Genetic Variants Influencing Insulin Deficiency and Resistance Are Associated with Adverse Pregnancy Outcomes

Background: We tested maternal genetic determinants of insulin deficiency (ID) and insulin resistance (IR) for association with hyperglycemia-related adverse pregnancy outcomes. Methods: We applied non-negative matrix factorization to GWAS data (325 type 2 diabetes [T2D]-associated variants, 135 T2D-related traits) to derive 2 trait/variant clusters. We verified associations between cluster polygenic scores (PGSs) and ID/IR-related traits in non-pregnant women (n=35341). In pregnant women (n=1521) we tested for associations between cluster PGSs and infant birthweight (BW) percentile for gestational age and secondary outcomes (gestational diabetes [GDM], large/small for gestational age BW, hypertensive disorders, neonatal ICU admission, preterm birth) using models adjusted for age, insurance, parity, race, and principal components. Effect sizes are for a 1-SD PGS increase. Results: Cluster 1 had ID-related traits/variants (e.g., decreased insulin response and disposition index, increased fasting glucose, variants near MTNR1B, CDKAL1, C2CD4A/B SLC30A8). Outside pregnancy, the ID cluster PGS was associated with T2D (OR=1.2, p=2×10-7) and HbA1c (β=0.05%, p=2.8×10-9). In pregnancy, the ID cluster PGS was associated with higher BW percentile (β=1.7, p=0.04) and GDM (OR=1.3, p=0.004), but not other outcomes. Cluster 2 had IR-related traits/variants (e.g., decreased HDL and insulin sensitivity, increased triglycerides [TG] and fasting insulin, variants near IRS1, GRB14, LPL, FTO). Outside pregnancy, the IR cluster PGS was associated with T2D (OR=1.1, p=2×10-5), HbA1c (β=0.06 %, p=1.2×10-14), TG (β =4.2 mg/dL, p=4.4×10-15) and inversely associated with HDL (β=-1.7mg/dL, p=5.5×10-32). In pregnancy, the IR cluster PGS was associated with preterm birth (OR=1.3, p=0.006), but not BW percentile or GDM. Conclusion: Maternal genetic determinants of ID are associated with increased BW; genetic determinants of IR are associated with preterm birth. Disclosure S.Hsu: None. K.James: None. A.Medina baez: None. K.Smith: None. J.M.Mercader: None. M.Udler: None. C.E.Powe: Consultant; Mediflix, Inc., Other Relationship; Wolters Kluwer Health.