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

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

doi:10.1038/s41598-021-96374-9

Cited by 14 publications

(29 citation statements)

References 78 publications

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“…All of these variants were predicted to be damaging by the SIFT and PolyPhen-2 tools (Table 4 ). As the role of HSPs in SPTB was studied previously [ 35 ], we focused on AAT/ SERPINA1 .…”

Section: Resultsmentioning

confidence: 99%

“…Proteomic findings were compared with three population sets with available whole exome sequencing (WES) data. Two datasets consisted of Northern Finnish mothers with preterm deliveries ( n = 17) [ 34 ] and their children ( n = 23) who were born preterm (GA < 36 weeks) [ 35 ]. The third dataset was Danish WES data of European ancestry, which included 192 women from 95 families.…”

Section: Methodsmentioning

confidence: 99%

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Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth

Tiensuu

Haapalainen

Tissarinen

et al. 2022

BMC Med

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Background Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth. Methods We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas. Results Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit–Robo signaling, and extracellular matrix organization. Conclusions Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.

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“…All of these variants were predicted to be damaging by the SIFT and PolyPhen-2 tools (Table 4 ). As the role of HSPs in SPTB was studied previously [ 35 ], we focused on AAT/ SERPINA1 .…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth

Tiensuu

Haapalainen

Tissarinen

et al. 2022

BMC Med

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“…Associations of heat shock protein (HSPA1L, SEC63, SACS) and nuclear receptor genes (AR) with sPTB have been found using multiple sPTB datasets based on GWASs, WES, and placental transcriptomics of maternal, fetal, and placental samples (Table 2). 98 …”

Section: Integrative Genomic Approachmentioning

confidence: 99%

Genetics, epigenetics, and transcriptomics of preterm birth

Jain

Monangi

Zhang

et al. 2022

American J Rep Immunol

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Preterm birth contributes significantly to neonatal mortality and morbidity. Despite its global significance, there has only been limited progress in preventing preterm birth. Spontaneous preterm birth (sPTB) results from a wide variety of pathological processes. Although many non‐genetic risk factors influence the timing of gestation and labor, compelling evidence supports the role of substantial genetic and epigenetic influences and their interactions with the environment contributing to sPTB. To investigate a common and complex disease such as sPTB, various approaches such as genome‐wide association studies, whole‐exome sequencing, transcriptomics, and integrative approaches combining these with other ‘omics studies have been used. However, many of these studies were typically small or focused on a single ethnicity or geographic region with limited data, particularly in populations at high risk for sPTB, or lacked a robust replication. These studies found many genes involved in the inflammation and immunity‐related pathways that may affect sPTB. Recent studies also suggest the role of epigenetic modifications of gene expression by the environmental signals as a potential contributor to the risk of sPTB. Future genetic studies of sPTB should continue to consider the contributions of both maternal and fetal genomes as well as their interaction with the environment.

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“…42,43 Multi omics (GWAS, whole exon sequencing, and transcriptome sequencing) also showed multiple correlations between hot shock protein, nuclear receptors, and preterm birth. 44 Genetic variations related with PTL have been revealed to involve in development, growth, EGFR and prolactin signaling, Notch 1 signaling, and inflammation-and immunity-related pathways. 43,45,46 However, in Asians, GWAS related with PTL is still absent.…”

Section: Maternal Genetic Variationsmentioning

confidence: 99%

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

Liu

2021

Maternal-Fetal Medicine

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Preterm labor (before 37 weeks' gestation) is the leading cause of neonatal mortality and morbidity, which can be divided into iatrogenic preterm labor, infectious preterm labor, and spontaneous preterm labor (sPTL). Up to now, there continue to be great difficulties in prediction and prevention of sPTL, owing to multiple risk factors, pathogenesis, and pathologic processes contributing to the event, which have not been fully clarified. Pregnancy maintenance and parturition is a complicated process with continuous maternal-fetal dialogue, in which both maternal and fetal factors participate and affect the outcome of pregnancy, including sPTL. Besides, external factors can also participate in sPTL, individually or through the interaction with internal factors. In this article, we summarize recent studies regarding sPTL from our and other groups, and discuss the risk factors and pathogenesis of preterm birth from both external and internal (maternal and fetal) aspects, so as to provide theoretical evidences for the diagnosis, prevention, and treatment of sPTL in the future.

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

Cited by 14 publications

References 78 publications

Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth

Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth

Genetics, epigenetics, and transcriptomics of preterm birth

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

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