322-OR: Higher Placental GKN1 Expression Is Associated with Reduced Pregnancy Beta-Cell Function

by sugaradmin



Introduction and Objective: We aimed to identify candidate placental proteins that impact beta-cell function in human pregnancy through transcriptome-wide placental gene expression analysis.Methods: In the Gen3G cohort, we measured glucose and insulin levels fasting, 1, and 2 hours after a 75-gram oral glucose load given at 24-30 weeks’ gestation. We calculated the Pregnancy Insulin Physiology (PIP) Index, a measure of pregnancy beta-cell function. We performed bulk RNA sequencing of placental samples (N=15,216 RNA transcripts) and analyzed differential gene expression to identify transcripts most strongly associated with beta-cell function (PIP index, box-cox transformed, standardized) after adjustment for maternal age, gravidity, body mass index (BMI), gestational age at delivery, and offspring sex. We used the false discovery rate (FDR) to adjust P-values. We then quantified nominal associations (P<0.05) between identified transcripts and other glycemia-related traits with weighted linear regression models.Results: In 433 cohort participants, we identified GKN1, encoding gastrokinin 1, as the top differentially expressed gene in relation to the PIP index. Gastrokinin 1, a secreted protein highly expressed in the stomach, has putative roles in mucosal homeostasis and fat metabolism. Higher placental GKN1 expression was associated with lower beta-cell function (log2 change in GKN1 expression per SD change in beta-cell function=-0.44, FDR=8.1×10-6). Placentas from pregnancies with gestational diabetes had higher GKN1 expression compared to unaffected pregnancies (log2 fold change=1.13, FDR= 4.2×10-3). Higher GKN1 expression was associated with higher BMI (β=0.2, P=0.04), post-load glucose (β=0.3, P=3.5×10-5) and insulin (β=0.2, P=0.007), and lower insulin sensitivity-adjusted Stumvoll first phase estimate (β=-0.2, P=0.001).Conclusion: Higher placental GKN1 expression is associated with reduced beta-cell function in pregnancy and gestational diabetes.

Disclosure

C.E. Powe: Research Support; Dexcom, Inc. Other Relationship; Mediflix, Wolters Kluwer Health. F. White: None. C. Allard: None. L. Shook: None. F. Aguet: Employee; Predicta Biosciences, Illumina, Inc. K. Ardlie: None. A. Edlow: Research Support; Merck Sharp & Dohme Corp. Consultant; Merck Sharp & Dohme Corp, Mirvie, Inc. L. Bouchard: None. P. Jacques: None. J.C. Florez: Research Support; Novo Nordisk. S. Karumanchi: Consultant; Thermofisher Scientific, Comanche Biopharma. Stock/Shareholder; Aggamin Therapeutics, Roche Diagnostics. Other Relationship; Beth Israel Deaconess Medical Center, Cedars-Sinai Medical Center. M. Hivert: None.

Funding

National Institutes of Health (R01HD094150)



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