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PMID: 17503332 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals.

American journal of human genetics ·Vol. 80 ·No. 6 ·2007-06-00 ·Pages 1150-61

Freathy RM, Weedon MN, Bennett A, Hypponen E, Relton CL, Knight B, Shields B, Parnell KS, Groves CJ, Ring SM, Pembrey ME, Ben-Shlomo Y, Strachan DP, Power C, Jarvelin MR, McCarthy MI, Davey Smith G, Hattersley AT, Frayling TM

Abstract

The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.

MeSH Terms
Alleles Birth Weight Diabetes Mellitus, Type 2/genetics Female Genetic Variation Genotype Gestational Age Glucokinase/genetics Humans Male Polymorphism, Genetic Pregnancy Risk Factors TCF Transcription Factors/genetics Transcription Factor 7-Like 2 Protein
Chemicals
TCF Transcription Factors TCF7L2 protein, human Transcription Factor 7-Like 2 Protein Glucokinase
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Freathy Rachel M
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
Weedon Michael N
Bennett Amanda
Hypponen Elina
Relton Caroline L
Knight Beatrice
Shields Beverley
Parnell Kirstie S
Groves Christopher J
Ring Susan M
Pembrey Marcus E
Ben-Shlomo Yoav
Strachan David P
Power Chris
Jarvelin Marjo-Riitta
McCarthy Mark I
Davey Smith George
Hattersley Andrew T
Frayling Timothy M
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/518517
Published
2007-06-00
Epub
2007-00-23
Pages
1150-61
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1867102
Subset
IM
Grants
Medical Research Council · G0500070 · United Kingdom
Medical Research Council · G0000934 · United Kingdom
Wellcome Trust · 068545/z/02 · United Kingdom
Department of Health · PHCS/C4/4/016 · United Kingdom
Medical Research Council · G0400546 · United Kingdom
Wellcome Trust · gr069224ma · United Kingdom
Medical Research Council · G9815508 · United Kingdom
External Links
PubMed source DOI: 10.1086/518517 PMC Full Text View journal details
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