Topic, Models, Statistical, Phenotype, Polymorphism, Single Nucleotide}, issn = {1097-0258}, doi = {10.1002/sim.3843}, author = {Burgess, Stephen and Thompson, Simon G and Burgess, S and Thompson, S G and Andrews, G and Samani, N J and Hall, A and Whincup, P and Morris, R and Lawlor, D A and Davey Smith, G and Timpson, N and Ebrahim, S and Ben-Shlomo, Y and Davey Smith, G and Timpson, N and Brown, M and Ricketts, S and Sandhu, M and Reiner, A and Psaty, B and Lange, L and Cushman, M and Hung, J and Thompson, P and Beilby, J and Warrington, N and Palmer, L J and Nordestgaard, B G and Tybjaerg-Hansen, A and Zacho, J and Wu, C and Lowe, G and Tzoulaki, I and Kumari, M and Sandhu, M and Yamamoto, J F and Chiodini, B and Franzosi, M and Hankey, G J and Jamrozik, K and Palmer, L and Rimm, E and Pai, J and Psaty, B and Heckbert, S and Bis, J and Anand, S and Engert, J and Collins, R and Clarke, R and Melander, O and Berglund, G and Ladenvall, P and Johansson, L and Jansson, J-H and Hallmans, G and Hingorani, A and Humphries, S and Rimm, E and Manson, J and Pai, J and Watkins, H and Clarke, R and Hopewell, J and Saleheen, D and Frossard, R and Danesh, J and Sattar, N and Robertson, M and Shepherd, J and Schaefer, E and Hofman, A and Witteman, J C M and Kardys, I and Ben-Shlomo, Y and Davey Smith, G and Timpson, N and de Faire, U and Bennet, A and Sattar, N and Ford, I and Packard, C and Kumari, M and Manson, J and Lawlor, Debbie A and Davey Smith, George and Anand, S and Collins, R and Casas, J P and Danesh, J and Davey Smith, G and Franzosi, M and Hingorani, A and Lawlor, D A and Manson, J and Nordestgaard, B G and Samani, N J and Sandhu, M and Smeeth, L and Wensley, F and Anand, S and Bowden, J and Burgess, S and Casas, J P and Di Angelantonio, E and Engert, J and Gao, P and Shah, T and Smeeth, L and Thompson, S G and Verzilli, C and Walker, M and Whittaker, J and Hingorani, A and Danesh, J} } @article {6811, title = {Association of Cardiometabolic Multimorbidity With Mortality.}, journal = {JAMA}, volume = {314}, year = {2015}, month = {2015 Jul 7}, pages = {52-60}, abstract = {

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95\% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95\% CI, 2.0-2.2) in those with stroke, 2.0 (95\% CI, 1.9-2.2) in those with MI, 3.7 (95\% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95\% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95\% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95\% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

}, keywords = {Adult, Aged, Comorbidity, Diabetes Mellitus, Female, Humans, Life Expectancy, Male, Middle Aged, Mortality, Myocardial Infarction, Risk Factors, Stroke}, issn = {1538-3598}, doi = {10.1001/jama.2015.7008}, author = {Di Angelantonio, Emanuele and Kaptoge, Stephen and Wormser, David and Willeit, Peter and Butterworth, Adam S and Bansal, Narinder and O{\textquoteright}Keeffe, Linda M and Gao, Pei and Wood, Angela M and Burgess, Stephen and Freitag, Daniel F and Pennells, Lisa and Peters, Sanne A and Hart, Carole L and H{\r a}heim, Lise Lund and Gillum, Richard F and Nordestgaard, B{\o}rge G and Psaty, Bruce M and Yeap, Bu B and Knuiman, Matthew W and Nietert, Paul J and Kauhanen, Jussi and Salonen, Jukka T and Kuller, Lewis H and Simons, Leon A and van der Schouw, Yvonne T and Barrett-Connor, Elizabeth and Selmer, Randi and Crespo, Carlos J and Rodriguez, Beatriz and Verschuren, W M Monique and Salomaa, Veikko and Sv{\"a}rdsudd, Kurt and van der Harst, Pim and Bj{\"o}rkelund, Cecilia and Wilhelmsen, Lars and Wallace, Robert B and Brenner, Hermann and Amouyel, Philippe and Barr, Elizabeth L M and Iso, Hiroyasu and Onat, Altan and Trevisan, Maurizio and D{\textquoteright}Agostino, Ralph B and Cooper, Cyrus and Kavousi, Maryam and Welin, Lennart and Roussel, Ronan and Hu, Frank B and Sato, Shinichi and Davidson, Karina W and Howard, Barbara V and Leening, Maarten J G and Leening, Maarten and Rosengren, Annika and D{\"o}rr, Marcus and Deeg, Dorly J H and Kiechl, Stefan and Stehouwer, Coen D A and Nissinen, Aulikki and Giampaoli, Simona and Donfrancesco, Chiara and Kromhout, Daan and Price, Jackie F and Peters, Annette and Meade, Tom W and Casiglia, Edoardo and Lawlor, Debbie A and Gallacher, John and Nagel, Dorothea and Franco, Oscar H and Assmann, Gerd and Dagenais, Gilles R and Jukema, J Wouter and Sundstr{\"o}m, Johan and Woodward, Mark and Brunner, Eric J and Khaw, Kay-Tee and Wareham, Nicholas J and Whitsel, Eric A and Nj{\o}lstad, Inger and Hedblad, Bo and Wassertheil-Smoller, Sylvia and Engstr{\"o}m, Gunnar and Rosamond, Wayne D and Selvin, Elizabeth and Sattar, Naveed and Thompson, Simon G and Danesh, John} } @article {8567, title = {Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.}, journal = {Lancet Diabetes Endocrinol}, volume = {4}, year = {2016}, month = {2016 10}, pages = {840-9}, abstract = {

