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Diabetologia. 2016 Sep;59(9):1920-7. doi: 10.1007/s00125-016-4019-z. Epub 2016 Jun 23.

Low birthweight and risk of type 2 diabetes: a Mendelian randomisation study.

Wang T1,2,3, Huang T1,2, Li Y2, Zheng Y2, Manson JE4,5,6, Hu FB2,6, Qi L7,8,9.

Author information

  • 1Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA.
  • 2Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 3Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • 4Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 5Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 6Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 7Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, New Orleans, LA, 70112, USA. lqi1@tulane.edu.
  • 8Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. lqi1@tulane.edu.
  • 9Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. lqi1@tulane.edu.

Abstract

AIMS/HYPOTHESIS:

Low birthweight has been associated with a high risk of type 2 diabetes mellitus in observational studies. However, it remains unclear whether this relation is causal.

METHODS:

The present study included 3627 individuals with type 2 diabetes and 12,974 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-Up Study. A genetic risk score (GRS) was calculated based on five low-birthweight-related single nucleotide polymorphisms (SNPs). We assessed the evidence for causality first by examining the association of the GRS and the individual SNPs with type 2 diabetes, and second by performing a Mendelian randomisation analysis to estimate the potentially causal effect size of low birthweight on type 2 diabetes.

RESULTS:

In a meta-analysis of the two studies, each 1 point increment in the GRS was associated with a 6% (95% CI 3%, 9%) higher risk of type 2 diabetes. CCNL1 rs900400 and 5q11.2 rs4432842 showed dose-response associations with risk of type 2 diabetes; the corresponding ORs and 95% CIs were 1.09 (1.03, 1.16) and 1.09 (1.02, 1.16), respectively. Furthermore, we observed an overall Mendelian randomisation OR of 2.94 (95% CI 1.70, 5.16; pā€‰<ā€‰0.001) for type 2 diabetes per 1 SD lower genetically determined birthweight.

CONCLUSIONS/INTERPRETATION:

A genetically lowered birthweight was associated with increased susceptibility to type 2 diabetes. Our findings support a potential causal relation between birthweight and risk of type 2 diabetes, providing new evidence to support the role of intrauterine exposures in the pathogenesis of type 2 diabetes.

KEYWORDS:

Birthweight; Mendelian randomisation; Type 2 diabetes

PMID:
27333884
PMCID:
PMC4970938
[Available on 2017-09-01]
DOI:
10.1007/s00125-016-4019-z
[PubMed - in process]
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