Maternal Physical Activity, Placental Variation In LEKR1/CCNL1, And Offspring Birthweight - A Sex-specific Gene-Environment Interaction

Abstract

Gene-environment interactions have been reported to contribute to fetal growth. The placenta mediates effects of maternal behaviors on fetal growth. The role of placental genetic variation in previously reported sex-specific associations of maternal leisure time physical activity (LTPA) with offspring birth size is unknown. PURPOSE: We examined whether offspring sex-specific associations of maternal LTPA with offspring birthweight (BW) differ by placental fetal growth-related common genetic variations. METHODS: Participants (N=412) were identified from the Omega study, a prospective pregnancy cohort study. Participants reported LTPA duration (hours/week) and energy expenditure (MET-hours/week) in the year before pregnancy (ppLTPA) and in early pregnancy (epLTPA). BW was abstracted from medical records. Placental tissue was collected at delivery and genotyped for common single nucleotide polymorphisms (minor allele frequency (MAF) >20%) related to fetal growth: rs1482853 (LEKR1/CCNL1), rs9883204 (ADCY5), rs1042725 (HMGA2), rs724557 (LCORL), rs1801253 (ADRB1), and rs4432842 (5q11.2). Interaction terms and stratified regression models were used to determine effect modification of associations of maternal LTPA with offspring BW by genotypes. RESULTS: Among females, rs1482853 (MAF=43%) modified associations of ppLTPA (P for interaction=0.05) and epLTPA (P for interaction=0.01) duration with BW. Each quartile increase in ppLTPA duration was associated with 154g greater BW (95% CI: 12, 295) among females homozygous for the rs1482853 minor allele, while it was associated with 120g lower BW (95% CI: -223, -18) among heterozygous females. Similarly, each quartile increase in epLTPA duration was associated with 158g greater BW (95% CI: 1, 316) among females homozygous for the rs1482853 minor allele, while it was associated with a marginally significant 53g lower BW (95% CI: -156, 50) among heterozygous females. Genotypes did not modify LTPA-BW associations among males. Results were similar for energy expenditure. CONCLUSIONS: Placental genetic variation in LEKR1/CCNL1 may modify associations between maternal LTPA and birthweight among females, but not males. Replication of results and research on mechanisms of interaction between LTPA, placental genes, and fetal growth are warranted.