Polymorphisms in the NR5A2, gene coding for Liver Receptor Homolog-1 are associated with Preterm Birth

KALUARACHCHI DC; MOMANY AM; BUSCH TD; GIMENEZ LG; RYCKMAN KK; COSENTINO VR; SALEME C; CHRISTENSEN K; DAGLE JM; MURRAY JC

San Diego

Exposición; Pediatric Academic Soccieties (PAS) meeting 2015; 2016

Pediatric Academic Soccieties

 Background. Preterm birth (PTB) is a major cause of neonatalmortality and morbidity. Etiology of PTB is multifactorial. There is strongevidence of genetic susceptibility. Objective. We aimed to identify genetic variants contributingto PTB. Methods. Genotyping was performed for 24 SNPs in 4 candidategenes (NR5A2, FSHR, FOXP3, SERPINH1). SNPs for FSHR & SERPINH1 were chosenas they have been previously reported to be associated with PTB. SNPs for FOXP3& NR5A2 were selected using Haploview to get 80% coverage (MAF= 0.2). SNPswere genotyped using the Fluidigm genotyping platform. Genotyping was completedon 661 maternal triads (mother & maternal grandparents of a preterm infant)from Denmark, Argentina & the US. The data analyzed using the Family BasedAssociation Test and p values were obtained from the maternal effect analysis. Weperformed whole exome sequencing on the same 4 candidate genes in 100 Danishsister pairs , where both sister had an early preterm birth (<34 weeksgestation). Results. For all maternal triads rs2737667 of NR5A2 showedsignificant association at P= 0.02. When stratifying by gestational age threeSNPs in NR5A2 found to have p value <0.05 in the <32 weeks gestationalage group (rs12131233, p=0.007; rs2737667, p=0.04; rs2816949, p=0.02). Therewere no significant findings in 32-36 weeks group. When PPROM cases wereexcluded rs2737667 of NR5A2 showed the strongest association with a p value<0.0002. This association was the only one to remain significant aftercorrection for multiple testing. We didn?t find any variants associated with PTB,reaching formal levels of statistical significance on whole exome sequencing. Conclusions. This study suggests a potentialassociation between intronic SNP in the NR5A2 gene and PTB. NR5A2 gene codesfor the Liver Receptor Homolog 1(LRH1), which plays a critical role inregulation of cholesterol metabolism and steroidogenesis. It also has a role inthe regulation of progesterone synthesis. While we did not find any significantassociations in the exons of the NR5A2 gene. These findings suggest NR5A2 maybe important in the pathophysiology of PTB and exploring of non-codingregulators of NR5A2 is warranted.