{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:50:58Z","timestamp":1791049858928,"version":"4.1.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,1,24]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase (\n              <jats:italic>MTRR<\/jats:italic>\n              ) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Here, we report that the c.56+781 A&gt;C (rs326119) variant of intron-1 of\n              <jats:italic>MTRR<\/jats:italic>\n              significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40;\n              <jats:italic>P<\/jats:italic>\n              =2.32\u00d710\n              <jats:sup>\u22127<\/jats:sup>\n              ) and 1.84-fold (odds ratio=1.84;\n              <jats:italic>P<\/jats:italic>\n              =2.3\u00d710\n              <jats:sup>\u221211<\/jats:sup>\n              ) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time polymerase chain reaction analysis of\n              <jats:italic>MTRR<\/jats:italic>\n              mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased\n              <jats:italic>MTRR<\/jats:italic>\n              transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CCAAT\/enhancer binding protein-\u03b1 binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with the wild-type AA carriers.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              We have demonstrated that the\n              <jats:italic>MTRR<\/jats:italic>\n              c.56+781 A&gt;C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced\n              <jats:italic>MTRR<\/jats:italic>\n              expression at the transcriptional level. Our results accentuate the significance of functional single-nucleotide polymorphisms in noncoding regions of the homocysteine\/folate metabolism pathway core genes for their potential contributions to the origin of CHD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.111.050245","type":"journal-article","created":{"date-parts":[[2011,12,17]],"date-time":"2011-12-17T02:26:02Z","timestamp":1324088762000},"page":"482-490","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population"],"prefix":"10.1161","volume":"125","author":[{"given":"Jian-Yuan","family":"Zhao","sequence":"first","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hong","family":"Gong","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo-Ya","family":"Gu","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yuan","family":"Duan","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Zhou","family":"Ye","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Bing","family":"Shen","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Hu","family":"Shi","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Hou","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jin","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital Shanghai (J.H., G.-Y.H.), and Institute of Biomedical Sciences (L.J., H.-Y.W.), Fudan University, Shanghai; Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan (W.-Y.D., B.Q.); Department of Epidemiology and Biostatistics, School of Public Health,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Qiao","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences (J.-Y.Z., X.-Y.Y., X.-H.G., Z.-Y.G., J.W., Z.-Z.Y., L.J., H.-Y.W.), Children's Hospital 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