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The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.

ABSTRACT: Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort, a large multiethnic multicenter study designed to address the impact of glycemia less than overt diabetes on pregnancy outcome.Fasting, 1-hour, and 2-hour glucose, fasting and 1-hour C-peptide, and HbA1c levels were measured in blood samples obtained from HAPO participants during an oral glucose tolerance test at 24-32 weeks gestation. We tested for association between 458 SNPs mapping to 31 genes in the inflammatory pathway and metabolic phenotypes in 3836 European ancestry and 1713 Thai pregnant women. The strongest evidence for association was observed with TNF alpha and HbA1c (rs1052248; 0.04% increase per allele C; p-value = 4.4×10(-5)), RETN and fasting plasma glucose (rs1423096; 0.7 mg/dl decrease per allele A; p-value = 1.1×10(-4)), IL8 and 1 hr plasma glucose (rs2886920; 2.6 mg/dl decrease per allele T; p-value = 1.3×10(-4)), ADIPOR2 and fasting C-peptide (rs2041139; 0.55 ug/L decrease per allele A; p-value = 1.4×10(-4)), LEPR and 1-hour C-peptide (rs1171278; 0.62 ug/L decrease per allele T; p-value = 2.4×10(-4)), and IL6 and 1-hour plasma glucose (rs6954897; -2.29 mg/dl decrease per allele G, p-value = 4.3×10(-4)).Based on the genes surveyed in this study the inflammatory pathway is unlikely to have a strong impact on maternal metabolic phenotypes in pregnancy although variation in individual members of the pathway (e.g. RETN, IL8, ADIPOR2, LEPR, IL6, and TNF alpha,) may contribute to metabolic phenotypes in pregnant women.

SUBMITTER: Urbanek M

PROVIDER: S-EPMC3316547 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.

Urbanek Margrit M Hayes M Geoffrey MG Lee Hoon H Freathy Rachel M RM Lowe Lynn P LP Ackerman Christine C Jafari Nadereh N Dyer Alan R AR Cox Nancy J NJ Dunger David B DB Hattersley Andrew T AT Metzger Boyd E BE Lowe William L WL

PloS one 20120330 3

<h4>Background</h4>Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort, a large multieth ...[more]

PMID: 22479352

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Project description:Despite well-known adverse health effects of maternal smoking during pregnancy (MSP), it is still unclear if MSP varies geographically and if neighborhood socioeconomic deprivation (SED) plays an important role in MSP. This study aims to investigate small-area geographic variation in MSP and examine the association of SED with MSP.The Missouri Adolescent Female Twin Study (MOAFTS) is a cohort study of female like-sex twins born in Missouri to Missouri-resident parents during 1975-1985. Biological mothers completed a baseline interview in 1995-1998 and reported MSP with the twins. Residential address of the mother at birth was geocoded. We developed a census tract-level SED index using a common factor approach based on 21 area-level socioeconomic variables from the 1980 Census data. Multilevel logistic regressions estimated geographic heterogeneity (random effect) in MSP and the odds ratios (ORs, fixed effects) of neighborhood SED associated with MSP.Of 1658 MOAFTS mothers, 35.2% reported any MSP and 21.9% reported MSP beyond the first trimester. Neighborhood SED was associated with any MSP (the highest vs. the lowest quartile: OR = 1.90, 95% confidence interval [CI] = 1.40-2.57, Ptrend<0.001) and MSP beyond the first trimester (OR = 1.98, 95% CI = 1.38-2.85, Ptrend = 0.002) in unadjusted analyses. After adjusting for individual covariates (demographics, socioeconomic conditions, alcohol use, and parents' cohabitation), neighborhood SED was not associated with MSP, but geographic variation still persisted in MSP (variance = 0.41, P = 0.003) and in MSP beyond the first trimester (variance = 0.82, P<0.001).Neighborhood SED was associated with MSP in unadjusted analyses but this association could be explained by individual socioeconomic conditions. Nonetheless, significant geographic variation in MSP persisted and was not accounted for by differences in neighborhood SED. To develop effective interventions to reduce MSP, further studies are necessary to explore underlying reasons for its geographic variation.

Project description:Obesity during pregnancy increases the risk of adverse clinical outcomes and is associated with low-grade chronic inflammation. We describe maternal metabolic risk and inflammation by maternal weight status, and evaluate the association of metabolic and inflammatory markers with birthweight in a group of pregnant Mexican women.This study derived from a prospective cohort of healthy pregnant women <14 weeks of gestation, receiving prenatal care at National Institute of Perinatology (Mexico, 2009-2013). Metabolic and inflammatory markers were measured in maternal serum in all three pregnancy trimesters (1st: 11.42±1.7; 2nd: 21.06±2.4; 3rd: 32.74±2.3 weeks). Pregestational weight was self-reported, and body mass index (BMI) was calculated. Gestational weight gain was evaluated in the third trimester. Newborn´s weight was measured at birth. We carried out correlations, general mixed linear model and regression analyses, based on pregestational weight (self-reported), body mass index (BMI), gestational weight gain (evaluated in the third trimester) and newborn weight (measured at birth).Of the 177 women included in the study (mean age = 26.93±8.49), thirty-eight percent (n = 67) were overweight or had obesity, and 32.8% (n = 58) showed excessive gestational weight gain. We found insulin, lipids (including total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides-TG), leptin and interleukin 1b (IL-1b) all increased significantly (p<0.05) during pregnancy. Pregestational maternal weight status altered longitudinal concentrations of insulin, leptin, adiponectin, TG and C reactive protein. Excessive gestational weight gain was associated with higher maternal insulin in the third trimester (p<0.05). Early pregnancy leptin and TNF? were determinants of birthweight in women with normal weight, but not in overweight or obese women.Maternal weight status affected the concentrations of insulin, leptin, adiponectin, triglycerides and C reactive protein throughout pregnancy. The role of early leptin and TNF? in fetal growth need further study given the association was only observed in normal weight women. This study presents data distribution of metabolic and inflammatory markers of normal weight and overweight/obese women that did not develop GDM, preeclampsia nor macrosomia.

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Project description:IntroductionTelomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth.Methods and materialsParticipants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth.ResultsAfter adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (β = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy.DiscussionThese findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.

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The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.

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The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.

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