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

Margrit Urbanek*, M. Geoffrey Hayes, Hoon Lee, Rachel M. Freathy, Lynn P. Lowe, Christine Ackerman, Nadereh Jafari, Alan R. Dyer, Nancy J. Cox, David B. Dunger, Andrew T. Hattersley, Boyd E. Metzger, William L. Lowe

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: 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. Results: 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). Conclusions: 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.

Original languageEnglish (US)
Article numbere32958
JournalPloS one
Volume7
Issue number3
DOIs
StatePublished - Mar 30 2012

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Alleles
Mothers
pregnancy
alleles
Phenotype
phenotype
Glucose
Pregnancy
pregnancy outcome
genetic variation
fasting
C-Peptide
Fasting
Pregnancy Outcome
Medical problems
Genes
glucose
glycohemoglobin
Gestational Diabetes
peptides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Urbanek, Margrit ; Hayes, M. Geoffrey ; Lee, Hoon ; Freathy, Rachel M. ; Lowe, Lynn P. ; Ackerman, Christine ; Jafari, Nadereh ; Dyer, Alan R. ; Cox, Nancy J. ; Dunger, David B. ; Hattersley, Andrew T. ; Metzger, Boyd E. ; Lowe, William L. / The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. In: PloS one. 2012 ; Vol. 7, No. 3.
@article{e00606a10c974307b8fc16b7b52a5153,
title = "The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy",
abstract = "Background: 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. Results: 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). Conclusions: 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.",
author = "Margrit Urbanek and Hayes, {M. Geoffrey} and Hoon Lee and Freathy, {Rachel M.} and Lowe, {Lynn P.} and Christine Ackerman and Nadereh Jafari and Dyer, {Alan R.} and Cox, {Nancy J.} and Dunger, {David B.} and Hattersley, {Andrew T.} and Metzger, {Boyd E.} and Lowe, {William L.}",
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The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. / Urbanek, Margrit; Hayes, M. Geoffrey; Lee, Hoon; Freathy, Rachel M.; Lowe, Lynn P.; Ackerman, Christine; Jafari, Nadereh; Dyer, Alan R.; Cox, Nancy J.; Dunger, David B.; Hattersley, Andrew T.; Metzger, Boyd E.; Lowe, William L.

In: PloS one, Vol. 7, No. 3, e32958, 30.03.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy

AU - Urbanek, Margrit

AU - Hayes, M. Geoffrey

AU - Lee, Hoon

AU - Freathy, Rachel M.

AU - Lowe, Lynn P.

AU - Ackerman, Christine

AU - Jafari, Nadereh

AU - Dyer, Alan R.

AU - Cox, Nancy J.

AU - Dunger, David B.

AU - Hattersley, Andrew T.

AU - Metzger, Boyd E.

AU - Lowe, William L.

PY - 2012/3/30

Y1 - 2012/3/30

N2 - Background: 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. Results: 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). Conclusions: 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.

AB - Background: 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. Results: 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). Conclusions: 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.

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