July 4, 2024

Impact of Genetic Risk and Lifestyle on Obesity and Related Health Conditions

Obesity is a non-infectious pandemic driven by sedentary lifestyles and high intake of energy-dense foods. It is heritable and polygenic, with over a thousand genetic variants linked to weight gain. Traditionally, it has been believed that genetic predisposition to obesity is unmodifiable.

However, gene-environment interaction studies suggest that certain lifestyle factors can mitigate the effects of specific obesity-related genes. These studies have been limited to a few genes and lifestyle factors. The interaction between modifiable lifestyle factors and genetic predisposition to obesity, and how they can alleviate its burden, remains largely unknown.

About the Study:

Researchers in the present study examined whether modifiable lifestyle factors can offset the genetic risk of obesity. They analyzed data from over 338,600 white British individuals from the United Kingdom Biobank who met genetic quality control standards, excluding more than 1,000 subjects with missing data on body mass index (BMI) or obesity-related morbidities (ORMs), resulting in a final sample of 337,554 individuals.

A polygenic score (PGS) was calculated based on a genome-wide association study for BMI in people of European ancestry. A healthy lifestyle score was computed from five lifestyle factors: alcohol intake, sleep duration, sedentary behaviors, diet, and physical activity. The primary outcome was incident obesity, determined by analyzing Biobank health data. Prevalent obesity, defined as a baseline BMI ? 30 kg/m�, was the secondary outcome.

Absolute risks were predicted by estimating odds ratios (ORs) and hazard ratios (HRs) for prevalent and incident obesity by PGS percentile and lifestyle. HRs were estimated using Cox proportional hazard regression models, and ORs were assessed using a logistic regression model. Additionally, the predicted probability of obesity by age 75 was calculated. Incident ORM was determined using hospital data, self-reports, or death registry records.

Interactions between genetic risk for obesity and lifestyle were evaluated using additive and multiplicative interaction analyses. Cox proportional hazard regression models examined the associations of lifestyle and genetic risk with incident obesity and ORMs. The association of lifestyle categories, genetic risk categories, or both with prevalent obesity was examined using multivariable logistic regression.

Findings:

Obese individuals had a higher PGS and fewer healthy lifestyle factors. Both an unhealthy lifestyle and high genetic risk were independently and jointly associated with obesity. The study examined the isolated effect of genetic risk on obesity by adjusting for lifestyle groups, and the effect of lifestyle on obesity by adjusting for genetic risk groups.

A high genetic risk was associated with a heightened risk of incident and prevalent obesity, regardless of lifestyle groups. Similarly, poor lifestyle risk was associated with a higher risk of incident and prevalent obesity, independent of genetic risk. The HR of obesity for individuals with a poor lifestyle and high genetic risk was 3.54 compared to those with a healthy lifestyle and low genetic risk.

For incident obesity, the median probability of obesity by age 75 was 2.8% in the poor lifestyle group and 1.7% in the healthy lifestyle group. The corresponding estimates based on prevalent obesity were 30.7% and 13.9%, respectively. Analysis of the relative excess risk due to the interaction between lifestyle and genetic risk revealed significant additive interactions; multiplicative interaction analysis also produced consistent results.

Avoiding sedentary behavior was associated with the lowest odds of obesity, independent of genetic risk. Individuals with a healthy lifestyle and high PGS had risks of ORMs comparable to those with low PGS. Conversely, individuals with a poor lifestyle and high PGS had higher ORM risks. The association between PGS and ORM risks was null after adjusting for BMI.