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Diabetologia

, Volume 61, Issue 8, pp 1758–1768 | Cite as

Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations

  • Ming Ding
  • Jorge Chavarro
  • Sjurdur Olsen
  • Yuan Lin
  • Sylvia H. Ley
  • Wei Bao
  • Shristi Rawal
  • Louise G. Grunnet
  • Anne Cathrine B. Thuesen
  • James L. Mills
  • Edwina Yeung
  • Stefanie N. Hinkle
  • Wei Zhang
  • Allan Vaag
  • Aiyi Liu
  • Frank B. Hu
  • Cuilin Zhang
Article

Abstract

Aims/hypothesis

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse.

Methods

We conducted a case–control study among 2636 women with GDM and 6086 non-GDM control women from the Nurses’ Health Study II and the Danish National Birth Cohort. A total of 112 susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for the false discovery rate.

Results

For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1) and rs7041847 (GLIS3). In addition, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs4506565 (TCF7L2), that had previously been significantly associated with GDM risk. Furthermore, compared with participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the ORs for GDM were 1.07 (95% CI 0.93, 1.22), 1.23 (95% CI 1.07, 1.41) and 1.53 (95% CI 1.34, 1.74) for participants in the second, third and fourth (highest) quartiles, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM, including family history of type 2 diabetes, smoking status, BMI and age.

Conclusions/interpretation

In this large-scale case–control study with women from two independent populations, eight novel GDM SNPs were identified. These findings offer the potential to improve our understanding of the aetiology of GDM, and particularly of biological mechanisms related to beta cell function.

Keywords

Genetic risk score Genetic variants Gestational diabetes mellitus 

Abbreviations

DNBC

Danish National Birth Cohort

DWH

Diabetes & Women’s Health study

FDR

False discovery rate

GDM

Gestational diabetes mellitus

GRS

Genetic risk score

GRS-BC

Genetic risk score related to beta cell function

GRS-IR

Genetic risk score related to insulin resistance

GWAS

Genome-wide association study

NHSII

Nurses’ Health Study II

Notes

Contribution statement

JC, AL, SO, LGG, ACBT, JLM, EY, AV, FBH, and CZ made substantial contributions to the conception and design of the study and acquisition of data. SNH, SR, and SHL contributed to acquisition of data. WZ, WB, and YL contributed to data interpretation. MD conducted data analysis and drafted the article. JC, SO, YL, SHL, WB, SR, LGG, ACBT, JLM, EY, SNH, WZ, AV, AL, FBH and CZ revised the article critically for important intellectual content; all authors gave final approval of the version to be published. CZ and MD are responsible for the integrity of the work as a whole.

Funding

This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (contract numbers HHSN275201000020C, HHSN275201500003C, HHSN275201300026I, HSN275201100002I). The NHSII cohort is supported by the National Institutes of Health (grant number R01 CA67262, UM1 CA176726, R01 CA50385, and NICHD contract HHSN275201000020C). Financial support for the Danish component was received from: March of Dimes Birth Defects Foundation (6-FY-96-0240, 6-FY97-0553, 6-FY97-0521, 6-FY00-407), Innovation Fund Denmark (grant number 09-067124 and 11-115923, ‘Centre for Fetal Programming’), the Health Foundation (11/263-96), the Heart Foundation (96-2-4-83-22450) and the EU (FP7-289346-EarlyNutrition).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4637_MOESM1_ESM.pdf (154 kb)
ESM Tables (PDF 153 kb)

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  • Ming Ding
    • 1
  • Jorge Chavarro
    • 1
    • 2
    • 3
  • Sjurdur Olsen
    • 4
  • Yuan Lin
    • 5
  • Sylvia H. Ley
    • 1
    • 3
  • Wei Bao
    • 6
  • Shristi Rawal
    • 7
  • Louise G. Grunnet
    • 8
  • Anne Cathrine B. Thuesen
    • 8
  • James L. Mills
    • 5
  • Edwina Yeung
    • 5
  • Stefanie N. Hinkle
    • 5
  • Wei Zhang
    • 4
  • Allan Vaag
    • 9
  • Aiyi Liu
    • 5
  • Frank B. Hu
    • 1
    • 2
    • 3
  • Cuilin Zhang
    • 5
  1. 1.Department of NutritionHarvard T. H. Chan School of Public HealthBostonUSA
  2. 2.Department of EpidemiologyHarvard T. H. Chan School of Public HealthBostonUSA
  3. 3.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  4. 4.Centre for Fetal Programming, Statens Serum InstitutCopenhagenDenmark
  5. 5.Division of Intramural Population ResearchEunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of HealthBethesdaUSA
  6. 6.Department of Epidemiology, College of Public HealthUniversity of IowaIowa CityUSA
  7. 7.Department of Nutritional Sciences, School of Health ProfessionsRutgers UniversityNewarkUSA
  8. 8.Department of EndocrinologyRigshospitalet University HospitalCopenhagenDenmark
  9. 9.AstraZeneca, Early Clinical Development and Innovative MedicinesMölndalSweden

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