(P31-075-23) Associations of Lifestyle and Genetic Risks With Obesity and Related Comorbidities in the UK Biobank

Objectives: To examine the independent and joint associations and interactions of lifestyle risk score (LRS) and body mass index (BMI)-related genetic risk score (GRS) with obesity and its comorbidities.

Methods: We included 352 324 UK Biobank participants aged 40-70 years in 2006-10. LRS included physical activity, dietary score, sedentary behavior, sleep quality, and smoking. Each factor was grouped into 5 levels, with 0 and 4 points for the healthiest and least healthy levels (LRS range: 0-20). Risk alleles of 940 BMI-related genetic variants were summed as GRS. Both LRS and GRS were grouped as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5). Multivariable linear or logistic regression examined cross-sectional associations of LRS and GRS with BMI, body fat percentage (BF%), and obesity (BMI≥30 kg/m²); Cox regression examined prospective associations with incident cardiovascular disease (CVD), diabetes, and obesity-related cancer (ORC).

Results: At baseline, 81 697 participants (23%) had obesity. During follow-up (median=12.5 years), 4% of the participants outcome-free at baseline developed CVD, diabetes, and ORC, respectively. LRS and GRS were independently associated with all outcomes. Multiplicative interactions of LRS and GRS were seen for BMI, BF%, and CVD (P≤0.074). Comparing high vs low LRS, βs (95% confidence intervals [CIs]) for BMI were 3.15 (3.03-3.26) and 2.21 (2.12-2.30) in the high and low GRS groups, respectively; βs for BF% were 4.34 and 4.05; hazard ratios (HRs) for CVD risk were 1.62 and 1.32. Associations of LRS with other outcomes were similar across GRS. Additive interactions were seen for all outcomes but BF% (P≤0.073). Compared with participants with low on both LRS and GRS, those high on both had 5.41 (5.32-5.50)-kg/m² higher BMI, 7.18% higher BF%, and 12.86-, 1.50-, 4.14-, and 1.43-fold risks of obesity, CVD, diabetes, and ORC, respectively.

Conclusions: Lifestyle was associated with higher risks of obesity and its comorbidities in all GRS groups, highlighting the broad benefits of healthy lifestyle. The synergistic associations of LRS and GRS with risks of obesity and its comorbidities, as well as stronger associations of lifestyle with BMI, BF%, and CVD risk among high genetic-risk people, emphasized the importance of lifestyle interventions targeting this population for public health purposes.

Funding Sources: None