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. 2009 Jun;58(6):1428-33.
doi: 10.2337/db08-1739. Epub 2009 Feb 19.

Type 2 diabetes risk alleles are associated with reduced size at birth

Rachel M Freathy  1 , Amanda J Bennett, Susan M Ring, Beverley Shields, Christopher J Groves, Nicholas J Timpson, Michael N Weedon, Eleftheria Zeggini, Cecilia M Lindgren, Hana Lango, John R B Perry, Anneli Pouta, Aimo Ruokonen, Elina Hyppönen, Chris Power, Paul Elliott, David P Strachan, Marjo-Riitta Järvelin, George Davey Smith, Mark I McCarthy, Timothy M Frayling, Andrew T Hattersley
Affiliations

Type 2 diabetes risk alleles are associated with reduced size at birth

Rachel M Freathy et al. Diabetes. 2009 Jun.

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 x 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 (P(trend) = 5 x 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.

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Figures

FIG. 1.
FIG. 1.
A: Meta-analysis plot showing the association of fetal CDKAL1 genotype with birth weight across all four studies (overall P = 2 × 10−5; total n = 18,679; heterogeneity statistics: I2 = 19.9%, P = 0.29). B: Meta-analysis plot showing association of fetal HHEX-IDE genotype with birth weight across all four studies (overall P = 0.004; total n = 18,958; heterogeneity statistics: I2 = 49.7%, P = 0.11). Analyses are adjusted for sex and gestational age.
FIG. 2.
FIG. 2.
Bar graph showing the association between birth weight and the number of fetal type 2 diabetes risk alleles at CDKAL1 (rs10946398) and HHEX-IDE (rs1111875) across all four studies (n = 18,438). Estimates of the difference in birth weight are adjusted for sex and gestational age. Error bars show 95% CIs.
See this image and copyright information in PMC

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References

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