Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease.
BACKGROUND
Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown.


RESULTS
To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent.


CONCLUSIONS
This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
Folkersen
Lasse
L
Atherosclerosis Research Unit, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
van't Hooft
Ferdinand
F
Chernogubova
Ekaterina
E
Agardh
Hanna E
HE
Hansson
Göran K
GK
Hedin
Ulf
U
Liska
Jan
J
Syvänen
Ann-Christine
AC
Paulsson-Berne
Gabrielle
G
Paulssson-Berne
Gabrielle
G
Franco-Cereceda
Anders
A
Hamsten
Anders
A
Gabrielsen
Anders
A
Eriksson
Per
P
D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D005796:Genes; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012306:Risk