Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes

AbstractBackgroundClinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and MethodsA genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10,543 mothers and up to 16,317 offspring of European origin, with replication in 10,660 mothers and 7,561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (e.g. maternal BMI and glucose, birthweight).ResultsWe found that approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and that the fetal genome made a surprisingly minor contribution to explaining variation in GWG. We were unable to identify any genetic variants that reached genome-wide levels of significance (P<5×10−8) and replicated. Some established maternal variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birthweight variants were largely unrelated to GWG.ConclusionWe found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

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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

Journal of Personalized Medicine ◽

10.3390/jpm11111175 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1175

Author(s):

Sunmin Park

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Genetic Variants ◽

Genetic Variant ◽

Later Life ◽

Serum Glucose ◽

Large Hospital ◽

Balanced Diet

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.

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