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. 2012 Feb;61(2):391-400.
doi: 10.2337/db11-1039. Epub 2011 Dec 21.

Postnatal growth and DNA methylation are associated with differential gene expression of the TACSTD2 gene and childhood fat mass

Alexandra Groom  1 , Catherine Potter, Daniel C Swan, Ghazaleh Fatemifar, David M Evans, Susan M Ring, Valerie Turcot, Mark S Pearce, Nicholas D Embleton, George Davey Smith, John C Mathers, Caroline L Relton
Affiliations

Postnatal growth and DNA methylation are associated with differential gene expression of the TACSTD2 gene and childhood fat mass

Alexandra Groom et al. Diabetes. 2012 Feb.

Abstract

Rapid postnatal growth is associated with increased risk of childhood adiposity. The aim of this study was to establish whether this pathway is mediated by altered DNA methylation and gene expression. Two distinct cohorts, one preterm (n=121) and one term born (n=6,990), were studied. Exploratory analyses were performed using microarrays to identify differentially expressed genes in whole blood from children defined as "slow" (n=10) compared with "rapid" (n=10) postnatal (term to 12 weeks corrected age) growers. Methylation within the identified TACSTD2 gene was measured in both cohorts, and rs61779296 genotype was determined by Pyrosequencing or imputation and analyzed in relation to body composition at 9-15 years of age. In cohort 1, TACSTD2 expression was inversely correlated with methylation (P=0.016), and both measures were associated with fat mass (expression, P=0.049; methylation, P=0.037). Although associated with gene expression (cohort 1, P=0.008) and methylation (cohort 1, P=2.98×10(-11); cohort 2, P=3.43×10(-15)), rs61779296 was not associated with postnatal growth or fat mass in either cohort following multiple regression analysis. Hence, the lack of association between fat mass and a methylation proxy SNP suggests that reverse causation or confounding may explain the initial association between fat mass and gene regulation. Noncausal methylation patterns may still be useful predictors of later adiposity.

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Figures

FIG. 1.
FIG. 1.
Topography of the TACSTD2 gene. DNA methylation analysis of TACSTD2 focused on seven CpG sites within the promoter region of the gene, located on chromosome (Chr)1. Positions are annotated with respect to the start codon. Two SNPs were identified at 162 and 158 base pairs from the closest CpG site analyzed (rs61779295 and rs61779296). Information was derived from UCSC Genome Browser on Human Mar. 2006 (NCBI36/hg18) Assembly.
FIG. 2.
FIG. 2.
Defining the causal pathway linking postnatal growth with fat mass. The schematic depicts the postulated relationship among postnatal growth, TACSTD2 methylation, TACSTD2 gene expression, and fat mass. The figure provides a framework with which to infer the direction of causality between exposure (postnatal growth), outcome (childhood adiposity), and intermediate phenotypes (DNA methylation and gene expression). A SNP in the gene of interest can be used to infer causality. A robust correlation was observed between rs61779196 and DNA methylation (bold arrow). This permitted the use of the SNP as a surrogate for methylation levels. Genotype is not influenced by confounding factors and cannot be influenced by reverse causation (where the outcome, in this instance adiposity, influences methylation). Lack of association of the TACSTD2 SNP rs61779296 with fat mass provides evidence that DNA methylation is unlikely to have a causal influence on adiposity. Confounding is the most likely explanation for the observed association between fat mass and DNA methylation (and expression) in the TACSTD2 gene.
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