{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T14:13:08Z","timestamp":1789740788778,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Although several observational studies have suggested positive associations between constipation and cardiovascular disease (CVD), a solid causal association has not been demonstrated. Therefore, a two-sample Mendelian randomization (MR) study was performed to investigate the causal associations between constipation and CVD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Independent genetic variants strongly associated with constipation were obtained from the FinnGen consortium. Summary-level data for CVD, including coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), stroke, and its subtypes, were collected from a few extensive genome-wide association studies (GWASs). The inverse-variance weighted methods, weighted median, and MR-Egger were used for the MR estimates. The Cochran\u2019s Q test, MR-Egger intercept tests, MR-PRESSO, MR Steiger test, leave-one-out analyses, and funnel plot were used in the sensitivity analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetically determined constipation was suggestively associated with AF risk (odds ratio (OR), 1.07; 95% confidence interval (CI), 1.01, 1.14; <jats:italic>p<\/jats:italic>\u2009=\u20090.016). Constipation and other CVD do not appear to be causally related. It was demonstrated that the results were robust through sensitivity analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This MR study demonstrated suggestive causal associations of constipation on AF, despite no associations achieving a significance value after multiple testing corrections. There was no evidence of an association between constipation and the risk of CAD, MI, HF, stroke, or stroke subtypes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2023.1080982","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T07:56:21Z","timestamp":1677225381000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Constipation and cardiovascular disease: A two-sample Mendelian randomization analysis"],"prefix":"10.3389","volume":"10","author":[{"given":"Qichao","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhui","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1146\/annurev-pathmechdis-012419-032544","article-title":"Cardiovascular disease, aging, and clonal hematopoiesis","volume":"15","author":"Evans","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e104","DOI":"10.1161\/CIR.0000000000000756","article-title":"Recommendations for cardiovascular health and disease surveillance for 2030 and beyond: a policy statement from the American Heart Association","volume":"141","author":"Roger","year":"2020","journal-title":"Circulation"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e037080","DOI":"10.1136\/bmjopen-2020-037080","article-title":"Constipation and risk of cardiovascular diseases: a Danish population-based matched cohort study","volume":"10","author":"Sundb\u00f8ll","year":"2020","journal-title":"BMJ Open"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.amjmed.2011.03.026","article-title":"Constipation and risk of cardiovascular disease among postmenopausal women","volume":"124","author":"Salmoirago-Blotcher","year":"2011","journal-title":"Am J Med"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.atherosclerosis.2018.12.021","article-title":"Constipation and risk of death and cardiovascular events","volume":"281","author":"Sumida","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1517\/17425255.2013.773974","article-title":"Understanding constipation treatment: do we need to strain to obtain better results?","volume":"9","author":"Bassotti","year":"2013","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1111\/jch.13489","article-title":"Constipation-induced pressor effects as triggers for cardiovascular events","volume":"21","author":"Ishiyama","year":"2019","journal-title":"J Clin Hypertens"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.atherosclerosis.2016.01.007","article-title":"Defecation frequency and cardiovascular disease mortality in Japan: the Ohsaki cohort study","volume":"246","author":"Honkura","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"\u2018Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.1681\/ASN.2016010098","article-title":"Mendelian randomization as an approach to assess causality using observational data","volume":"27","author":"Sekula","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"a040501","DOI":"10.1101\/cshperspect.a040501","article-title":"Mendelian randomization: concepts and scope","volume":"12","author":"Richmond","year":"2022","journal-title":"Cold Spring Harb Perspect Med"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1093\/aje\/kwu283","article-title":"Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects","volume":"181","author":"Burgess","year":"2015","journal-title":"Am J Epidemiol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e1002893","DOI":"10.1371\/journal.pmed.1002893","article-title":"Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: a Mendelian randomization analysis","volume":"16","author":"Yarmolinsky","year":"2019","journal-title":"PLoS Med"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur J Epidemiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1146\/annurev-genom-090314-050016","article-title":"Mendelian randomization: new applications in the coming age of hypothesis-free causality","volume":"16","author":"Evans","year":"2015","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1101\/2022.03.03.22271360","article-title":"Finngen: unique genetic insights from combining isolated population and national health register data","author":"Mitja","year":"2022","journal-title":"MedRxiv"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","article-title":"Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease","volume":"122","author":"van der Harst","year":"2018","journal-title":"Circ Res"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1038\/ng.3396","article-title":"A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease","volume":"47","author":"Nikpay","year":"2015","journal-title":"Nat Genet"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41467-019-13690-5","article-title":"Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure","volume":"11","author":"Shah","year":"2020","journal-title":"Nat Commun"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1038\/s41588-018-0171-3","article-title":"Biobank-driven genomic discovery yields new insight into atrial fibrillation biology","volume":"50","author":"Nielsen","year":"2018","journal-title":"Nat