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Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations
  1. Mengying Li1,
  2. Mohammad L Rahman1,2,
  3. Jing Wu3,
  4. Ming Ding4,
  5. Jorge E Chavarro4,5,
  6. Yuan Lin6,
  7. Sylvia H Ley4,7,
  8. Wei Bao8,
  9. Louise G Grunnet9,
  10. Stefanie N Hinkle1,
  11. Anne Cathrine B Thuesen10,11,
  12. Edwina Yeung1,
  13. Robert E Gore-Langton12,
  14. Seth Sherman12,
  15. Line Hjort9,13,
  16. Freja Bach Kampmann9,14,
  17. Anne Ahrendt Bjerregaard15,
  18. Peter Damm13,16,
  19. Fasil Tekola-Ayele1,
  20. Aiyi Liu1,
  21. James L Mills1,
  22. Allan Vaag17,
  23. Sjurdur F Olsen15,
  24. Frank B Hu4,5,
  25. Cuilin Zhang1
  1. 1Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
  2. 2Department of Population Medicine and Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Glotech, Rockville, Maryland, USA
  4. 4Department of Nutrition, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
  5. 5Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
  6. 6Epidemiology Department, Richard M. Fairbanks School of Public Health, Indiana University, Bloomington, Indiana, USA
  7. 7Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA
  8. 8Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA
  9. 9Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark
  10. 10Steno Diabetes Center Copenhagen, Gentofte, Denmark
  11. 11Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
  12. 12The Emmes Company, LLC, Rockville, Maryland, USA
  13. 13Departments of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark
  14. 14Division for Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Lyngby, Denmark
  15. 15Nutrition Group, Statens Serum Institut, Copenhagen, Denmark
  16. 16Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  17. 17Early Clinical Development and Innovative Medicines, AstraZeneca, Mölndal, Sweden
  1. Correspondence to Dr Cuilin Zhang; zhangcu{at}


Objective Women 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 methods This 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.

Results Women 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).

Conclusions Among white women with a history of GDM, higher GRS for T2D was associated with an increased risk of T2D.

  • type 2 diabetes
  • gestational diabetes
  • genetic risk score
  • dietary quality
  • prospective cohort studies

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  • ML and MLR contributed equally.

  • Contributors CZ obtained the funding, designed the Diabetes & Women’s Health Study and oversighted the study. JEC, AL, SFO, LGG, ACBT, JLM, EY, AV, FBH and CZ made substantial contribution to the acquisition of data. ML and JW conducted data analysis. ML and MLR drafted the manuscript. ML, MLR, JW, MD, JEC, YL, SHL, WB, LGG, SNH, ACBT, EY, REG-L, SS, LH, FBK, AAB, PD, FT-A, AL, JLM, AV, SFO, FBH and CZ contributed to the interpretation of data and revised the article critically for important intellectual content. All authors gave final approval of the version to be published. CZ and ML 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 (NICHD) at the National Institutes of Health (contract numbers HHSN275201000020C, HHSN275201500003C, HHSN275201300026I, HSN275201100002I). The Nurses’ Health Study II 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 EU (FP7-289346-EarlyNutrition). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement We have enforced a restriction on the data used in our analysis to protect the identity of the participants involved in the analysis. Please contact the corresponding author to access the data.

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