Advertisement

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

  1. Rachel M. Freathy1,2,
  2. Amanda J. Bennett3,
  3. Susan M. Ring4,
  4. Beverley Shields2,
  5. Christopher J. Groves3,
  6. Nicholas J. Timpson5,6,
  7. Michael N. Weedon1,2,
  8. Eleftheria Zeggini5,
  9. Cecilia M. Lindgren5,
  10. Hana Lango1,2,
  11. John R.B. Perry1,2,
  12. Anneli Pouta7,8,
  13. Aimo Ruokonen9,
  14. Elina Hyppönen10,
  15. Chris Power10,
  16. Paul Elliott11,
  17. David P. Strachan12,
  18. Marjo-Riitta Järvelin7,1113,
  19. George Davey Smith4,6,
  20. Mark I. McCarthy3,5,
  21. Timothy M. Frayling1,2 and
  22. Andrew T. Hattersley1,2
  1. 1Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.;
  2. 2Department of Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.;
  3. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.;
  4. 4Department of Social Medicine, University of Bristol, Bristol, U.K.;
  5. 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.;
  6. 6Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, U.K.;
  7. 7National Public Health Institute, Oulu, Finland;
  8. 8Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland;
  9. 9Department of Clinical Chemistry, University of Oulu, Oulu, Finland;
  10. 10MRC Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, U.K.;
  11. 11Department of Epidemiology and Public Health, Imperial College London, London, U.K.;
  12. 12Division of Community Health Sciences, St. George's, University of London, London, U.K.;
  13. 13Institute of Health, University of Oulu, Oulu, Finland.
  1. Corresponding author: Andrew T. Hattersley, andrew.hattersley{at}pms.ac.uk.

Abstract

OBJECTIVE Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.

RESEARCH DESIGN AND METHODS We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.

RESULTS We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.

CONCLUSIONS Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying brief report, p. 1440, and commentary, p. 1255.

    • Received December 15, 2008.
    • Accepted February 16, 2009.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Published online before print February 19, 2009, doi: 10.2337/db08-1739 Diabetes June 2009 vol. 58 no. 6 1428-1433
  1. » Abstract
  2. Full Text
  3. Full Text (PDF)
  4. Online-Only Appendix
  5. All Versions of this Article:
    1. db08-1739v1
    2. 58/6/1428 most recent

Social Bookmarking

Current Issue

  1. February 2012, 61 (2)
  1. Current Issue
  1. Alert me to new issues of Diabetes
Advertisement