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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wang, L; Hauser, ER; Shah, SH; Seo, D; Sivashanmugam, P; Exum, ST; Gregory, SG; Granger, CB; Haines, JL; Jones, CJH; Crossman, D; Haynes, C; Kraus, WE; Freedman, NJ; Pericak-Vance, MA; Goldschmidt-Clermont, PJ; Vance, JM

Published Date

  • July 2008

Published In

Volume / Issue

  • 72 / Pt 4

Start / End Page

  • 443 - 453

PubMed ID

  • 18318786

International Standard Serial Number (ISSN)

  • 0003-4800

Digital Object Identifier (DOI)

  • 10.1111/j.1469-1809.2008.00433.x

Language

  • eng

Conference Location

  • England