Genetic Determinants of Adiponectin Regulation Revealed by Pregnancy

Abstract

Objective: We investigated genetic determinants of adiponectin during pregnancy to reveal novel biology of adipocyte regulation. Methods: We conducted a genome-wide association study in 1,322 pregnant women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with adiponectin measured at ~28 weeks of gestation. We selected variants reaching P<5x10−5 for de novo genotyping in two replication cohorts (Genetics of Glycemic regulation in Gestation and Growth (Gen3G) N=522; ECOGENE-21 N=174). Results: In the combined meta-analysis, the maternal T allele of rs900400 located on chr3q25 (near LEKR1/CCNL1) was associated with lower maternal adiponectin (β±SE= −0.18±0.03 SD of adiponectin per risk allele; P=1.5x10−8; N=2004; multivariable adjusted models). In contrast, rs900400 showed only nominal association with adiponectin in a large sample of non-pregnant women (β±SE= −0.012±0.006; P=0.05; N=16,678 women from the ADIPOgen consortium). Offspring rs900400 T risk allele was associated with greater neonatal skin fold thickness (β±SE=0.19±0.04 SD per risk allele; P=4.1x10−8; N=1489) and higher cord blood leptin (β±SE=0.28±0.05 log-leptin per risk allele; P=8.2x10−9; N=502), but not with cord blood adiponectin (P=0.23; N=495). T allele of rs900400 was associated with higher expression of TIPARP in adipocytes. Conclusion: Our investigations of adipokines during pregnancy and early life suggest that rs900400 has a role in adipocyte function.