{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T12:43:51Z","timestamp":1763642631443,"version":"3.37.3"},"reference-count":44,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,6,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>GDF1 plays an important role in left\u2013right 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\u2013control 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.<\/jats:p>","DOI":"10.1042\/cs20181024","type":"journal-article","created":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T16:55:14Z","timestamp":1559840114000},"page":"1281-1295","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5"],"prefix":"10.1042","volume":"133","author":[{"given":"Xiaobo","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panpan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"},{"name":"Graduate School of Peking Union Medical College, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Fujian Medical University, Fuzhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"},{"name":"Graduate School of Peking Union Medical College, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqiang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Union Clinical Medical College of Research Institute of Fujian Medical University, Fuzhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoying","family":"Huang","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Fudan University,\u00a0Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Sheng","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Fudan University,\u00a0Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"},{"name":"Graduate School of Peking Union Medical College, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2350-416X","authenticated-orcid":false,"given":"Cailing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Genetics, National Research Institute for Family Planning, Beijing, China"},{"name":"Graduate School of Peking Union Medical College, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"2021113012303607900_B1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.carpath.2007.06.005","article-title":"Genetic insights into normal and abnormal heart development","volume":"17","author":"Nemer","year":"2008","journal-title":"Cardiovasc. 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