Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease

Liyong Wang, E. R. Hauser, S. H. Shah, David M Seo, P. Sivashanmugam, S. T. Exum, S. G. Gregory, C. B. Granger, J. L. Haines, C. J H Jones, D. Crossman, C. Haynes, W. E. Kraus, N. J. Freedman, Margaret A Pericak-Vance, Pascal Goldschmidt-Clermont, Jeffery M Vance

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17 Scopus citations

Abstract

Previous association mapping on chromosome 3q13-21 detected evidence for association at the limbic system-associated membrane protein (LSAMP) gene in individuals with late-onset coronary artery disease (CAD). LSAMP has never been implicated in the pathogenesis of CAD. We sought to thoroughly characterize the association and the gene. Non-redundant single nucleotide polymorphisms (SNPs) across the gene were examined in an initial dataset (168 cases with late-onset CAD, 149 controls). Stratification analysis on left main CAD (N = 102) revealed stronger association, which was further validated in a validation dataset (141 cases with left main CAD, 215 controls), a third control dataset (N = 255), and a family-based dataset (N = 2954). A haplotype residing in a novel alternative transcript of the LSAMP gene was significant in all independent case-control datasets (p = 0.0001 to 0.0205) and highly significant in the joint analysis (p = 0.00004). Lower expression of the novel alternative transcript was associated with the risk haplotype (p = 0.0002) and atherosclerosis burden in human aortas (p = 0.0001). Furthermore, silencing LSAMP expression in human aortic smooth muscle cells (SMCs) substantially augmented SMC proliferation (p < 0.01). Therefore, the risk conferred by the LSAMP haplotype appears to be mediated by LSAMP down-regulation, which may promote SMC proliferation in the arterial wall and progression of atherosclerosis.

Original languageEnglish
Pages (from-to)443-453
Number of pages11
JournalAnnals of Human Genetics
Volume72
Issue number4
DOIs
StatePublished - Jul 1 2008

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Keywords

  • Association
  • Atherosclerosis
  • Coronary artery disease
  • Genetics
  • LSAMP

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Wang, L., Hauser, E. R., Shah, S. H., Seo, D. M., Sivashanmugam, P., Exum, S. T., Gregory, S. G., Granger, C. B., Haines, J. L., Jones, C. J. H., Crossman, D., Haynes, C., Kraus, W. E., Freedman, N. J., Pericak-Vance, M. A., Goldschmidt-Clermont, P., & Vance, J. M. (2008). Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease. Annals of Human Genetics, 72(4), 443-453. https://doi.org/10.1111/j.1469-1809.2008.00433.x