Longitudinal association of cumulative risk factors in early life, genetic risk, and healthy lifestyles during adulthood with the risk of type 2 diabetes

BACKGROUND: The combined influence of early life risk factors on the type 2 diabetes (T2D) development is not well-studied, and it is unclear whether these associations can by modified by genetic risk and healthy lifestyles in later life. METHODS: We studied 148,621 participants in the UK Biobank. We calculated early-life risk scores (ERS) by summing the cumulative number of three early-life risk factors: low birth weight, maternal smoking during pregnancy, and non-breastfed as a baby. We estimated polygenic risk scores (PRS) for T2D and calculated participants' modifiable healthy lifestyle score (MHS) during adulthood. RESULTS: A total of 7,408 incident T2D were identified. ERS showed a positive dose-response association with T2D risk. Compared with participants with 0 ERS, those with 3 ERS had the highest risk of developing T2D (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.65, 2.26). This association was not modified by T2D-PRS or MHS. In the joint exposure analyses, compared with participants with the lowest risk exposure (i.e., lowest ERS combined with lowest T2D-PRS/healthy lifestyle in later life), we observed highest risk of T2D among individuals with the highest ERS combined with the highest tertile of T2D-PRS (HR = 6.67, 95% CI: 5.43, 8.20) or an unhealthy lifestyle in later life (HR = 4.99, 95% CI: 3.54, 7.02), respectively. CONCLUSIONS: Early-life risk factors are associated with a higher risk of T2D in a dose-response manner, regardless of genetic risk or later-life healthy lifestyle. Therefore, identifying early-life modifiable risk factors is helpful to develop strategies of T2D prevention.