The genetic risk of gestational diabetes in South Asian women
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eLife assessment
This paper asks whether a risk score integrating the impact of common genetic variants across the genome (polygenic risk score) on Type II Diabetes is also to any degree predictive of diabetes in pregnancy (Gestational diabetes or GDM).The study population comprises women of South Asian ancestry, who are particularly susceptible to GDM. Strong evidence is presented in favour of the hypothesis of the hypothesis in two sizeable cohorts, one from Canada and the other from the UK. The paper will be useful to those studying women's health in pregnancy, and in particular GDM, which is associated with a number of adverse pregnancy outcomes.
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Abstract
South Asian women are at increased risk of developing gestational diabetes mellitus (GDM). Few studies have investigated the genetic contributions to GDM risk. We investigated the association of a type 2 diabetes (T2D) polygenic risk score (PRS), on its own, and with GDM risk factors, on GDM-related traits using data from two birth cohorts in which South Asian women were enrolled during pregnancy. 837 and 4372 pregnant South Asian women from the SouTh Asian BiRth CohorT (START) and Born in Bradford (BiB) cohort studies underwent a 75-g glucose tolerance test. PRSs were derived using genome-wide association study results from an independent multi-ethnic study (~18% South Asians). Associations with fasting plasma glucose (FPG); 2 hr post-load glucose (2hG); area under the curve glucose; and GDM were tested using linear and logistic regressions. The population attributable fraction (PAF) of the PRS was calculated. Every 1 SD increase in the PRS was associated with a 0.085 mmol/L increase in FPG ([95% confidence interval, CI=0.07–0.10], p=2.85×10 −20 ); 0.21 mmol/L increase in 2hG ([95% CI=0.16–0.26], p=5.49×10 −16 ); and a 45% increase in the risk of GDM ([95% CI=32–60%], p=2.27×10 −14 ), independent of parental history of diabetes and other GDM risk factors. PRS tertile 3 accounted for 12.5% of the population’s GDM alone, and 21.7% when combined with family history. A few weak PRS and GDM risk factors interactions modulating FPG and GDM were observed. Taken together, these results show that a T2D PRS and family history of diabetes are strongly and independently associated with multiple GDM-related traits in women of South Asian descent, an effect that could be modulated by other environmental factors.
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eLife assessment
This paper asks whether a risk score integrating the impact of common genetic variants across the genome (polygenic risk score) on Type II Diabetes is also to any degree predictive of diabetes in pregnancy (Gestational diabetes or GDM).The study population comprises women of South Asian ancestry, who are particularly susceptible to GDM. Strong evidence is presented in favour of the hypothesis of the hypothesis in two sizeable cohorts, one from Canada and the other from the UK. The paper will be useful to those studying women's health in pregnancy, and in particular GDM, which is associated with a number of adverse pregnancy outcomes.
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Reviewer #1 (Public Review):
The clearly stated authors' aims were to test the association of a type 2 diabetes polygenic risk score (PRS) generated from a multiethnic GWAS with GDM and related traits (Fasting glucose and 2 hour post load glucose, and area under the curve glucose) in pregnant South Asian women from two large well characterized cohorts. Also to test the population attributable fraction of the PRS on GDM and to determine whether the effect of the PRs is modulated by other GDM risk factors including age, BMI, diet quality, birth country, education and parity.
Major strengths are the large and well characterized populations used for generation of the PRS and GDM data and for testing the performance of the PRS thus providing clear results.
The authors achieved their aims and the results support their conclusions. The work …
Reviewer #1 (Public Review):
The clearly stated authors' aims were to test the association of a type 2 diabetes polygenic risk score (PRS) generated from a multiethnic GWAS with GDM and related traits (Fasting glucose and 2 hour post load glucose, and area under the curve glucose) in pregnant South Asian women from two large well characterized cohorts. Also to test the population attributable fraction of the PRS on GDM and to determine whether the effect of the PRs is modulated by other GDM risk factors including age, BMI, diet quality, birth country, education and parity.
Major strengths are the large and well characterized populations used for generation of the PRS and GDM data and for testing the performance of the PRS thus providing clear results.
The authors achieved their aims and the results support their conclusions. The work provides insight into which South Asian women are predisposed to GDM.
Who develops GDM and which of these women then develop T2DM later are major research questions of public health importance. This study provides important insight into the first question and provides a hypothesis for the second question but the PRS won't be available for clinical use in the near future.
Ultimately the aim is to find practical ways to direct resources to those at highest risk in detecting and managing GDM and its complications and in identifying and intervening in those at highest risk of developing T2DM later on.
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Reviewer #2 (Public Review):
Aims:
This paper asks whether a risk score integrating the impact of common genetic variants across the genome (polygenic risk score) on Type II Diabetes is also to any degree predictive of diabetes in pregnancy (Gestational Diabetes Mellitus or GDM). A number of quantitative endpoints relevant to the risk of GDM are also evaluated. The authors also test for any evidence of statistical interaction between the GDM polygenic risk score and some predictive risk factors - asking if a high polygenic risk score has a more (or less) powerful effect on GDM risk in certain strata of BMI and diet quality. They find no evidence of such interaction.
Strengths/Weaknesses:
The cohorts are strong for the investigation of this question. The paper integrates data from well phenotyped pregnant South Asian women participants …
Reviewer #2 (Public Review):
Aims:
This paper asks whether a risk score integrating the impact of common genetic variants across the genome (polygenic risk score) on Type II Diabetes is also to any degree predictive of diabetes in pregnancy (Gestational Diabetes Mellitus or GDM). A number of quantitative endpoints relevant to the risk of GDM are also evaluated. The authors also test for any evidence of statistical interaction between the GDM polygenic risk score and some predictive risk factors - asking if a high polygenic risk score has a more (or less) powerful effect on GDM risk in certain strata of BMI and diet quality. They find no evidence of such interaction.
Strengths/Weaknesses:
The cohorts are strong for the investigation of this question. The paper integrates data from well phenotyped pregnant South Asian women participants on two continents - 837 participants from the Canadian START study and 4372 participants from the UK Born in Bradford cohort. Among these, 734 women had GDM.
There are some differences between the cohorts - for example the occurrence of GDM was about 25% in the START study participants and only around half that in the BIB study, there were differences in the specific origins of the two cohorts within South Asia, and there were life course and lifestyle differences. Appropriate caveats are made by the authors.
The T2D PRS used was derived from previously published data in which only 18% of the population was of South Asian ethnic origins. This could lead to some inaccuracy when applied to an entirely South Asian population, which the authors acknowledge. It seems the "best available" approach to the problem.
Regarding the analyses for interaction, even these cohorts seem likely underpowered to detect this.
Aims achieved?
The authors achieved their aims and showed that the PRS for T2D had small magnitude, but highly significant, association with fasting plasma glucose, two hour post OGTT glucose, and the risk of GDM (47% increase in risk overall). They calculated the population attributable fraction of being in the top tertile of PRS compared with the bottom two tertiles. They did not find any evidence of interactions.
Likely impact:
This paper adds to the literature supporting the hypothesis that genetic factors predisposing to T2D and GDM substantially overlap.
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