Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations

Abstract

ObjectiveWomen with a history of gestational diabetes mellitus (GDM) have an exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for T2D in this population. We examined the association of a genetic risk score (GRS) with risk of T2D in two independent populations of women with a history of GDM and how this association might be modified by non-genetic determinants for T2D.Research design and methodsThis cohort study included 2434 white women with a history of GDM from the Nurses’ Health Study II (NHSII, n=1884) and the Danish National Birth Cohort (DNBC, n=550). A GRS for T2D was calculated using 59 candidate single nucleotide polymorphisms for T2D identified from genome-wide association studies in European populations. An alternate healthy eating index (AHEI) score was derived to reflect dietary quality after the pregnancy affected by GDM.ResultsWomen on average were followed for 21 years in NHSII and 13 years in DNBC, during which 446 (23.7%) and 155 (28.2%) developed T2D, respectively. The GRS was generally positively associated with T2D risk in both cohorts. In the pooled analysis, the relative risks (RRs) for increasing quartiles of GRS were 1.00, 0.97, 1.25 and 1.19 (p trend=0.02). In both cohorts, the association appeared to be stronger among women with poorer (AHEI <median) than better dietary quality (AHEI ≥median), although the interaction was not significant. For example, in NHSII, the RRs across increasing quartiles of GRS were 1.00, 0.99, 1.51 and 1.29 (p trend=0.06) among women with poorer dietary quality and 1.00, 0.83, 0.81 and 0.94 (p trend=0.79) among women with better dietary quality (p interaction=0.11).ConclusionsAmong white women with a history of GDM, higher GRS for T2D was associated with an increased risk of T2D.

Harnessing the power of polygenic risk scores to predict type 2 diabetes and its subtypes in a high-risk population of British Pakistanis and Bangladeshis in a routine healthcare setting

“…This finding persists after adjustment for established clinical risk factors and the QDiabetes risk score. Our findings are in keeping with prior reports of an association between a type 2 diabetes-PRS and development of type 2 diabetes in white (18) and South-East Asian (19) women with a history of GDM. While previous studies have applied alternative type 2 diabetes-PRSs to women of South Asian origin to identify those at higher risk of GDM(39), none to date have explored their association with type 2 diabetes development in women with GDM.…”

“…Secondly, we tested whether the PRS enhances the prediction of incident type 2 diabetes when integrated with the commonly-used clinical risk score, QDiabetes (17). Thirdly, we sought to investigate whether the PRS alone might predict the progression to type 2 diabetes from gestational diabetes in BPB women, as has been observed in European and South-East Asian populations (18,19). Finally, we explored whether the PRS might predict clinically heterogeneous type 2 diabetes subgroups at diagnosis.…”

All thresholds of maternal hyperglycaemia from the WHO 2013 criteria for gestational diabetes identify women with a higher genetic risk for type 2 diabetes

“…However, non-genetic environmental factors related to development of type 2 diabetes such as diet, exercise and socioeconomic deprivation remain a key consideration, as genetics will explain only a portion of risk for type 2 diabetes in women with a history of GDM. For example, a recent study of 2,434 women of white ethnicity found that ~26% women with a history of GDM and a type 2 diabetes genetic risk score in the highest quartile had developed diabetes at follow-up compared with ~23% of women in the lowest genetic risk score quartile 16 . The GSs in this study were not analysed for their association with incident T2D in the HAPO Follow-Up Study, but this would be useful to establish and make direct comparisons with the results of this work in the future…”

“…It is not known whether lifestyle interventions such as guided diet and exercise programmes could modify risk of progressing to type 2 diabetes in women with a history of GDM and a high genetic risk. A study of 1,744 white women suggested that risk of developing type 2 diabetes after a pregnancy affected by GDM was greatest in women with a high genetic risk score and poor diet 16 . On the other hand, while the Diabetes Prevention Program (DPP) 50 trial found that lifestyle intervention or metformin treatment reduced risk of progression to type 2 diabetes in women with impaired glucose tolerance and a history of GDM (according to relevant criteria at time of diagnosis), a genetic risk score for type 2 diabetes did not influence treatment response 51 .…”

“…Whilst these thresholds were chosen for their Obstetric risks, the HAPO Follow-Up Study found that women diagnosed by the newer criteria have a higher risk of developing disorders of glucose metabolism, including T2D, 10 years after the episode of GDM 8 . A proportion of this risk can be attributed to genetic predisposition, since genome wide association study (GWAS) data from large, non-pregnant population-based studies have identified multiple loci associated with FPG 9 and type 2 diabetes 10 and some of these are shared with GDM 11 – 16 . Specific to the WHO 2013 criteria, single nucleotide polymorphisms (SNPs) at the GCK and TCF7L2 loci were shown to be associated with FPG and 2-hour glucose levels post-OGTT in women with GDM 17 .…”