Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease.
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.
Wang
L
L
Miami Institute of Human Genomics, University of Miami, Miami, FL 33101, USA.
Hauser
E R
ER
Shah
S H
SH
Seo
D
D
Sivashanmugam
P
P
Exum
S T
ST
Gregory
S G
SG
Granger
C B
CB
Haines
J L
JL
Jones
C J H
CJ
Crossman
D
D
Haynes
C
C
Kraus
W E
WE
Freedman
N J
NJ
Pericak-Vance
M A
MA
Goldschmidt-Clermont
P J
PJ
Vance
J M
JM
D017668:Age of Onset; D000368:Aged; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D025521:Tumor Suppressor Proteins; C095362:limbic system-associated membrane protein