Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p.
Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.
Broadbent
Helen M
HM
Department of Cardiovascular Medicine, University of Oxford, UK.
Peden
John F
JF
Lorkowski
Stefan
S
Goel
Anuj
A
Ongen
Halit
H
Green
Fiona
F
Clarke
Robert
R
Collins
Rory
R
Franzosi
Maria Grazia
MG
Tognoni
Gianni
G
Seedorf
Udo
U
Rust
Stephan
S
Eriksson
Per
P
Hamsten
Anders
A
Farrall
Martin
M
Watkins
Hugh
H
D001483:Base Sequence; D002899:Chromosomes, Human, Pair 9; D003324:Coronary Artery Disease / Q000235:genetics*; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D022661:RNA, Untranslated / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
D017931:DNA Primers; D022661:RNA, Untranslated