Causal effects of obesity on hypertension: a Mendelian Randomization and gene-environment interaction analysis

Abstract

Introduction: Hypertension is a risk factor for cardiovascular disease, and the burden of this disease gradually increased from 1990 and 2010. In 2014, 22% of people over the age of 18 worldwide were diagnosed with hypertension. Although previous observational studies have shown that obesity is a major risk factor for hypertension, unmeasured confounding factors or reverse causation may exist. In addition, the randomized controlled trials have had limitations because of short study periods or small numbers of subjects. Therefore, Mendelian Randomization (MR) is necessary to prove causality. Genome-wide association studies have reported that some genetic variants are related to hypertension, but genetic contributions to the development of hypertension have been reported to be low, i.e., less than 3%. It is important to reveal the candidate single nucleotide polymorphism (SNP) –obesity relationship to address this low accountability of genetic polymorphisms and identify groups with genetic susceptibility. The aim of this study was to use MR to assess the causal effect of obesity on hypertension. Second, we analyzed the gene-obesity interaction for hypertension. Methods: First, the MR analysis was performed in a well-defined community cohort study of 8832 adults (40-69 years) in Ansung and Ansan 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 the causal odds ratio (OR) was derived using the Wald ratio estimator and then exponentiation was used to express the result as an OR. The IV estimate of the causal hazard ratio (HR) was derived using the Wald ratio estimator and then exponentiation was used to express the result as a HR. Second, in the interaction study, we used non-hypertensive subjects at baseline and for obesity variables, BMI, waist-to-hip ratio (WHR), and waist circumference (WC). We selected 3608 SNPs related to the pathway between obesity and hypertension and performed one degree-of-freedom (1df) and two degree-of-freedom (2df) tests for the interaction. Results: The odds ratios (OR) with 95% confidence intervals for hypertension in an MR study using a multivariable model adjusting for age, sex, study area, education, smoking and current alcohol consumption was 1.19 (95% confidence interval (CI): 1.17-1.21) per unit increase in body mass index. We selected 6 SNPs (P-value <1.0×10-5) associated with BMI by genome-wide screening using linear regression and created six types of genetic risk score (GRS). We demonstrated that each standard-deviation increase in BMI GRS was associated with an OR for hypertension of 1.06-1.07 (all P-values <0.05). Using BMI GRS as the IV, we found a causal relationship between BMI and hypertension (OR: 1.16-1.30, all P-values <0.05). Sensitivity analysis showed causality for baseline hypertension but not for incident hypertension. Second, in the interaction study, we found 4 significant interactions (WHR and the SNPs rs6020611 and rs754118 in PTPN1

WC and rs3817588 in GCKR, and rs1864815 in ABCG5) for the development of hypertension (1df P<0.01, 2df P<2 × 10-6). We calculated GRS by summing the values of significant SNPs. The increment in the contributory proportions of BMI, WC, and WHR that explained hypertension, from the lowest to the highest weighted GRS, were 0.90%, 3.82%, and 2.65%, respectively, which were higher than the contributory proportions of GRS. Conclusions: 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. Also, we found that certain loci of the genes significantly interacted with obesity in the development of hypertension. Our study demonstrated that genetic predispositions contribute to the development of hypertension more by the interaction with obesity than SNP effects themselves.