Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5
GDF1 plays an important role in left-right patterning and genetic mutations in the coding region of GDF1 are associated with congenital heart disease (CHD). However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the...
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| Veröffentlicht in: | Clinical science (1979) 2019-06, Vol.133 (12), p.1281-1295 |
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| container_title | Clinical science (1979) |
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| creator | Gao, Xiaobo Zheng, Panpan Yang, Liping Luo, Haiyan Zhang, Chen Qiu, Yongqiang Huang, Guoying Sheng, Wei Ma, Xu Lu, Cailing |
| description | GDF1 plays an important role in left-right patterning and genetic mutations in the coding region of GDF1 are associated with congenital heart disease (CHD). However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the genetic variation in GDF1 promoter with CHD was examined in two case-control studies, including 1084 cases and 1198 controls in the first study and 582 cases and 615 controls in the second study. We identified one single nucleotide polymorphism (SNP) rs181317402 and two novel genetic mutations located in the promoter region of GDF1. Analysis of combined samples revealed a significant association in genotype and allele frequencies of rs181317402 T/G polymorphism between CHD cases in overall or ventricular septal defects or Tetralogy of Fallot and the control group. rs181317402 allele G polymorphism was significantly associated with a decreased risk of CHD. Furthermore, luciferase assay, chromatin immunoprecipitation and DNA pulldown assay indicated that Nkx2.5 transactivated the expression of GDF1 by binding to the promoter of GDF1. Luciferase activity assay showed that rs181317402 allele G significantly increased the basal and Nkx2.5-mediated activity of GDF1 promoter, while the two genetic mutations had the opposite effect. rs181317402 TG genotype was associated with significantly increased mRNA level of GDF1 compared with TT genotype in 18 CHD individuals. Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression. |
| doi_str_mv | 10.1042/CS20181024 |
| format | Article |
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However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the genetic variation in GDF1 promoter with CHD was examined in two case-control studies, including 1084 cases and 1198 controls in the first study and 582 cases and 615 controls in the second study. We identified one single nucleotide polymorphism (SNP) rs181317402 and two novel genetic mutations located in the promoter region of GDF1. Analysis of combined samples revealed a significant association in genotype and allele frequencies of rs181317402 T/G polymorphism between CHD cases in overall or ventricular septal defects or Tetralogy of Fallot and the control group. rs181317402 allele G polymorphism was significantly associated with a decreased risk of CHD. Furthermore, luciferase assay, chromatin immunoprecipitation and DNA pulldown assay indicated that Nkx2.5 transactivated the expression of GDF1 by binding to the promoter of GDF1. Luciferase activity assay showed that rs181317402 allele G significantly increased the basal and Nkx2.5-mediated activity of GDF1 promoter, while the two genetic mutations had the opposite effect. rs181317402 TG genotype was associated with significantly increased mRNA level of GDF1 compared with TT genotype in 18 CHD individuals. Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.</description><identifier>ISSN: 0143-5221</identifier><identifier>EISSN: 1470-8736</identifier><identifier>DOI: 10.1042/CS20181024</identifier><identifier>PMID: 31171573</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Case-Control Studies ; Child ; Child, Preschool ; China ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Growth Differentiation Factor 1 - genetics ; Growth Differentiation Factor 1 - metabolism ; Heart Defects, Congenital - diagnosis ; Heart Defects, Congenital - genetics ; Heart Defects, Congenital - metabolism ; HEK293 Cells ; Homeobox Protein Nkx-2.5 - genetics ; Homeobox Protein Nkx-2.5 - metabolism ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Myocytes, Cardiac - metabolism ; Phenotype ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Rats ; Risk Factors ; Transcription, Genetic ; Transcriptional Activation ; Zebrafish - embryology</subject><ispartof>Clinical science (1979), 2019-06, Vol.133 (12), p.1281-1295</ispartof><rights>2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c323t-6c5747ee8012278e1dee1985398aa65bd0aa507b3787fca02fcd6aa84ddb04b53</citedby><cites>FETCH-LOGICAL-c323t-6c5747ee8012278e1dee1985398aa65bd0aa507b3787fca02fcd6aa84ddb04b53</cites><orcidid>0000-0002-2350-416X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3266,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31171573$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gao, Xiaobo</creatorcontrib><creatorcontrib>Zheng, Panpan</creatorcontrib><creatorcontrib>Yang, Liping</creatorcontrib><creatorcontrib>Luo, Haiyan</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Qiu, Yongqiang</creatorcontrib><creatorcontrib>Huang, Guoying</creatorcontrib><creatorcontrib>Sheng, Wei</creatorcontrib><creatorcontrib>Ma, Xu</creatorcontrib><creatorcontrib>Lu, Cailing</creatorcontrib><title>Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5</title><title>Clinical science (1979)</title><addtitle>Clin Sci (Lond)</addtitle><description>GDF1 plays an important role in left-right patterning and genetic mutations in the coding region of GDF1 are associated with congenital heart disease (CHD). However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the genetic variation in GDF1 promoter with CHD was examined in two case-control studies, including 1084 cases and 1198 controls in the first study and 582 cases and 615 controls in the second study. We identified one single nucleotide polymorphism (SNP) rs181317402 and two novel genetic mutations located in the promoter region of GDF1. Analysis of combined samples revealed a significant association in genotype and allele frequencies of rs181317402 T/G polymorphism between CHD cases in overall or ventricular septal defects or Tetralogy of Fallot and the control group. rs181317402 allele G polymorphism was significantly associated with a decreased risk of CHD. Furthermore, luciferase assay, chromatin immunoprecipitation and DNA pulldown assay indicated that Nkx2.5 transactivated the expression of GDF1 by binding to the promoter of GDF1. Luciferase activity assay showed that rs181317402 allele G significantly increased the basal and Nkx2.5-mediated activity of GDF1 promoter, while the two genetic mutations had the opposite effect. rs181317402 TG genotype was associated with significantly increased mRNA level of GDF1 compared with TT genotype in 18 CHD individuals. Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.</description><subject>Animals</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>China</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Growth Differentiation Factor 1 - genetics</subject><subject>Growth Differentiation Factor 1 - metabolism</subject><subject>Heart Defects, Congenital - diagnosis</subject><subject>Heart Defects, Congenital - genetics</subject><subject>Heart Defects, Congenital - metabolism</subject><subject>HEK293 Cells</subject><subject>Homeobox Protein Nkx-2.5 - genetics</subject><subject>Homeobox Protein Nkx-2.5 - metabolism</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Male</subject><subject>Mutation</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Promoter Regions, Genetic</subject><subject>Rats</subject><subject>Risk Factors</subject><subject>Transcription, Genetic</subject><subject>Transcriptional Activation</subject><subject>Zebrafish - embryology</subject><issn>0143-5221</issn><issn>1470-8736</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtPwzAQhC0EgvK48AOQjwgp4GfsHqtCC1IFB-AcbZwNGNIEbIfHvydVC2gPs4dvRqMh5Jizc86UuJjeC8YtZ0JtkRFXhmXWyHybjBhXMtNC8D2yH-MLY0IOt0v2JOeGayNHpJ_E2DkPyXct7Wpa961b_dDQDwge2kR9S-eXM07fQrfsEgb66dMzDT6-rgyua5-w9WkwPCOERCsfESJSaCvqU6QBn_pmnV9-09vXL3GuD8lODU3Eo40ekMfZ1cP0OlvczW-mk0XmhqIpy502yiBaxoUwFnmFyMdWy7EFyHVZMQDNTCmNNbUDJmpX5QBWVVXJVKnlATld5w7d33uMqVj66LBpoMWuj4UQSljF2NgO6NkadaGLMWBdvAW_hPBdcFasZi7-Zx7gk01uXy6x-kN_d5U_ZnV3vw</recordid><startdate>20190628</startdate><enddate>20190628</enddate><creator>Gao, Xiaobo</creator><creator>Zheng, Panpan</creator><creator>Yang, Liping</creator><creator>Luo, Haiyan</creator><creator>Zhang, Chen</creator><creator>Qiu, Yongqiang</creator><creator>Huang, Guoying</creator><creator>Sheng, Wei</creator><creator>Ma, Xu</creator><creator>Lu, Cailing</creator><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>7X8</scope><orcidid>https://orcid.org/0000-0002-2350-416X</orcidid></search><sort><creationdate>20190628</creationdate><title>Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5</title><author>Gao, Xiaobo ; Zheng, Panpan ; Yang, Liping ; Luo, Haiyan ; Zhang, Chen ; Qiu, Yongqiang ; Huang, Guoying ; Sheng, Wei ; Ma, Xu ; Lu, Cailing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-6c5747ee8012278e1dee1985398aa65bd0aa507b3787fca02fcd6aa84ddb04b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Case-Control Studies</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>China</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>Growth Differentiation Factor 1 - genetics</topic><topic>Growth Differentiation Factor 1 - metabolism</topic><topic>Heart Defects, Congenital - diagnosis</topic><topic>Heart Defects, Congenital - genetics</topic><topic>Heart Defects, Congenital - metabolism</topic><topic>HEK293 Cells</topic><topic>Homeobox Protein Nkx-2.5 - genetics</topic><topic>Homeobox Protein Nkx-2.5 - metabolism</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Male</topic><topic>Mutation</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Promoter Regions, Genetic</topic><topic>Rats</topic><topic>Risk Factors</topic><topic>Transcription, Genetic</topic><topic>Transcriptional Activation</topic><topic>Zebrafish - embryology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gao, Xiaobo</creatorcontrib><creatorcontrib>Zheng, Panpan</creatorcontrib><creatorcontrib>Yang, Liping</creatorcontrib><creatorcontrib>Luo, Haiyan</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Qiu, Yongqiang</creatorcontrib><creatorcontrib>Huang, Guoying</creatorcontrib><creatorcontrib>Sheng, Wei</creatorcontrib><creatorcontrib>Ma, Xu</creatorcontrib><creatorcontrib>Lu, Cailing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical science (1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gao, Xiaobo</au><au>Zheng, Panpan</au><au>Yang, Liping</au><au>Luo, Haiyan</au><au>Zhang, Chen</au><au>Qiu, Yongqiang</au><au>Huang, Guoying</au><au>Sheng, Wei</au><au>Ma, Xu</au><au>Lu, Cailing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5</atitle><jtitle>Clinical science (1979)</jtitle><addtitle>Clin Sci (Lond)</addtitle><date>2019-06-28</date><risdate>2019</risdate><volume>133</volume><issue>12</issue><spage>1281</spage><epage>1295</epage><pages>1281-1295</pages><issn>0143-5221</issn><eissn>1470-8736</eissn><abstract>GDF1 plays an important role in left-right patterning and genetic mutations in the coding region of GDF1 are associated with congenital heart disease (CHD). However, the genetic variation in the promoter of GDF1 with sporadic CHD and its expression regulation is little known. The association of the genetic variation in GDF1 promoter with CHD was examined in two case-control studies, including 1084 cases and 1198 controls in the first study and 582 cases and 615 controls in the second study. We identified one single nucleotide polymorphism (SNP) rs181317402 and two novel genetic mutations located in the promoter region of GDF1. Analysis of combined samples revealed a significant association in genotype and allele frequencies of rs181317402 T/G polymorphism between CHD cases in overall or ventricular septal defects or Tetralogy of Fallot and the control group. rs181317402 allele G polymorphism was significantly associated with a decreased risk of CHD. Furthermore, luciferase assay, chromatin immunoprecipitation and DNA pulldown assay indicated that Nkx2.5 transactivated the expression of GDF1 by binding to the promoter of GDF1. Luciferase activity assay showed that rs181317402 allele G significantly increased the basal and Nkx2.5-mediated activity of GDF1 promoter, while the two genetic mutations had the opposite effect. rs181317402 TG genotype was associated with significantly increased mRNA level of GDF1 compared with TT genotype in 18 CHD individuals. Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.</abstract><cop>England</cop><pmid>31171573</pmid><doi>10.1042/CS20181024</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-2350-416X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Case-Control Studies Child Child, Preschool China Female Genetic Association Studies Genetic Predisposition to Disease Growth Differentiation Factor 1 - genetics Growth Differentiation Factor 1 - metabolism Heart Defects, Congenital - diagnosis Heart Defects, Congenital - genetics Heart Defects, Congenital - metabolism HEK293 Cells Homeobox Protein Nkx-2.5 - genetics Homeobox Protein Nkx-2.5 - metabolism Humans Infant Infant, Newborn Male Mutation Myocytes, Cardiac - metabolism Phenotype Polymorphism, Single Nucleotide Promoter Regions, Genetic Rats Risk Factors Transcription, Genetic Transcriptional Activation Zebrafish - embryology |
| title | Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5 |
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