Association of polymorphisms in long non-coding RNA H19 with coronary artery disease risk in a Chinese population.

H19 is an imprinted gene transcribing a long non-coding RNA and is downregulated postnatally. Re-expression of H19 has been observed in patients with atherosclerosis. However, to date, no data has been published on the association of H19 polymorphisms with the risk of coronary artery disease (CAD). In this study, four polymorphisms, rs217727, rs2067051, rs2251375, rs4929984, were analyzed in 701 CAD patients and 873 age- and sex-matched control subjects. Polymorphisms were genotyped by TaqMan technology. Our data showed that the T variant of rs217727 was associated with an increased risk of CAD [additive model: odds ratio (OR)=2.05, 95%CI=1.35-3.12; dominant model: OR=1.46, 95% confidence interval (CI)=1.12-1.90; recessive model: OR=1.75, 95%CI=1.18-2.58], while A variant of rs2067051 was associated with a decreased risk of CAD (additive model: OR=0.66, 95%CI=0.45-0.96; recessive model: OR=0.71, 95%CI=0.50-0.99). Combined analysis showed that subjects carrying 3 or 4 risk alleles had a significantly increased risk of CAD, relative to those with 0-2 risk alleles (OR=1.61, 95%CI=1.20-2.15). Moreover, CAD patients with 3 or 4 risk alleles also had significantly higher Gensini scores than those with 0-2 risk alleles (P=0.001). Further haplotype-based analysis revealed that individuals with C-G-C-C, T-G-A-A, and T-A-A-A haplotypes indicated a higher prevalence of CAD (OR=1.88, 95%CI=1.03-3.43; OR=2.26, 95%CI=1.19-4.31; OR=2.66, 95%CI=1.34-5.25, respectively), compared to individuals with the most common C-G-A-C haplotype. In conclusion, our study demonstrates for the first time that common polymorphisms of H19 are associated with the risk and severity of CAD in a Chinese population. Future studies are needed to explore the underlying mechanisms of our findings.

[1]  V. Dzau,et al.  H19, a developmentally regulated gene, is reexpressed in rat vascular smooth muscle cells after injury. , 1994, The Journal of clinical investigation.

[2]  A. Devlin,et al.  Tissue-specific Changes in H19 Methylation and Expression in Mice with Hyperhomocysteinemia* , 2005, Journal of Biological Chemistry.

[3]  Qin Chen,et al.  lncRNA H19/miR‐675 axis represses prostate cancer metastasis by targeting TGFBI , 2014, The FEBS journal.

[4]  J. Xie,et al.  Homocysteine harasses the imprinting expression of IGF2 and H19 by demethylation of differentially methylated region between IGF2/H19 genes. , 2009, Acta biochimica et biophysica Sinica.

[5]  A. Gabory,et al.  The H19 locus: Role of an imprinted non‐coding RNA in growth and development , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[6]  Ilaria Sansoni,et al.  Birth weight and coronary artery disease. The effect of gender and diabetes , 2009, International journal of biological sciences.

[7]  A. Fatica,et al.  Long non-coding RNAs: new players in cell differentiation and development , 2013, Nature Reviews Genetics.

[8]  James B. Hill,et al.  Association of Birth Weight With Polymorphisms in the IGF2, H19, and IGF2R Genes , 2010, Pediatric Research.

[9]  H. Taylor,et al.  Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation , 2014, Oncogene.

[10]  S. Buckberry,et al.  Circulating IGF 1 and IGF 2 and SNP genotypes inmen and pregnant and non-pregnant women , 2014 .

[11]  B. Xiao,et al.  MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis. , 2012, BMB reports.

[12]  Kimberley C. W. Wang,et al.  Fetal growth restriction and the programming of heart growth and cardiac insulin‐like growth factor 2 expression in the lamb , 2011, The Journal of physiology.

