{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:20:48Z","timestamp":1778145648846,"version":"3.51.4"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T00:00:00Z","timestamp":1541030400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T00:00:00Z","timestamp":1541030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2017M623215"],"award-info":[{"award-number":["2017M623215"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pathology of non-traumatic osteonecrosis of the femoral head (ONFH) is complex. Several studies have linked some polymorphisms of vascular endothelial growth factors A (<jats:italic>VEGFA<\/jats:italic>) with ONFH, but the results are not consistent and are even conflicting. In the study, 22 single nucleotide polymorphisms (SNPs) in <jats:italic>VEGFA<\/jats:italic> were genotyped in 1,762 subjects (489 cases and 1,273 controls). Genetic association analyses were performed in single markers and haplotype levels. Stratification analysis was conducted for ONFH patients. Gene by environment interactions were tested between <jats:italic>VEGFA<\/jats:italic> and the smoking status of the subjects. Gene expression and eQTL data of significant SNPs were extracted from GTEx to examine their potential biological function. The SNP, rs2010963, was identified to be significantly associated with ONFH (\u03c7<jats:sup>2<\/jats:sup>\u2009=\u200911.66, <jats:italic>P<\/jats:italic>\u2009=\u20090.0006, OR\u2009=\u20091.29). Haplotypes including rs2010963 were also identified to be correlated with ONFH in the haplotype-based analyses. After stratifying by the causes of ONFH, a significant signal from rs2010963 could only be identified in alcohol-induced patients (<jats:italic>P<\/jats:italic><jats:sub>allelic<\/jats:sub>\u2009=\u20090.0009) but not in steroid-induced patients (<jats:italic>P<\/jats:italic><jats:sub>allelic<\/jats:sub>\u2009=\u20090.055). No significant results were obtained from the gene by environmental interaction analyses. Significant expression differences of <jats:italic>VEGFA<\/jats:italic> were identified in multiple human tissues for different genotypes of rs2010963. Our findings indicate that SNP rs2010963 is significantly associated with ONFH.<\/jats:p>","DOI":"10.1038\/s41598-018-34352-4","type":"journal-article","created":{"date-parts":[[2018,10,26]],"date-time":"2018-10-26T14:32:53Z","timestamp":1540564373000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Relationship of common variants in VEGFA gene with osteonecrosis of the femoral head: A Han Chinese population based association study"],"prefix":"10.1038","volume":"8","author":[{"given":"Wenlong","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongtao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honggan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqiang","family":"Zhi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongliang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,11,1]]},"reference":[{"key":"34352_CR1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1053\/sarh.2002.33724b","volume":"32","author":"Y Assouline-Dayan","year":"2002","unstructured":"Assouline-Dayan, Y., Chang, C., Greenspan, A., Shoenfeld, Y. & Gershwin, M. E. Pathogenesis and natural history of osteonecrosis. Seminars in arthritis and rheumatism 32, 94\u2013124 (2002).","journal-title":"Seminars in arthritis and rheumatism"},{"key":"34352_CR2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1385\/CRIAI:25:1:13","volume":"25","author":"M Abu-Shakra","year":"2003","unstructured":"Abu-Shakra, M., Buskila, D. & Shoenfeld, Y. Osteonecrosis in patients with SLE. Clinical reviews in allergy & immunology 25, 13\u201324, https:\/\/doi.org\/10.1385\/CRIAI:25:1:13 (2003).","journal-title":"Clinical reviews in allergy & immunology"},{"key":"34352_CR3","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s12016-010-8217-z","volume":"41","author":"C Powell","year":"2011","unstructured":"Powell, C., Chang, C. & Gershwin, M. E. Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clinical reviews in allergy & immunology 41, 102\u2013113, https:\/\/doi.org\/10.1007\/s12016-010-8217-z (2011).","journal-title":"Clinical reviews in allergy & immunology"},{"key":"34352_CR4","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1007\/s00439-011-1120-8","volume":"131","author":"F Guan","year":"2012","unstructured":"Guan, F. et al. Association of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese. Hum Genet. 131, 1047\u20131056 (2012).","journal-title":"Hum Genet."},{"key":"34352_CR5","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.schres.2013.11.004","volume":"152","author":"F Guan","year":"2014","unstructured":"Guan, F. et al. MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. Schizophr Res. 152, 97\u2013104 (2014).","journal-title":"Schizophr Res."