Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth

Johanna M Huusko,Mika Rämet,Antti M Haapalainen,Bo Jacobsson,Anu Pasanen,Louis J Muglia,Stephen F Kingsmore,Kelli K Ryckman,Ge Zhang,Heli Tiensuu,Minna K Karjalainen,Jeffrey C Murray,Kaare Christensen,Pinja Tissarinen,Mikko Hallman

doi:10.1038/s41598-021-96374-9

Abstract

Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal–fetal tolerance and promote labor.

Highlights

Heat shock proteins are involved in the response to stress including activation of the immune response
We investigated all 97 genes encoding members of the Heat shock proteins (HSPs) families and all 49 genes encoding nuclear hormone receptors (NRs), the targets of HSPs, for their role in spontaneous preterm birth (SPTB) susceptibility (Table S1 and S2, respectively)
We examined maternal and fetal exomes belonging to the Northern Finnish population set and in maternal exomes belonging to the Danish population set for potentially damaging, rare variants in HSP and NR genes

Summary

Introduction

Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA. Addressing single risk factors independently does not prevent preterm birth, suggesting that multiple etiologies are part of a complex parturition-initiating m echanism[11,12]

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