Causal Effects of Body Mass Index on Cardiometabolic Traits and Events: A Mendelian Randomization Analysis

Abstract

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.

Type 2 Diabetes Genetic Predisposition, Obesity, and All-Cause Mortality Risk in the U.S.: A Multiethnic Analysis

“…A Mendelian randomization study showed that BMI-related genetic variants did not increase the CVD or stroke risk despite being associated with multiple cardiometabolic traits, including T2D (41). A previous study (42) of 2,607 NHANES III participants with T2D showed that BMI and measures of adiposity did not predict mortality over 6.5 years.…”

Association of lactase persistence genotype with milk consumption, obesity and blood pressure: a Mendelian randomization study in the 1982 Pelotas (Brazil) Birth Cohort, with a systematic review and meta-analysis

“…Estimates were obtained from the aforementioned large Danish study 30 —the largest study included in our meta-analysis—and two Mendelian randomization studies 54 , 55 . A detailed description of the simulations is provided in Supplementary Methods (available as Supplementary data at IJE online).…”

Genetic and environmental determinants of population variation in interleukin-6, its soluble receptor and C-reactive protein: Insights from identical and fraternal twins

“…Although previous genetic and heritability studies have demonstrated direct and independent effects on CRP levels(de Maat et al, 2004; Dehghan et al, 2011; Pankow et al, 2001; Wörns et al, 2006), there is evidence suggesting a causal relationship between the genetics of obesity and circulating CRP levels. SNPs associated with body mass index (BMI) can influence blood levels of CRP, while the converse has not been demonstrated (Holmes et al, 2014; Welsh et al, 2010). Thus, to further probe the unique nature and strength of the association between adiposity and IL-6, we also considered the relationship between adiposity and CRP.…”

“…Associations between a genetic score, consisting of 14 SNPs related to BMI, and multiple cardiovascular and inflammatory traits including both IL-6 and CRP, were recently assessed (Holmes et al, 2014). However, it is still not known whether the heritable influence of obesity on IL-6 and its soluble receptor are coordinated, and whether CRP is affected in a similarly linked manner.…”