},{"key":"34352_CR6","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/jhg.2015.66","volume":"60","author":"G Chen","year":"2015","unstructured":"Chen, G., Guan, F., Lin, H., Li, L. & Fu, D. Genetic analysis of common variants in the HDAC2 gene with schizophrenia susceptibility in Han Chinese. Journal of human genetics. 60, 479\u2013484 (2015).","journal-title":"Journal of human genetics."},{"key":"34352_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/srep12935","volume":"5","author":"F Guan","year":"2015","unstructured":"Guan, F. et al. Evaluation of genetic susceptibility of common variants in CACNA1D with schizophrenia in Han Chinese. Scientific reports. 5, 12935 (2015).","journal-title":"Scientific reports."},{"key":"34352_CR8","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.schres.2015.10.012","volume":"169","author":"B Zhang","year":"2015","unstructured":"Zhang, B. et al. Common variants in SLC1A2 and schizophrenia: Association and cognitive function in patients with schizophrenia and healthy individuals. Schizophr Res. 169, 128\u2013134 (2015).","journal-title":"Schizophr Res."},{"key":"34352_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/srep38048","volume":"6","author":"F Guan","year":"2016","unstructured":"Guan, F. et al. Evaluation of association of common variants in HTR1A and HTR5A with schizophrenia and executive function. Scientific reports. 6, 38048 (2016).","journal-title":"Scientific reports."},{"key":"34352_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/srep24914","volume":"6","author":"F Guan","year":"2016","unstructured":"Guan, F. et al. Evaluation of voltage-dependent calcium channel \u03b3 gene families identified several novel potential susceptible genes to schizophrenia. Scientific reports. 6, 24914 (2016).","journal-title":"Scientific reports."},{"key":"34352_CR11","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1007\/BF02346191","volume":"97","author":"MH Wei","year":"1996","unstructured":"Wei, M. H., Popescu, N. C., Lerman, M. I., Merrill, M. J. & Zimonjic, D. B. Localization of the human vascular endothelial growth factor gene, VEGF at chromosome 6p12. Hum Genet 97, 794\u2013797 (1996).","journal-title":"Hum Genet"},{"key":"34352_CR12","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.joca.2007.06.017","volume":"16","author":"TH Kim","year":"2008","unstructured":"Kim, T. H. et al. Promoter polymorphisms of the vascular endothelial growth factor gene is associated with an osteonecrosis of the femoral head in the Korean population. Osteoarthritis and cartilage 16, 287\u2013291, https:\/\/doi.org\/10.1016\/j.joca.2007.06.017 (2008).","journal-title":"Osteoarthritis and cartilage"},{"key":"34352_CR13","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/jor.21492","volume":"30","author":"YJ Lee","year":"2012","unstructured":"Lee, Y. J. et al. Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis. Journal of Orthopaedic Research 30, 21\u201327 (2012).","journal-title":"Journal of Orthopaedic Research"},{"key":"34352_CR14","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1089\/gtmb.2011.0384","volume":"16","author":"B Liu","year":"2012","unstructured":"Liu, B., Cao, Y., Wang, D., Yao, G. & Bi, Z. Vascular endothelial growth factor \u2212634G\/C polymorphism associated with osteonecrosis of the femoral head in a Chinese population. Genet Test Mol Biomarkers 16, 739\u2013743, https:\/\/doi.org\/10.1089\/gtmb.2011.0384 (2012).","journal-title":"Genet Test Mol Biomarkers"},{"key":"34352_CR15","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.schres.2012.03.030","volume":"138","author":"F Guan","year":"2012","unstructured":"Guan, F. et al. Association study of a new schizophrenia susceptibility locus of 10q24.32-33 in a Han Chinese population. Schizophr Res. 138, 63\u201368 (2012).","journal-title":"Schizophr Res."},{"key":"34352_CR16","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics 81, 559\u2013575, https:\/\/doi.org\/10.1086\/519795 (2007).","journal-title":"American journal of human genetics"},{"key":"34352_CR17","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","volume":"21","author":"JC Barrett","year":"2005","unstructured":"Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263\u2013265, https:\/\/doi.org\/10.1093\/bioinformatics\/bth457 (2005).","journal-title":"Bioinformatics"},{"key":"34352_CR18","first-page":"12","volume":"1","author":"CR Team","year":"2016","unstructured":"Team, C. R. & Team RDC., R. A Language And Environment For Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria. Computing 1, 12\u201321 (2016).","journal-title":"Computing"},{"key":"34352_CR19","doi-asserted-by":"publisher","first-page":"1790","DOI":"10.1101\/gr.137323.112","volume":"22","author":"AP Boyle","year":"2012","unstructured":"Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Research 22, 1790 (2012).","journal-title":"Genome Research"},{"key":"34352_CR20","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","volume":"45","author":"GT Consortium","year":"2013","unstructured":"Consortium, G. T. The Genotype-Tissue Expression (GTEx) project. Nature genetics 45, 580\u2013585, https:\/\/doi.org\/10.1038\/ng.2653 (2013).","journal-title":"Nature genetics"},{"key":"34352_CR21","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/367576a0","volume":"367","author":"B Millauer","year":"1994","unstructured":"Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367, 576\u2013579, https:\/\/doi.org\/10.1038\/367576a0 (1994).","journal-title":"Nature"},{"key":"34352_CR22","doi-asserted-by":"publisher","first-page":"10972","DOI":"10.1073\/pnas.200377097","volume":"97","author":"MD Mueller","year":"2000","unstructured":"Mueller, M. D. et al. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proceedings of the National Academy of Sciences of the United States of America 97, 10972\u201310977, https:\/\/doi.org\/10.1073\/pnas.200377097 (2000).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"34352_CR23","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/S0002-9394(02)01568-4","volume":"134","author":"N Ogata","year":"2002","unstructured":"Ogata, N., Nishikawa, M., Nishimura, T., Mitsuma, Y. & Matsumura, M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. American journal of ophthalmology 134, 348\u2013353 (2002).","journal-title":"American journal of ophthalmology"},{"key":"34352_CR24","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1038\/nature07598","volume":"457","author":"PS Ray","year":"2009","unstructured":"Ray, P. S. et al. A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 915\u2013919, https:\/\/doi.org\/10.1038\/nature07598 (2009).","journal-title":"Nature"},{"key":"34352_CR25","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1038\/nature07445","volume":"456","author":"C Stockmann","year":"2008","unstructured":"Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814\u2013U107, https:\/\/doi.org\/10.1038\/nature07445 (2008).","journal-title":"Nature"},{"key":"34352_CR26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/9467","volume":"5","author":"HP Gerber","year":"1999","unstructured":"Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5, 623\u2013628 (1999).","journal-title":"Nat Med"},{"key":"34352_CR27","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1016\/j.jpsychires.2013.01.025","volume":"47","author":"F Guan","year":"2013","unstructured":"Guan, F. et al. A population-based association study of 2q32.3 and 8q21.3 loci with schizophrenia in Han Chinese. Journal of psychiatric research. 47, 712\u2013717 (2013).","journal-title":"Journal of psychiatric research."},{"key":"34352_CR28","doi-asserted-by":"publisher","first-page":"e80165","DOI":"10.1371\/journal.pone.0080165","volume":"8","author":"H Yang","year":"2013","unstructured":"Yang, H. et al. 4q22.1 contributes to bone mineral density and osteoporosis susceptibility in postmenopausal women of Chinese Han population. PloS one. 8, e80165 (2013).","journal-title":"PloS one."},{"key":"34352_CR29","doi-asserted-by":"crossref","unstructured":"Guan F et al. Two-stage association study to identify the genetic susceptibility of a novel common variant of rs2075290 in ZPR1 to type 2diabetes. Scientific reports. 6, 29586 (2016).","DOI":"10.1038\/srep29586"},{"key":"34352_CR30","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.schres.2016.07.004","volume":"176","author":"F Guan","year":"2016","unstructured":"Guan, F. et al. Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population. Schizophr Res. 176, 125\u2013130 (2016).","journal-title":"Schizophr Res."},{"key":"34352_CR31","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/ajmg.b.32491","volume":"171","author":"X Jia","year":"2016","unstructured":"Jia, X. et al. Two-stage additional evidence support association of common variants in the HDAC3 with the increasing risk of schizophrenia susceptibility. American journal of medical genetics. Part B, Neuropsychiatric genetics. 171, 1105\u20131111 (2016).","journal-title":"American journal of medical genetics. Part B, Neuropsychiatric genetics."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34352-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34352-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34352-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T11:17:35Z","timestamp":1671621455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34352-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,1]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["34352"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-34352-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,1]]},"assertion":[{"value":"21 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"16221"}}