[13]  S. Miyagawa,et al.  Tissue- and Plasma-Specific MicroRNA Signatures for Atherosclerotic Abdominal Aortic Aneurysm , 2012, Journal of the American Heart Association.

[14]  Y. Cheng,et al.  Protective Effects of Let-7a and Let-7b on Oxidized Low-Density Lipoprotein Induced Endothelial Cell Injuries , 2014, PloS one.

[15]  A. Hochberg,et al.  The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma , 2000, Molecular pathology : MP.

[16]  W. Engström,et al.  Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review , 2012, Gerontology.

[17]  George A Calin,et al.  Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  Y. Cheng,et al.  Let-7 in Cardiovascular Diseases, Heart Development and Cardiovascular Differentiation from Stem Cells , 2013, International journal of molecular sciences.

[19]  J. Hata,et al.  Epidemiology of stroke and coronary artery disease in Asia. , 2013, Circulation journal : official journal of the Japanese Circulation Society.

[20]  I. Gorlov,et al.  Interplay between polymorphisms and methylation in the H19/IGF2 gene region may contribute to obesity in Mexican-American children , 2013, Journal of Developmental Origins of Health and Disease.

[21]  Daniel O. Stram,et al.  Modeling and E-M Estimation of Haplotype-Specific Relative Risks from Genotype Data for a Case-Control Study of Unrelated Individuals , 2003, Human Heredity.

[22]  C. Haudenschild,et al.  H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells. , 1996, The Journal of clinical investigation.

[23]  Christian Gieger,et al.  Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. , 2014, American journal of human genetics.

[24]  Martin Mueller,et al.  The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells , 2014, Nucleic acids research.

[25]  T. Katsuya,et al.  Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. , 2012, Atherosclerosis.

[26]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[27]  Yusuke Nakamura,et al.  Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction , 2006, Journal of Human Genetics.

[28]  L. Boyer,et al.  Getting to the heart of the matter: long non‐coding RNAs in cardiac development and disease , 2013, The EMBO journal.

[29]  J. Alpert,et al.  The epidemic of the 20(th) century: coronary heart disease. , 2014, The American journal of medicine.

[30]  Yong-yong Shi,et al.  SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci , 2023, Cell Research.

[31]  Chaochun Liu,et al.  The imprinted H19 lncRNA antagonizes let-7 microRNAs. , 2013, Molecular cell.

[32]  C. Deal,et al.  H19 sense and antisense transgenes modify insulin-like growth factor-II mRNA levels. , 2000, European journal of biochemistry.

[33]  W. Engström,et al.  Epigenetic regulation of the Igf2/H19 gene cluster , 2014, Cell proliferation.

[34]  G. Gensini,et al.  A more meaningful scoring system for determining the severity of coronary heart disease. , 1983, The American journal of cardiology.

[35]  J. Todd,et al.  Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans , 2005, BMC Genetics.

[36]  Zhenggang Zhu,et al.  Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer , 2014, Oncotarget.

[37]  Zhou Yuan,et al.  H19 promotes pancreatic cancer metastasis by derepressing let-7’s suppression on its target HMGA2-mediated EMT , 2014, Tumor Biology.

[38]  G. Lucas,et al.  Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants , 2014, The application of clinical genetics.

[39]  B. Zehnbauer,et al.  Constitutional H19 hypermethylation in a patient with isolated cardiac tumor , 2008, American journal of medical genetics. Part A.

[40]  A. Gabory,et al.  The H19 gene: regulation and function of a non-coding RNA , 2006, Cytogenetic and Genome Research.

[41]  C. Roberts,et al.  Circulating IGF1 and IGF2 and SNP genotypes in men and pregnant and non-pregnant women , 2014, Endocrine connections.

[42]  C. Rosser,et al.  Long-Term Exposure to Cigarette Smoke Extract Induces Hypomethylation at the RUNX3 and IGF2-H19 Loci in Immortalized Human Urothelial Cells , 2013, PLoS ONE.