Human Molecular Genetics Advance Access published online on November 29, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm352
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Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked, SNPs in the ANRIL locus on chromosome 9p
1 Dept. Cardiovascular Medicine, University of Oxford, Oxford, UK 2 Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany 3 School of Biomedical and Molecular Sciences, University of Surrey, UK 4 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UK 5 Department of Cardiovascular Research, ‘Mario Negri’ Institute for Pharmacological Research, Milano, Italy 6 Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy 7 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
* To whom correspondence should be addressed at: Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK. Tel: +44 1865 287 601; Email: martin.farrall{at}cardiov.ox.ac.uk
Received November 9, 2007; Revised November 28, 2007; Accepted November 28, 2007
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 4,251 CAD cases and 4,443 controls in four European populations using previously reported ("literature") and tagging SNPs. We replicated the literature SNPs (p = 8 x 10–13; 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 LDL-cholesterol, HDL-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.
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The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors