Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA
Harvard Medical School, Boston, MA.
Diabetes. 2018 Dec;67(12):2703-2709. doi: 10.2337/db18-0203. Epub 2018 Sep 26.
Many common genetic polymorphisms are associated with glycemic traits and type 2 diabetes (T2D), but knowledge about genetic determinants of glycemic traits in pregnancy is limited. We tested genetic variants known to be associated with glycemic traits and T2D in the general population for associations with glycemic traits in pregnancy and gestational diabetes mellitus (GDM). Participants in two cohorts (Genetics of Glucose regulation in Gestation and Growth [Gen3G] and Hyperglycemia and Adverse Pregnancy Outcome [HAPO]) underwent oral glucose tolerance testing at 24-32 weeks' gestation. We built genetic risk scores (GRSs) for elevated fasting glucose and insulin, reduced insulin secretion and sensitivity, and T2D, using variants discovered in studies of nonpregnant individuals. We tested for associations between these GRSs, glycemic traits in pregnancy, and GDM. In both cohorts, the fasting glucose GRS was strongly associated with fasting glucose. The insulin secretion and sensitivity GRSs were also significantly associated with these traits in Gen3G, where insulin measurements were available. The fasting insulin GRS was weakly associated with fasting insulin (Gen3G) or C-peptide (HAPO). In HAPO (207 GDM case subjects), all five GRSs (T2D, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity) were significantly associated with GDM. In Gen3G (43 GDM case subjects), both the T2D and insulin secretion GRSs were associated with GDM; effect sizes for the other GRSs were similar to those in HAPO. Thus, despite the profound changes in glycemic physiology during pregnancy, genetic determinants of fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk.
许多常见的遗传多态性与血糖特征和 2 型糖尿病（T2D）有关，但关于妊娠期间血糖特征的遗传决定因素的知识有限。我们检测了在一般人群中与血糖特征和 T2D 相关的遗传变异，以研究其与妊娠期间血糖特征和妊娠糖尿病（GDM）的关系。两个队列（妊娠和生长期间葡萄糖调节的遗传学[Gen3G]和高血糖与不良妊娠结局[HAPO]）的参与者在妊娠 24-32 周时进行口服葡萄糖耐量试验。我们使用在非妊娠个体研究中发现的变异，构建了升高的空腹血糖和胰岛素、降低的胰岛素分泌和敏感性以及 T2D 的遗传风险评分（GRS）。我们检测了这些 GRS 与妊娠期间血糖特征和 GDM 之间的关系。在两个队列中，空腹血糖 GRS 与空腹血糖高度相关。胰岛素分泌和敏感性 GRS 也与 Gen3G 中这些特征显著相关，其中有胰岛素测量值。空腹胰岛素 GRS 与空腹胰岛素（Gen3G）或 C 肽（HAPO）弱相关。在 HAPO（207 例 GDM 病例）中，所有五个 GRS（T2D、空腹血糖、空腹胰岛素、胰岛素分泌和胰岛素敏感性）与 GDM 显著相关。在 Gen3G（43 例 GDM 病例）中，T2D 和胰岛素分泌 GRS 与 GDM 相关；其他 GRS 的效应大小与 HAPO 相似。因此，尽管妊娠期间血糖生理发生了深刻变化，但在妊娠之外发现的与空腹血糖、空腹胰岛素、胰岛素分泌和胰岛素敏感性相关的遗传决定因素会影响 GDM 风险。
