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Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.

TitleCausal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.
Publication TypeJournal Article
Year of Publication2014
AuthorsHolmes MV, Lange LA, Palmer T, Lanktree MB, North KE, Almoguera B, Buxbaum S, Chandrupatla HR, Elbers CC, Guo Y, Hoogeveen RC, Li J, Li YR, Swerdlow DI, Cushman M, Price TS, Curtis SP, Fornage M, Hakonarson H, Patel SR, Redline S, Siscovick DS, Tsai MY, Wilson JG, van der Schouw YT, FitzGerald GA, Hingorani AD, Casas JP, de Bakker PIW, Rich SS, Schadt EE, Asselbergs FW, Reiner AP
Secondary AuthorsKeating BJ
JournalAm J Hum Genet
Date Published2014 Feb 06
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, Body Mass Index, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Fasting, Female, Genetic Association Studies, Humans, Insulin, Interleukin-6, Longitudinal Studies, Male, Mendelian Randomization Analysis, Meta-Analysis as Topic, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Selection, Genetic, Sensitivity and Specificity, Stroke, Young Adult

Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.

Alternate JournalAm J Hum Genet
PubMed ID24462370
PubMed Central IDPMC3928659
Grant ListG0802432 / / Medical Research Council / United Kingdom
MR/K006584/1 / / Medical Research Council / United Kingdom
P20 MD006899 / MD / NIMHD NIH HHS / United States
PG/09/022/26739 / / British Heart Foundation / United Kingdom