Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

Background Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk. Methods and findings We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m(2) BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m(2) BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12-1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m(2)) without a family history of diabetes, similar to that in obese individuals (BMI >= 30 kg/m(2)) with a family history (1.21-fold reduction, 95% CI 1.13-1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual's entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life. Conclusions In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk. Author summaryWhy was this study done? Excessive body weight is a key risk factor for type 2 diabetes, and weight loss is known to dramatically reduce risk, at least among people who were at high risk to begin with. However, even people without obvious risk factors like excessive weight or a family history of the disease still have a relatively large chance (about 1 percent) of developing type 2 diabetes: Could these individuals also reduce their risk of type 2 diabetes through weight loss? What did the researchers do and find? We looked at inherited genetic mutations that predispose people to lower body weight, and asked how much these mutations tend to protect people from type 2 diabetes, across 287,394 self-reported white British individuals from the UK Biobank cohort. We found that these mutations seem to offer about the same degree of protection against type 2 diabetes regardless of a person's body weight, family history of type 2 diabetes, or genetic risk for type 2 diabetes, suggesting that weight loss would have a similarly uniform protective effect for all individuals. What do these findings mean? These findings suggest that all individuals can substantially reduce their type 2 diabetes risk through weight loss, and support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk as a public health measure. However, a key limitation to keep in mind is that genetic mutations, because they act across an individual's entire lifespan, are not a perfect proxy for weight loss interventions that happen only later in life.