Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
PLoS One. 2012;7(3):e32958. doi: 10.1371/journal.pone.0032958. Epub 2012 Mar 30.
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.
由于炎症介质与胰岛素抵抗以及发生糖尿病和妊娠糖尿病的风险相关，我们假设炎症基因途径成员的遗传变异会影响妊娠期间的血糖水平和相关表型。我们通过在 Hyperglycemia and Adverse Pregnancy Outcome（HAPO）队列中检测 31 个炎症途径基因中的遗传变异与关联来评估这一假设，HAPO 是一项大型多民族多中心研究，旨在解决血糖低于显性糖尿病对妊娠结局的影响。
在 24-32 周妊娠期间进行口服葡萄糖耐量试验时，从 HAPO 参与者的血液样本中测量空腹、1 小时和 2 小时血糖、空腹和 1 小时 C 肽以及 HbA1c 水平。我们在 3836 名欧洲血统和 1713 名泰国孕妇中检测了 31 个炎症途径基因中 458 个映射到 SNPs 与代谢表型之间的关联。与 TNF alpha 和 HbA1c 关联最强（rs1052248；每个等位基因 C 增加 0.04%；p 值=4.4×10(-5)），与 RETN 和空腹血浆葡萄糖（rs1423096；每个等位基因 A 降低 0.7mg/dl；p 值=1.1×10(-4)）、IL8 和 1 小时血浆葡萄糖（rs2886920；每个等位基因 T 降低 2.6mg/dl；p 值=1.3×10(-4)）、ADIPOR2 和空腹 C 肽（rs2041139；每个等位基因 A 降低 0.55ug/L；p 值=1.4×10(-4)）、LEPR 和 1 小时 C 肽（rs1171278；每个等位基因 T 降低 0.62ug/L；p 值=2.4×10(-4)）和 IL6 和 1 小时血浆葡萄糖（rs6954897；每个等位基因 G 降低 2.29mg/dl，p 值=4.3×10(-4)）。
根据本研究中检测的基因，炎症途径不太可能对妊娠期间的母体代谢表型产生重大影响，但途径中个别成员（如 RETN、IL8、ADIPOR2、LEPR、IL6 和 TNF alpha）的变异可能会对孕妇的代谢表型产生影响。
