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

Freathy RM, Bennett AJ, Ring SM, Shields B, Groves CJ, Timpson NJ, Weedon MN, Zeggini E, Lindgren CM, Lango H, Perry JR, Pouta A, Ruokonen A, Hyppönen E, Power C, Elliott P, Strachan DP, Järvelin MR, Smith GD, McCarthy MI, Frayling TM, Hattersley AT - Diabetes (2009)

Bottom Line: 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 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)).

View Article: PubMed Central - PubMed

Affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, 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 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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Related in: MedlinePlus

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.
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Figure 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.

Mentions: The fetal risk alleles of SNPs rs10946398 (CDKAL1) and rs1111875 (HHEX-IDE) were associated with reduced birth weight in the meta-analysis (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) (Table 2 and Fig. 1) (see Table 3 for individual study results). Fetal genotypes at the other three loci were not associated with birth weight (all P> 0.01). The variability of effect size estimates among studies was consistent with random statistical fluctuations, suggesting no underlying heterogeneity (all P> 0.1). Adjustment for additional covariates of birth weight made little difference to the results (data not shown).


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

Freathy RM, Bennett AJ, Ring SM, Shields B, Groves CJ, Timpson NJ, Weedon MN, Zeggini E, Lindgren CM, Lango H, Perry JR, Pouta A, Ruokonen A, Hyppönen E, Power C, Elliott P, Strachan DP, Järvelin MR, Smith GD, McCarthy MI, Frayling TM, Hattersley AT - Diabetes (2009)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682672&req=5

Figure 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.
Mentions: The fetal risk alleles of SNPs rs10946398 (CDKAL1) and rs1111875 (HHEX-IDE) were associated with reduced birth weight in the meta-analysis (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) (Table 2 and Fig. 1) (see Table 3 for individual study results). Fetal genotypes at the other three loci were not associated with birth weight (all P> 0.01). The variability of effect size estimates among studies was consistent with random statistical fluctuations, suggesting no underlying heterogeneity (all P> 0.1). Adjustment for additional covariates of birth weight made little difference to the results (data not shown).

Bottom Line: 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 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)).

View Article: PubMed Central - PubMed

Affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, 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 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.

Show MeSH
Related in: MedlinePlus