CASyM winter school of Systems Medicine took place between March 29th and April 1st 2017 in Ljubljana, Slovenia and is entitled »The 3rd SysBioMed hands-on tutorial: Systems Medicine Approaches in Personalized Medicine«
Statistical modeling of circadian clock and cholesterol metabolism genes in mothers with preterm delivery
Ursa Kovac1,Caitlin J. Smith2,Ursula Prosenc Zmrzljak1,Bruce Bedell2,Nancy Weathers2,Laura Jeliffe-Pawlowski3,5,Rebecca Baer4,5,Damjana Rozman1,Kelli K. Ryckman2
1Center for Functional genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,2Department of Epidemiology, University of Iowa, Iowa City, IA 52242, USA,3Department of Epidemiology and Biostatistics, Division of Preventive Medicine and Public Health, University of California San Francisco School of Medicine, San Francisco, USA,4Department of Pediatrics, University of California San Diego, La Jolla, CA, USA Genetic Disease,5Screening Program, California Department of Public Health, Richmond, CA, USA
Background Many physiological processes are controlled by the molecular clock including the female reproductive system. Deregulation of the circadian system in humans and animals can lead to the development of pathologies due to genetic and environmental factors. Specifically, there is evidence to support circadian disruption in preterm delivery; however, few studies have extensively examined this relationship. It is known that circadian rhythms have a profound effect on the delivery time with approximately 80% of women going into spontaneous labor between late night and early morning. Some researchers have shown that disruption of either circadian or lipid metabolism can affect fetus’ growth and development. Plasma lipids vary depending the time of the day the blood is sampled, illustrating a connection between circadian and lipid metabolism. Studies in mice have shown that mutations in circadian clock genes affect expression of genes that are critical for the regulation of lipid metabolism. The specific objectives were to determine the role between single nucleotide polymorphisms (SNPs) in lipid and circadian clock genes with 2nd trimester lipid levels and to identify interactions between SNPs with preterm delivery.
Methods A custom genotyping platform of 72 SNPs was created covering genes with a strong role in the circadian clock and lipid metabolism. Genotyping was performed on the EP1 SNP Genotyping System and GT 192.24 Dynamic Array Integrated Fluidic Circuits (Fluidigm, San Francisco, CA, USA) with TaqMan assays (Applied Biosystems, Foster City, CA). Different statistical modeling approaches were used for assessing the role of SNPs in circadian and lipid metabolism genes with each lipid level and preterm delivery. 904 women from prenatal screening program were genotyped.
Results and conclusions Six SNPs met the statistical threshold with Bonferroni correction (0.05/ (72 x 4) = p < 2 x 10-4), rs7412 from APOE, rs646776, rs599839 from the CELSR2-PSRC1-SORT1 gene cluster, rs228669 from the circadian candidate PER3, rs738409 from PNPLA3 and rs2066716 from ABCA1. Other SNPs mostly from circadian clock metabolism, rs6850524, rs4580704, rs6843722 (CLOCK), rs2292912 (CRY2), rs2640908 (PER3), rs6486121 (BMAL), rs12413112 (SIRT1), rs3027178 (PER1) were close to the threshold after correction (p < 0.005). Since the preterm delivery presents the high cause of death in children under 5 years, this research represents an important progress towards revealing genetic background of spontaneous preterm delivery.
2006 - University of Ljubljana, Faculty of Medicine, Center for Functional Genomics and Bio-chips.