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5 results on '"Muglia, L. J. (Louis J.)"'

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

Author

Tiensuu, H. (Heli), Haapalainen, A. M. (Antti M.), Tissarinen, P. (Pinja), Pasanen, A. (Anu), Määttä, T. A. (Tomi A.), Huusko, J. M. (Johanna M.), Ohlmeier, S. (Steffen), Bergmann, U. (Ulrich), Ojaniemi, M. (Marja), Muglia, L. J. (Louis J), Hallman, M. (Mikko), Rämet, M. (Mika), Tiensuu, H. (Heli), Haapalainen, A. M. (Antti M.), Tissarinen, P. (Pinja), Pasanen, A. (Anu), Määttä, T. A. (Tomi A.), Huusko, J. M. (Johanna M.), Ohlmeier, S. (Steffen), Bergmann, U. (Ulrich), Ojaniemi, M. (Marja), Muglia, L. J. (Louis J), Hallman, M. (Mikko), and Rämet, M. (Mika)

Abstract

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.

Published
2022

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

Author

Huusko, J. M. (Johanna M.), Tiensuu, H. (Heli), Haapalainen, A. M. (Antti M.), Pasanen, A. (Anu), Tissarinen, P. (Pinja), Karjalainen, M. K. (Minna K.), Zhang, G. (Ge), Christensen, K. (Kaare), Ryckman, K. K. (Kelli K.), Jacobsson, B. (Bo), Murray, J. C. (Jeffrey C.), Kingsmore, S. F. (Stephen F.), Hallman, M. (Mikko), Muglia, L. J. (Louis J.), and Rämet, M. (Mika)

Subjects
Medical research, Genetics
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.

Published
2021

3. Spontaneous premature birth as a target of genomic research

Author

Hallman, M. (Mikko), Haapalainen, A. (Antti), Huusko, J. M. (Johanna M.), Karjalainen, M. K. (Minna K.), Zhang, G. (Ge), Muglia, L. J. (Louis J.), and Rämet, M. (Mika)

Abstract

Spontaneous preterm birth is a serious and common pregnancy complication associated with hormonal dysregulation, infection, inflammation, immunity, rupture of fetal membranes, stress, bleeding, and uterine distention. Heredity is 25–40% and mostly involves the maternal genome, with contribution of the fetal genome. Significant discoveries of candidate genes by genome-wide studies and confirmation in independent replicate populations serve as signposts for further research. The main task is to define the candidate genes, their roles, localization, regulation, and the associated pathways that influence the onset of human labor. Genomic research has identified some candidate genes that involve growth, differentiation, endocrine function, immunity, and other defense functions. For example, selenocysteine-specific elongation factor (EEFSEC) influences synthesis of selenoproteins. WNT4 regulates decidualization, while a heat-shock protein family A (HSP70) member 1 like, HSPAIL, influences expression of glucocorticoid receptor and WNT4. Programming of pregnancy duration starts before pregnancy and during placentation. Future goals are to understand the interactive regulation of the pathways in order to define the clocks that influence the risk of prematurity and the duration of pregnancy. Premature birth has a great impact on the duration and the quality of life. Intensification of focused research on causes, prediction and prevention of prematurity is justified.

Published
2019

4. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author

Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), Feenstra, B. (Bjarke), Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), and Feenstra, B. (Bjarke)

Abstract

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Published
2019

5. Genome-wide association study of bronchopulmonary dysplasia:a potential role for variants near the CRP gene

Author

Mahlman, M. (Mari), Karjalainen, M. K. (Minna K.), Huusko, J. M. (Johanna M.), Andersson, S. (Sture), Kari, M. A. (M. Anneli), Tammela, O. K. (Outi K. T.), Sankilampi, U. (Ulla), Lehtonen, L. (Liisa), Marttila, R. H. (Riitta H.), Bassler, D. (Dirk), Poets, C. F. (Christian F.), Lacaze-Masmonteil, T. (Thierry), Danan, C. (Claude), Delacourt, C. (Christophe), Palotie, A. (Aarno), Muglia, L. J. (Louis J.), Lavoie, P. M. (Pascal M.), Hadchouel, A. (Alice), Rämet, M. (Mika), Hallman, M. (Mikko), Mahlman, M. (Mari), Karjalainen, M. K. (Minna K.), Huusko, J. M. (Johanna M.), Andersson, S. (Sture), Kari, M. A. (M. Anneli), Tammela, O. K. (Outi K. T.), Sankilampi, U. (Ulla), Lehtonen, L. (Liisa), Marttila, R. H. (Riitta H.), Bassler, D. (Dirk), Poets, C. F. (Christian F.), Lacaze-Masmonteil, T. (Thierry), Danan, C. (Claude), Delacourt, C. (Christophe), Palotie, A. (Aarno), Muglia, L. J. (Louis J.), Lavoie, P. M. (Pascal M.), Hadchouel, A. (Alice), Rämet, M. (Mika), and Hallman, M. (Mikko)

Abstract

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24–30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10⁻⁶). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10⁻⁴) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10⁻⁵), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

Published
2017

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