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.
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America. m-urbanek@northwestern.edu
authors.forename: Margrit
authors.initials: M
authors.lastname: Urbanek
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.forename: Hoon
authors.initials: H
authors.lastname: Lee
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.forename: Lynn P
authors.initials: LP
authors.lastname: Lowe
authors.forename: Christine
authors.initials: C
authors.lastname: Ackerman
authors.forename: Nadereh
authors.initials: N
authors.lastname: Jafari
authors.forename: Alan R
authors.initials: AR
authors.lastname: Dyer
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Boyd E
authors.initials: BE
authors.lastname: Metzger
authors.forename: William L
authors.initials: WL
authors.lastname: Lowe
mesh_terms: D044466:Asian People / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D015331:Cohort Studies; D005215:Fasting / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D011256:Pregnancy Outcome; D054419:Receptors, Adiponectin / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D052243:Resistin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013785:Thailand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D006442:Glycated Hemoglobin; D015850:Interleukin-6; D016209:Interleukin-8; D054419:Receptors, Adiponectin; D054411:Receptors, Leptin; D052243:Resistin; D014409:Tumor Necrosis Factor-alpha; C475420:ADIPOR2 protein, human; C499624:RETN protein, human