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Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly dama...

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Autores principales: Huusko, Johanna M., Karjalainen, Minna K., Graham, Britney E., Zhang, Ge, Farrow, Emily G., Miller, Neil A., Jacobsson, Bo, Eidem, Haley R., Murray, Jeffrey C., Bedell, Bruce, Breheny, Patrick, Brown, Noah W., Bødker, Frans L., Litterman, Nadia K., Jiang, Pan-Pan, Russell, Laura, Hinds, David A., Hu, Youna, Rokas, Antonis, Teramo, Kari, Christensen, Kaare, Williams, Scott M., Rämet, Mika, Kingsmore, Stephen F., Ryckman, Kelli K., Hallman, Mikko, Muglia, Louis J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042692/
https://www.ncbi.nlm.nih.gov/pubmed/30001343
http://dx.doi.org/10.1371/journal.pgen.1007394
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author Huusko, Johanna M.
Karjalainen, Minna K.
Graham, Britney E.
Zhang, Ge
Farrow, Emily G.
Miller, Neil A.
Jacobsson, Bo
Eidem, Haley R.
Murray, Jeffrey C.
Bedell, Bruce
Breheny, Patrick
Brown, Noah W.
Bødker, Frans L.
Litterman, Nadia K.
Jiang, Pan-Pan
Russell, Laura
Hinds, David A.
Hu, Youna
Rokas, Antonis
Teramo, Kari
Christensen, Kaare
Williams, Scott M.
Rämet, Mika
Kingsmore, Stephen F.
Ryckman, Kelli K.
Hallman, Mikko
Muglia, Louis J.
author_facet Huusko, Johanna M.
Karjalainen, Minna K.
Graham, Britney E.
Zhang, Ge
Farrow, Emily G.
Miller, Neil A.
Jacobsson, Bo
Eidem, Haley R.
Murray, Jeffrey C.
Bedell, Bruce
Breheny, Patrick
Brown, Noah W.
Bødker, Frans L.
Litterman, Nadia K.
Jiang, Pan-Pan
Russell, Laura
Hinds, David A.
Hu, Youna
Rokas, Antonis
Teramo, Kari
Christensen, Kaare
Williams, Scott M.
Rämet, Mika
Kingsmore, Stephen F.
Ryckman, Kelli K.
Hallman, Mikko
Muglia, Louis J.
author_sort Huusko, Johanna M.
collection PubMed
description Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2–4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.
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spelling pubmed-60426922018-07-19 Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth Huusko, Johanna M. Karjalainen, Minna K. Graham, Britney E. Zhang, Ge Farrow, Emily G. Miller, Neil A. Jacobsson, Bo Eidem, Haley R. Murray, Jeffrey C. Bedell, Bruce Breheny, Patrick Brown, Noah W. Bødker, Frans L. Litterman, Nadia K. Jiang, Pan-Pan Russell, Laura Hinds, David A. Hu, Youna Rokas, Antonis Teramo, Kari Christensen, Kaare Williams, Scott M. Rämet, Mika Kingsmore, Stephen F. Ryckman, Kelli K. Hallman, Mikko Muglia, Louis J. PLoS Genet Research Article Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2–4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB. Public Library of Science 2018-07-12 /pmc/articles/PMC6042692/ /pubmed/30001343 http://dx.doi.org/10.1371/journal.pgen.1007394 Text en © 2018 Huusko et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Huusko, Johanna M.
Karjalainen, Minna K.
Graham, Britney E.
Zhang, Ge
Farrow, Emily G.
Miller, Neil A.
Jacobsson, Bo
Eidem, Haley R.
Murray, Jeffrey C.
Bedell, Bruce
Breheny, Patrick
Brown, Noah W.
Bødker, Frans L.
Litterman, Nadia K.
Jiang, Pan-Pan
Russell, Laura
Hinds, David A.
Hu, Youna
Rokas, Antonis
Teramo, Kari
Christensen, Kaare
Williams, Scott M.
Rämet, Mika
Kingsmore, Stephen F.
Ryckman, Kelli K.
Hallman, Mikko
Muglia, Louis J.
Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title_full Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title_fullStr Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title_full_unstemmed Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title_short Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth
title_sort whole exome sequencing reveals hspa1l as a genetic risk factor for spontaneous preterm birth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042692/
https://www.ncbi.nlm.nih.gov/pubmed/30001343
http://dx.doi.org/10.1371/journal.pgen.1007394
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