Dataset Information

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

ABSTRACT: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (? = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

SUBMITTER: Hagg S

PROVIDER: S-EPMC4553708 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

Hägg Sara S Fall Tove T Ploner Alexander A Mägi Reedik R Fischer Krista K Draisma Harmen H M HH Kals Mart M de Vries Paul S PS Dehghan Abbas A Willems Sara M SM Sarin Antti-Pekka AP Kristiansson Kati K Nuotio Marja-Liisa ML Havulinna Aki S AS de Bruijn Renée F A G RF Ikram M Arfan MA Kuningas Maris M Stricker Bruno H BH Franco Oscar H OH Benyamin Beben B Gieger Christian C Hall Alistair S AS Huikari Ville V Jula Antti A Järvelin Marjo-Riitta MR Kaakinen Marika M Kaprio Jaakko J Kobl Michael M Mangino Massimo M Nelson Christopher P CP Palotie Aarno A Samani Nilesh J NJ Spector Tim D TD Strachan David P DP Tobin Martin D MD Whitfield John B JB Uitterlinden André G AG Salomaa Veikko V Syvänen Ann-Christine AC Kuulasmaa Kari K Magnusson Patrik K PK Esko Tõnu T Hofman Albert A de Geus Eco J C EJ Lind Lars L Giedraitis Vilmantas V Perola Markus M Evans Alun A Ferrières Jean J Virtamo Jarmo J Kee Frank F Tregouet David-Alexandre DA Arveiler Dominique D Amouyel Philippe P Gianfagna Francesco F Brambilla Paolo P Ripatti Samuli S van Duijn Cornelia M CM Metspalu Andres A Prokopenko Inga I McCarthy Mark I MI Pedersen Nancy L NL Ingelsson Erik E

International journal of epidemiology 20150401 2

<h4>Background</h4>Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.<h4>Methods</h4>The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular out ...[more]

PMID: 26016847

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Project description:Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N?=?806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N?=?24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2?kg/m2) was associated with 1.23 (95% confidence interval (CI)?=?1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2?kg/m2) was associated with 1.09 (95% CI?=?0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR?=?1.25, 95% CI?=?1.08, 1.43) than men (IVW OR?=?1.05, 95% CI?=?0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P???0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI?=?1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways. Supplementary information The online version contains supplementary material available at 10.1186/s12916-020-01855-9.

Dataset Information

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

Publications

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

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