Causal Association of Body Mass Index with Hypertension Using a Mendelian Randomization Design

Observational studies have shown that obesity is a major risk factor for hypertension, but unmeasured confounding factors may exist. We used Mendelian randomization (MR) to assess the causal effect of obesity on hypertension.The MR analysis was performed in a well-defined community cohort study of 8832 middle-aged (40-69 years) adults in Korea enrolled from 2001 to 2013. We used baseline hypertension and newly diagnosed hypertension during the 10-year follow-up period as the outcome variable. Genetic risk score associated with body mass index (BMI GRS) was used as the instrumental variable (IV) to measure the causal relationship between obesity and hypertension. The IV estimate of causal odds ratio (OR) was derived using the Wald ratio estimator and then exponentiation to express the result as an OR.In the multivariable model adjusting for age, sex, study area, education, smoking, and current alcohol consumption, each 1 kg/m increase in BMI was associated with a 19% (OR: 1.19, 95% confidence interval [CI]: 1.17-1.21) increase in hypertension risk. We selected 6 single-nucleotide polymorphisms (P < 1.0 × 10) associated with BMI by genome-wide screening using linear regression and created 6 types of GRS. We demonstrated that each standard-deviation increase in BMI GRS was associated with a 5% to 6% (OR: 1.05-1.06) increased risk of hypertension (all P < .05). Using BMI GRS as the IV, we found a causal relationship between BMI and hypertension (OR: 1.13-1.26, all P < .05 except weighted GRS [n = 6]).Using Mendelian randomization, we found that obesity is causally associated with hypertension. This information will have important public health implications, supporting evidence that obesity-reduction programs will reduce the incidence of hypertension.