Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease

Abstract

Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m(2) [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic -0.859 mmHg [-1.099, -0.618]; P = 3E-12 and diastolic -0.394 mmHg [-0.534, -0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (-0.004 cm [95% CI -0.005, -0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.

Figure 1

The effect of favourable adiposity on measures of adiposity and cardiometabolic disease risk in the UK Biobank study. Effects are given by comparing the 50% of people carrying the most favourable adiposity alleles with the 50% of people carrying the fewest favourable adiposity alleles. The error bars indicate 95% confidence intervals. All models were adjusted for age, sex, genotyping array, study center and within UK principle components.

Figure 1

The effect of favourable adiposity on measures of adiposity and cardiometabolic disease risk in the UK Biobank study. Effects are given by comparing the 50% of people carrying the most favourable adiposity alleles with the 50% of people carrying the fewest favourable adiposity alleles. The error bars indicate 95% confidence intervals. All models were adjusted for age, sex, genotyping array, study center and within UK principle components.

Figure 2

The effect of favourable adiposity on measures of body distribution including waist circumference, hip circumference and waist-hip ratio separated by sex. Effects are per additional weighted copy of the adiposity increasing allele. All models were adjusted for age, sex, genotyping array, study center and principle components where applicable.

Figure 3

The effect of favourable adiposity on measures of adiposity and cardiometabolic disease risk in the UK Biobank study in all individuals and in individuals split into BMI categories. Effects are given by comparing the 50% of people carrying the most favourable adiposity alleles with the 50% of people carrying the fewest favourable adiposity alleles in all individuals and within BMI strata. The error bars indicate 95% confidence intervals. All models were adjusted for age, sex, genotyping array, study center and within UK principle components.

Figure 4

The combined effect of favorable adiposity and BMI genetic scores on cardiometabolic disease risk. We grouped the UK Biobank individuals based on the median of the two genetic score distributions: (i) low BMI – high FA: individuals with below median BMI genetic score and above median favorable adiposity genetic score, (ii) low BMI – low FA: individuals with below median BMI genetic score and below median favorable adiposity genetic score, (iii) high BMI – high FA: individuals with above median BMI genetic score and above median favorable adiposity genetic score and (iv) high BMI – low FA: individuals with above median BMI genetic score and below median favorable adiposity genetic score. The error bars indicate 95% confidence intervals.