Department of Community and Family Medicine, Duke University Medical Center, 2200 West Main Street, Ste. 600, Durham, NC 27705, USA.
Cancer Causes Control. 2012 Apr;23(4):635-45. doi: 10.1007/s10552-012-9932-y. Epub 2012 Mar 6.
Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.
Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.
Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = -9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m(2), β = -20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.
Our data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
胰岛素样生长因子 2（IGF2）调控区的甲基化改变先前与肥胖有关，并且几种恶性肿瘤包括结肠癌、食管癌和前列腺腺癌也与这种改变有关，其机制可能是通过表达改变和/或印记丢失，但这些 DNA 甲基化标记在人体中的功能意义尚未得到证实。我们研究了 IGF2 差异甲基化区域（DMR）的 DNA 甲基化、脐带血（UCB）中循环 IGF2 蛋白浓度和新生儿出生体重之间的相关性。
我们于 2005 年至 2009 年期间招募了 300 名孕妇，获取了她们的问卷调查数据。通过亚硫酸氢盐焦磷酸测序法检测 UCB 中的 DNA 甲基化，通过 ELISA 检测 UCB 中可溶性 IGF2 的浓度。采用广义线性回归模型来检验 DMR 甲基化与 IGF2 水平之间的关系。
较低的 IGF2 DMR 甲基化与血浆 IGF2 蛋白浓度升高相关（β = -9.87，p < 0.01）；这种关联在肥胖孕妇（孕前 BMI > 30 kg/m2，β = -20.21，p < 0.0001）所生的婴儿中更强。在调整了母亲种族/民族、孕前 BMI、吸烟、妊娠期糖尿病和婴儿性别后，IGF2 浓度升高与较高的出生体重相关（p < 0.0001）。在 H19 DMR 中未出现这些关联模式。
我们的数据表明，IGF2 DMR 甲基化的变异是调节循环 IGF2 浓度的重要机制，而循环 IGF2 浓度是肥胖以及结肠癌、食管癌和前列腺癌的潜在危险因素；这种关联可能取决于孕前肥胖。