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5\%, 5\% to <7{\textperiodcentered}5\%, and >=7{\textperiodcentered}5\%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1{\textperiodcentered}76 (95\% CI 1{\textperiodcentered}56-1{\textperiodcentered}98) for the combination of coronary heart disease and stroke and 2{\textperiodcentered}00 (1{\textperiodcentered}77-2{\textperiodcentered}26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0{\textperiodcentered}012 (0{\textperiodcentered}010-0{\textperiodcentered}014) and a net reclassification improvement of 0{\textperiodcentered}027 (0{\textperiodcentered}019-0{\textperiodcentered}036) for the combination of coronary heart disease and stroke and a C-index increase of 0{\textperiodcentered}019 (0{\textperiodcentered}016-0{\textperiodcentered}022) and a net reclassification improvement of 0{\textperiodcentered}028 (0{\textperiodcentered}019-0{\textperiodcentered}038) for the combination of coronary heart disease, stroke, and heart failure.

INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Assessment}, issn = {2213-8595}, doi = {10.1016/S2213-8587(16)30196-6}, author = {Willeit, Peter and Kaptoge, Stephen and Welsh, Paul and Butterworth, Adam and Chowdhury, Rajiv and Spackman, Sarah and Pennells, Lisa and Gao, Pei and Burgess, Stephen and Freitag, Daniel and Sweeting, Michael and Wood, Angela and Cook, Nancy and Judd, Suzanne and Trompet, Stella and Nambi, Vijay and Olsen, Michael and Everett, Brendan and Kee, Frank and Arnl{\"o}v, Johan and Salomaa, Veikko and Levy, Daniel and Kauhanen, Jussi and Laukkanen, Jari and Kavousi, Maryam and Ninomiya, Toshiharu and Casas, Juan-Pablo and Daniels, Lori and Lind, Lars and Kistorp, Caroline and Rosenberg, Jens and Mueller, Thomas and Rubattu, Speranza and Panagiotakos, Demosthenes and Franco, Oscar and de Lemos, James and Luchner, Andreas and Kizer, Jorge and Kiechl, Stefan and Salonen, Jukka and Goya Wannamethee, S and de Boer, Rudolf and Nordestgaard, B{\o}rge and Andersson, Jonas and J{\o}rgensen, Torben and Melander, Olle and Ballantyne, Christie and DeFilippi, Christopher and Ridker, Paul and Cushman, Mary and Rosamond, Wayne and Thompson, Simon and Gudnason, Vilmundur and Sattar, Naveed and Danesh, John and Di Angelantonio, Emanuele} } @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 {7923, title = {Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.}, journal = {Eur Heart J}, year = {2018}, month = {2018 Nov 22}, abstract = {

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after {\textquoteright}recalibration{\textquoteright}, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.

Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at {\textquoteright}high{\textquoteright} 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10\%, 52\%, and 41\%, respectively, whereas RRS under-predicted by 10\%. Original versions of algorithms classified 29-39\% of individuals aged >=40 years as high risk. By contrast, recalibration reduced this proportion to 22-24\% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.

Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehy653}, author = {Pennells, Lisa and Kaptoge, Stephen and Wood, Angela and Sweeting, Mike and Zhao, Xiaohui and White, Ian and Burgess, Stephen and Willeit, Peter and Bolton, Thomas and Moons, Karel G M and van der Schouw, Yvonne T and Selmer, Randi and Khaw, Kay-Tee and Gudnason, Vilmundur and Assmann, Gerd and Amouyel, Philippe and Salomaa, Veikko and Kivimaki, Mika and Nordestgaard, B{\o}rge G and Blaha, Michael J and Kuller, Lewis H and Brenner, Hermann and Gillum, Richard F and Meisinger, Christa and Ford, Ian and Knuiman, Matthew W and Rosengren, Annika and Lawlor, Debbie A and V{\"o}lzke, Henry and Cooper, Cyrus and Mar{\'\i}n Iba{\~n}ez, Alejandro and Casiglia, Edoardo and Kauhanen, Jussi and Cooper, Jackie A and Rodriguez, Beatriz and Sundstr{\"o}m, Johan and Barrett-Connor, Elizabeth and Dankner, Rachel and Nietert, Paul J and Davidson, Karina W and Wallace, Robert B and Blazer, Dan G and Bj{\"o}rkelund, Cecilia and Donfrancesco, Chiara and Krumholz, Harlan M and Nissinen, Aulikki and Davis, Barry R and Coady, Sean and Whincup, Peter H and J{\o}rgensen, Torben and Ducimetiere, Pierre and Trevisan, Maurizio and Engstr{\"o}m, Gunnar and Crespo, Carlos J and Meade, Tom W and Visser, Marjolein and Kromhout, Daan and Kiechl, Stefan and Daimon, Makoto and Price, Jackie F and G{\'o}mez de la C{\'a}mara, Agustin and Wouter Jukema, J and Lamarche, Beno{\^\i}t and Onat, Altan and Simons, Leon A and Kavousi, Maryam and Ben-Shlomo, Yoav and Gallacher, John and Dekker, Jacqueline M and Arima, Hisatomi and Shara, Nawar and Tipping, Robert W and Roussel, Ronan and Brunner, Eric J and Koenig, Wolfgang and Sakurai, Masaru and Pavlovic, Jelena and Gansevoort, Ron T and Nagel, Dorothea and Goldbourt, Uri and Barr, Elizabeth L M and Palmieri, Luigi and Nj{\o}lstad, Inger and Sato, Shinichi and Monique Verschuren, W M and Varghese, Cherian V and Graham, Ian and Onuma, Oyere and Greenland, Philip and Woodward, Mark and Ezzati, Majid and Psaty, Bruce M and Sattar, Naveed and Jackson, Rod and Ridker, Paul M and Cook, Nancy R and D{\textquoteright}Agostino, Ralph B and Thompson, Simon G and Danesh, John and Di Angelantonio, Emanuele} } @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 {7978, title = {Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.}, journal = {Neurology}, volume = {92}, year = {2019}, month = {2019 Feb 26}, pages = {e944-e950}, abstract = {

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.

METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).

RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95\% confidence interval [CI] 0.69-0.89; = 1.3 {\texttimes} 10) for all ischemic stroke, 0.63 (95\% CI 0.50-0.80; = 1.6 {\texttimes} 10) for cardioembolic stroke, and 0.60 (95\% CI 0.44-0.82; = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95\% CI 0.67-1.20; = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95\% CI 0.88-1.21) or with any subtype.

CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000007001}, author = {Larsson, Susanna C and Traylor, Matthew and Burgess, Stephen and Boncoraglio, Giorgio B and Jern, Christina and Micha{\"e}lsson, Karl and Markus, Hugh S} } @article {8835, title = {Genetic insights into biological mechanisms governing human ovarian ageing.}, journal = {Nature}, volume = {596}, year = {2021}, month = {2021 Aug}, pages = {393-397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H{\r a}kansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Lo{\"\i}c and Li, Jingmei and Lindblom, Annika and Lindstr{\"o}m, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H{\r a}kan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chloe and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} }