Type 2 Diabetes TCF7L2 Risk Genotypes Alter Birth Weight: A Study of 24,053 Individuals

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.

Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS

“…The largest study to date, which genotyped TCF7L2 rs7903146 in 24,053 subjects including 4578 subjects from NFBC1966, has demonstrated a modest effect of genotype on the early insulin response to oral glucose [5]. Our findings therefore support the notion that, in contrast to type 2 diabetes, genetic variation influencing beta cell dysfunction is not a primary and essential determinant of PCOS pathogenesis.…”

“…Common variants in the gene encoding transcription factor 7-like 2 (TCF7L2) have been reproducibly shown to display powerful associations with type 2 diabetes in a number of studies [2][3][4], with a typical per allele odds ratio (OR) of ∼1.35. Most current evidence favours impaired insulin secretion as the mechanism responsible [3,5]. Although insulin resistance clearly plays a major role in the aetiology of PCOS, there is evidence for a concomitant (potentially primary) disturbance of beta cell function [6], endorsing the biological candidacy of TCF7L2 with respect to susceptibility to PCOS.…”

No evidence that established type 2 diabetes susceptibility variants in the PPARG and KCNJ11 genes have pleiotropic effects on early growth

“…This power is similar to studies in this cohort of the glucokinase −30 G/A variant (8.5%, ∼46 g for birthweight) or TCF7L2 rs7903146 (7%, ∼38 g for birthweight) [9]. …”

“…In contrast, the largest study to date, involving 1,930 women and child pairs, found no association between the P12A variant and indices of early growth [8]. Finally, a large-scale study, which found evidence for higher birthweight amongst infants carrying type 2 diabetes-susceptibility alleles at the TCF7L2 locus, attributed this to an indirect effect mediated by the effects of maternal genotype on glucose levels during the pregnancy [9].…”

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

“…All participants were born at term and none had parents, grandparents or siblings with any type of diabetes; none was receiving medication known to interfere with glucose homeostasis. Freathy et al [21] found each risk allele of the rs7903146 variant to be associated with an increase in birthweight by 18 g, which was subsequently explained by maternal hypoinsulinaemia and hyperglycaemia in pregnancy and consequently increased offspring birthweight. Since birthweight was an original inclusion variable, this was adjusted for in all analyses.…”