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BACKGROUND: Early-life development plays a key role in adult type 2 diabetes (T2D), but the extent to which this can be attenuated by lifestyle is unknown. OBJECTIVES: The aim was to investigate the independent relevance of genetic predisposition to low birth weight and childhood obesity for T2D, and their attenuation, by adherence to a healthy lifestyle in adulthood. METHODS: Genetic risk scores (GRSs) were estimated for birth weight and childhood BMI with genetic risk categories according to their quintiles in 90,029 and 321,225 participants from the China Kadoorie Biobank (CKB; mean age, 53.0 y) and UK Biobank (UKB; 56.1 y). Healthy lifestyle scores were defined on noncurrent smoking, moderate alcohol consumption, healthy diet, regular physical activity, and nonobesity, and 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 T2D risks. Healthy lifestyle was related to lower T2D risk, and there was an additive interaction with increasing childhood BMI GRS and decreasing healthy lifestyle factors on T2D risk, whereas no additive interaction was observed for birth weight. Participants with a healthy compared with an unhealthy lifestyle had a 68% (HR: 0.32; 95% CI: 0.22, 0.47) and 77% (0.23; 0.19, 0.28) lower T2D risk among participants at high genetic risk (lowest quintile) of low birth weight in the CKB and UKB. Among participants with high genetic risk (highest quintile) of childhood obesity, compared with those with an 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 of T2D in the CKB and UKB. CONCLUSIONS: Genetic predisposition to low birth weight and childhood obesity were associated with higher risk of adult T2D and these excess risks were attenuated by adherence to a healthy lifestyle in adulthood, particularly among those at high genetic risk of childhood obesity.

Original publication




Journal article


Am J Clin Nutr

Publication Date





749 - 758


birth weight, childhood obesity, gene–environment interaction, healthy lifestyle, type 2 diabetes, Adult, Birth Weight, Child, China, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Humans, Life Style, Middle Aged, Pediatric Obesity, Prospective Studies, Risk Factors