The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2nd Trimester Lipid Levels and Preterm Birth

Deregulation of the circadian system in humans and animals can lead to various adverse reproductive outcomes due to genetic mutations and environmental factors. In addition to the clock, lipid metabolism may also play an important role in influencing reproductive outcomes. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with preterm birth (PTB). In this study we aimed to determine if single nucleotide polymorphisms (SNPs) in genes from the circadian clock and lipid metabolism influence 2nd trimester maternal lipid levels and if this is associated with an increased risk for PTB. We genotyped 72 SNPs across 40 genes previously associated with various metabolic abnormalities on 930 women with 2nd trimester serum lipid measurements. SNPs were analyzed for their relationship to levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides (TG) using linear regression. SNPs were also evaluated for their relationship to PTB using logistic regression. Five SNPs in four genes met statistical significance after Bonferroni correction (p < 1.8 × 10-4) with one or more lipid levels. Of these, four SNPs were in lipid related metabolism genes: rs7412 in APOE with total cholesterol, HDL and LDL, rs646776 and rs599839 in CELSR2-PSRC1-SORT1 gene cluster with total cholesterol, HDL and LDL and rs738409 in PNPLA3 with HDL and TG and one was in a circadian clock gene: rs228669 in PER3 with TG. Of these SNPs only PER3 rs228669 was marginally associated with PTB (p = 0.02). In addition, PER3 rs228669 acts as an effect modifier on the relationship between TG and PTB.