Genet"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41588-018-0058-3","article-title":"Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes","volume":"50","author":"Malik","year":"2018","journal-title":"Nat Genet"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1038\/nature09534","article-title":"A map of human genome variation from population-scale sequencing","volume":"467","author":"Abecasis","year":"2010","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int J Epidemiol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e0120758","DOI":"10.1371\/journal.pone.0120758","article-title":"A multivariate genome-wide association analysis of 10 Ldl subfractions, and their response to statin treatment, in 1868 Caucasians","volume":"10","author":"Shim","year":"2015","journal-title":"PLoS One"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e2572","DOI":"10.1210\/clinem\/dgac048","article-title":"Causal associations between circulating Adipokines and cardiovascular disease: a Mendelian randomization study","volume":"107","author":"Chen","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1093\/bioinformatics\/btz469","article-title":"Phenoscanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"Kamat","year":"2019","journal-title":"Bioinformatics"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies","volume":"42","author":"Brion","year":"2013","journal-title":"Int J Epidemiol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/aje\/kwt084","article-title":"Efficient Design for Mendelian Randomization Studies: subsample and 2-sample instrumental variable estimators","volume":"178","author":"Pierce","year":"2013","journal-title":"Am J Epidemiol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using Gwas summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PLoS Genet"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1111\/j.1572-0241.2001.05259.x","article-title":"An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking","volume":"96","author":"Pare","year":"2001","journal-title":"Am J Gastroenterol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1471-230X-8-5","article-title":"Epidemiology of constipation in Europe and Oceania: a systematic review","volume":"8","author":"Peppas","year":"2008","journal-title":"BMC Gastroenterol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s10620-006-9298-7","article-title":"Etiologic factors of chronic constipation: review of the scientific evidence","volume":"52","author":"Leung","year":"2007","journal-title":"Dig Dis Sci"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"242","DOI":"10.2188\/jea.JE20150123","article-title":"Bowel movement frequency, laxative use, and mortality from coronary heart disease and stroke among Japanese men and women: the Japan collaborative cohort (Jacc) study","volume":"26","author":"Kubota","year":"2016","journal-title":"J Epidemiol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"33005","DOI":"10.1038\/srep33005","article-title":"Associations of bowel movement frequency with risk of cardiovascular disease and mortality among us women","volume":"6","author":"Ma","year":"2016","journal-title":"Sci Rep"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3389\/fmed.2019.00019","article-title":"Gut microbiota and chronic constipation: a review and update","volume":"6","author":"Ohkusa","year":"2019","journal-title":"Front Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1186\/s40064-016-2821-1","article-title":"Intestinal microbiota and chronic constipation","volume":"5","author":"Zhao","year":"2016","journal-title":"Springerplus"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.mib.2019.09.007","article-title":"The emerging role of gut microbial metabolism on cardiovascular disease","volume":"50","author":"Kasahara","year":"2019","journal-title":"Curr Opin Microbiol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/nature11552","article-title":"Functional interactions between the gut microbiota and host metabolism","volume":"489","author":"Tremaroli","year":"2012","journal-title":"Nature"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.4239\/wjd.v12.i9.1463","article-title":"Holistic perspective of the role of gut microbes in diabetes mellitus and its management","volume":"12","author":"Alagiakrishnan","year":"2021","journal-title":"World J Diabetes"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1017\/S0007114520001853","article-title":"Dietary inflammatory potential in relation to the gut microbiome: results from a cross-sectional study","volume":"124","author":"Zheng","year":"2020","journal-title":"Br J Nutr"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1093\/cvr\/cvab114","article-title":"Gut microbiota Dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of Nlrp3-inflammasome","volume":"118","author":"Zhang","year":"2022","journal-title":"Cardiovasc Res"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1161\/HYPERTENSIONAHA.115.05315","article-title":"Gut Dysbiosis is linked to hypertension","volume":"65","author":"Yang","year":"2015","journal-title":"Hypertension"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1111\/apt.13257","article-title":"Letter: chronic constipation - a warning sign for oxidative stress?","volume":"42","author":"Vermorken","year":"2015","journal-title":"Aliment Pharmacol Ther"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e1009922","DOI":"10.1371\/journal.pgen.1009922","article-title":"Combining the strengths of inverse-variance weighting and egger regression in Mendelian randomization using a mixture of regressions model","volume":"17","author":"Lin","year":"2021","journal-title":"PLoS Genet"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e1003679","DOI":"10.1371\/journal.pmed.1003679","article-title":"Obesity and risk of female reproductive conditions: a Mendelian randomisation study","volume":"19","author":"Venkatesh","year":"2022","journal-title":"PLoS Med"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1186\/s12967-022-03407-6","article-title":"Causal relationship between physical activity, leisure sedentary behaviors and Covid-19 risk: a Mendelian randomization study","volume":"20","author":"Chen","year":"2022","journal-title":"J Transl Med"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1080982\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T07:56:25Z","timestamp":1677225385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2023.1080982\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,24]]},"references-count":49,"alternative-id":["10.3389\/fcvm.2023.1080982"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2023.1080982","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,24]]},"article-number":"1080982"}}