Interaction of Polygenetic Variants for Gestational Diabetes Mellitus Risk with Breastfeeding and Korean Balanced Diet to Influence Type 2 Diabetes Risk in Later Life in a Large Hospital-Based Cohort

The etiologies of gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) are similar. Genetic and environmental factors interact to influence the risk of both types of diabetes. We aimed to determine if the polygenetic risk scores (PRS) for GDM risk interacted with lifestyles to influence type 2 diabetes risk in women aged >40 years in a large hospital-based city cohort. The participants with GDM diagnosis without T2DM before pregnancy were considered the case group (n = 384) and those without GDM and T2DM as the control (n = 33,956) to explore GDM-related genetic variants. The participants with T2DM were the case (n = 2550), and the control (n = 33,956) was the same as GDM genetic analysis for the interaction analysis of GDM genetic risk with lifestyles to influence T2DM risk. The genetic variants for the GDM risk were selected from a genome-wide association study (GWAS), and their PRS from the best model with gene-gene interactions were generated. GDM was positively associated with age at first pregnancy, body mass index (BMI) at age 20, and education level. A previous GDM diagnosis increased the likelihood of elevated fasting serum glucose concentrations and HbA1c contents by 8.42 and 9.23 times in middle-aged and older women. However, it was not associated with the risk of any other metabolic syndrome components. Breast-feeding (≥1 year) was inversely associated with the T2DM risk in later life. In the genetic variant-genetic variant interaction, the best model with 5-SNPs included PTPRD_rs916855529, GPC6_rs9589710, CDKAL1_rs7754840, PRKAG2_rs11975504, and PTPRM_rs80164908. The PRS calculated from the 5-SNP model was positively associated with the GDM risk by 3.259 (2.17-4.89) times after adjusting GDM-related covariates. The GDM experience interacted with PRS for the T2DM risk. Only in non-GDM women PRS was positively associated with T2DM risk by 1.36-times. However, long breastfeeding did not interact with the PRS for T2DM risk. Among dietary patterns, only a Korean-style balanced diet (KBD) showed an interaction with PRS for the T2DM risk. Participants with a low-PRS had the lowest serum glucose concentrations in the high KBD intake but not low KBD intake. In conclusion, participants with a high PRS for GDM risk are positively associated with T2DM risk, and breastfeeding for ≥1 year and consuming KBD offset the PRS for GDM risk to influence T2DM risk in middle-aged and older.