Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort
Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negativ...
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| description | Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes. |
| doi_str_mv | 10.1371/journal.pone.0104913 |
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The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0104913</identifier><identifier>PMID: 25115650</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Adults ; Analysis ; Arousal ; Arousal - genetics ; Biology and life sciences ; Bisulfite ; Brain ; Cohort Studies ; Cortisol ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Exposure ; Female ; Fetuses ; Gene expression ; Genetic aspects ; Genetic diversity ; Genetic research ; Genetic Variation ; Genotype ; Genotypes ; Glucocorticoids ; Humans ; Hydrocortisone - physiology ; Infant Behavior - physiology ; Infant, Newborn ; Infants ; Male ; Maternal-Fetal Exchange - genetics ; Maternal-Fetal Exchange - physiology ; Medicine and Health Sciences ; Mental disorders ; Methylation ; Neonates ; Newborn babies ; Placenta ; Placenta - metabolism ; Post traumatic stress disorder ; Posttraumatic stress disorder ; Pregnancy ; Prenatal exposure ; Prenatal Exposure Delayed Effects - genetics ; Prenatal Exposure Delayed Effects - physiopathology ; Prenatal Exposure Delayed Effects - psychology ; Protein binding ; Psychiatric-mental health nursing ; Risk ; Risk groups ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Single-nucleotide polymorphism ; Tacrolimus ; Tacrolimus Binding Proteins - genetics ; Tacrolimus Binding Proteins - metabolism ; Tacrolimus-binding protein ; Young Adult</subject><ispartof>PloS one, 2014-08, Vol.9 (8), p.e104913</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Paquette et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.</description><subject>Adult</subject><subject>Adults</subject><subject>Analysis</subject><subject>Arousal</subject><subject>Arousal - genetics</subject><subject>Biology and life sciences</subject><subject>Bisulfite</subject><subject>Brain</subject><subject>Cohort Studies</subject><subject>Cortisol</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Exposure</subject><subject>Female</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic research</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Glucocorticoids</subject><subject>Humans</subject><subject>Hydrocortisone - physiology</subject><subject>Infant Behavior - physiology</subject><subject>Infant, Newborn</subject><subject>Infants</subject><subject>Male</subject><subject>Maternal-Fetal Exchange - genetics</subject><subject>Maternal-Fetal Exchange - physiology</subject><subject>Medicine and Health Sciences</subject><subject>Mental disorders</subject><subject>Methylation</subject><subject>Neonates</subject><subject>Newborn babies</subject><subject>Placenta</subject><subject>Placenta - metabolism</subject><subject>Post traumatic stress disorder</subject><subject>Posttraumatic stress disorder</subject><subject>Pregnancy</subject><subject>Prenatal exposure</subject><subject>Prenatal Exposure Delayed Effects - genetics</subject><subject>Prenatal Exposure Delayed Effects - physiopathology</subject><subject>Prenatal Exposure Delayed Effects - psychology</subject><subject>Protein binding</subject><subject>Psychiatric-mental health nursing</subject><subject>Risk</subject><subject>Risk groups</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Single-nucleotide polymorphism</subject><subject>Tacrolimus</subject><subject>Tacrolimus Binding Proteins - genetics</subject><subject>Tacrolimus Binding Proteins - metabolism</subject><subject>Tacrolimus-binding protein</subject><subject>Young Adult</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-LEzEUxQdR3HX1G4gGBMGH1vyZyaQvwlpct7iwy676Gu4kmU7KdFKTTFe_vamdLh1QkDwkN_ndk8vhZNlLgqeEleT9yvW-g3a6cZ2ZYoLzGWGPslMyY3TCKWaPj84n2bMQVhgXTHD-NDuhBSEFL_Bpdn_TgjJdhBZdfPl4U6Cl6Uy0CkGnkdnYQ7kFbyFa1yEbEITgVCqNRvc2Nsh2NXQRdab3rjINbK3zSdD1Ubm1Cekdxcag28X88g4p1zgfn2dPamiDeTHsZ9m3i09f55eTq-vPi_n51UTxGY0T4GVlclbWlKSZsQBCeF4ypQnHmohcCy1MRTUpaJEDYCoKxWoFuqaVmglgZ9nrve6mdUEOngVJcfKwLAkrErHYE9rBSm68XYP_JR1Y-efC-aUEnyxojSSc4LI0uBY4z0FXYLhgIoeZEDSNZpLWh-G3vlobvTM2GTESHb90tpFLt5U5YZgTmgTeDALe_ehNiP8YeaCWkKZK7rskptY2KHmeE8FZPuM8UdO_UGlps7Yqpaa26X7U8G7UkJhofsYl9CHIxd3t_7PX38fs2yO2MdDGJri238UpjMF8DyrvQvCmfnCOYLkL_cENuQu9HEKf2l4du_7QdEg5-w2D-_yq</recordid><startdate>20140812</startdate><enddate>20140812</enddate><creator>Paquette, Alison G</creator><creator>Lester, Barry M</creator><creator>Koestler, Devin C</creator><creator>Lesseur, Corina</creator><creator>Armstrong, David A</creator><creator>Marsit, Carmen J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140812</creationdate><title>Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort</title><author>Paquette, Alison G ; Lester, Barry M ; Koestler, Devin C ; Lesseur, Corina ; Armstrong, David A ; Marsit, Carmen J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a67be437f2125108a116473cd160d184d8d8eb2d15254aa0285c3fcadf2bc98a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Adults</topic><topic>Analysis</topic><topic>Arousal</topic><topic>Arousal - 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The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = -0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = -0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07-4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92-4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta's ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25115650</pmid><doi>10.1371/journal.pone.0104913</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-08, Vol.9 (8), p.e104913 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2013777135 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Adults Analysis Arousal Arousal - genetics Biology and life sciences Bisulfite Brain Cohort Studies Cortisol Deoxyribonucleic acid DNA DNA Methylation Epigenesis, Genetic Epigenetic inheritance Epigenetics Exposure Female Fetuses Gene expression Genetic aspects Genetic diversity Genetic research Genetic Variation Genotype Genotypes Glucocorticoids Humans Hydrocortisone - physiology Infant Behavior - physiology Infant, Newborn Infants Male Maternal-Fetal Exchange - genetics Maternal-Fetal Exchange - physiology Medicine and Health Sciences Mental disorders Methylation Neonates Newborn babies Placenta Placenta - metabolism Post traumatic stress disorder Posttraumatic stress disorder Pregnancy Prenatal exposure Prenatal Exposure Delayed Effects - genetics Prenatal Exposure Delayed Effects - physiopathology Prenatal Exposure Delayed Effects - psychology Protein binding Psychiatric-mental health nursing Risk Risk groups RNA RNA, Messenger - genetics RNA, Messenger - metabolism Single-nucleotide polymorphism Tacrolimus Tacrolimus Binding Proteins - genetics Tacrolimus Binding Proteins - metabolism Tacrolimus-binding protein Young Adult |
| title | Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort |
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