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

Abstract

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 2 nd 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 2 nd 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 C ELSR2-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.

hPER3 promotes adipogenesis via hHSP90AA1-mediated inhibition of Notch1 pathway

“…Some studies have reported the association of hPER3 with obesity, for instance, PER3 methylation levels are related to childhood obesity 42 , hPER3 increased the BMI of those who sleep too late 13 , rs228669 of hPER3 showed association with triglycerides 43 , and cg10059324 also showed correlation with insulin resistance 44 . In our experiment, PER3 in humans or mice showed high expression in adipose tissues than in other tissues.…”

Influence of Dietary Behaviors on Dyslipidemia in Pregnant Women and Its Effects on Physical Development of Fetuses and Infants: A Bidirectional Cohort Study

“…Meanwhile, there were no statistically significant differences in exercise and sleep conditions of pregnant women between the control and case groups, however, we still found they tended to spend more time on TV and phones and less time doing exercise on the whole. As exercise and sleep conditions could influence blood lipid levels, this phenomenon should arouse our attention [ 32 , 33 ].…”

Labour classified by cervical dilatation & fetal membrane rupture demonstrates differential impact on RNA-seq data for human myometrium tissues

“…AREG encodes amphiregulin, a ligand of epidermal growth factor receptors (EGFRs), which are expressed in human uterine tissues at labour [73] and EGFR signalling was identified as relevant to human parturition by previous integrative analysis [21]. PER3 is a circadian rhythm gene, which encodes a transcriptional repressor that controls the circadian clock system in peripheral tissues [74] and, incidentally, a genetic polymorphism within its 'rs228669' coding region [74] has been linked to high risk spontaneous preterm births [75].…”