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

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.

• Authors: L Wang, E R Hauser, S H Shah, D 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, M A Pericak-Vance, P J Goldschmidt-Clermont, J M Vance
• Journal: Annals of human genetics (Ann Hum Genet) Vol. 72 Issue Pt 4 Pg. 443-53 (Jul 2008) ISSN: 0003-4800 [Print] England
• PMID: 18318786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Cell Adhesion Molecules, Neuronal
• GPI-Linked Proteins
• Tumor Suppressor Proteins
• limbic system-associated membrane protein

Topics

• Age of Onset
• Aged
• Aorta (metabolism)
• Atherosclerosis (genetics, metabolism)
• Case-Control Studies
• Cell Adhesion Molecules, Neuronal (genetics, metabolism)
• Cells, Cultured
• Chromosomes, Human, Pair 3 (genetics)
• Coronary Artery Disease (genetics, metabolism)
• Down-Regulation
• Female
• GPI-Linked Proteins
• Gene Expression
• Haplotypes
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Risk Factors
• Tumor Suppressor Proteins (genetics, metabolism)