Lifestyle factors and fetal and childhood origins of type 2 diabetes: A prospective study of Chinese and European adults.

Background Early life development plays a key role in adult type 2 diabetes mellitus (T2DM), but the extent to which can be attenuated by lifestyle is unknown. Objectives To investigate the independent relevance of genetic predisposition to low birth weight and childhood obesity for T2DM, and their attenuation by adherence to a healthy lifestyle in adulthood. Methods Genetic risk scores (GRSs) were estimated for birth weight and childhood body mass index (BMI) with genetic risk categories according to their quintiles in 90,029 and 321,225 participants from China Kadoorie Biobank (CKB) (mean age, 53.0 years) and UK Biobank (UKB) (56.1 years). Healthy lifestyle scores were defined on non-current smoking, moderate alcohol consumption, healthy diet, regular physical activity, non-obesity, categorized into healthy (4∼5 factors), intermediate (2∼3 factors) and unhealthy (0∼1 factor) lifestyle. Results GRSs for low birth weight and childhood BMI were associated with higher T2DM risks. Healthy lifestyle was related to lower T2DM risk, and there was an additive interaction with increasing childhood BMI GRS and decreasing healthy lifestyle factors on T2DM risk, while no additive interaction was observed for birth weight. Participants with a healthy compared with an unhealthy lifestyle had a 68% (hazard ratio: 0.32; 95%CI: 0.22, 0.47) and 77% (0.23; 0.19, 0.28) lower T2DM risk among participants at high genetic risk (lowest quintile) of low birth weight in CKB and UKB. Among participants with high genetic risk (highest quintile) of childhood obesity, compared with unhealthy lifestyle, adherence to a healthy lifestyle was associated with a 69% (0.31; 0.22, 0.46) and 80% (0.20; 0.17, 0.25) lower risk in CKB and UKB. Conclusions Genetic predisposition to low birth weight and childhood obesity were associated with higher risk of adult T2DM and these excess risks were attenuated by adherence to a healthy lifestyle in adulthood, particularly among those at high genetic risk of childhood obesity.