Human Molecular Genetics Advance Access originally published online on November 29, 2007
Human Molecular Genetics 2008 17(6):806-814; 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 Department of Cardiovascular Medicine 2 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UK 3 Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany 4 Faculty of Health and Medical Sciences, University of Surrey, 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 1865287601; Email: martin.farrall{at}cardiov.ox.ac.uk
Received November 9, 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 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.
To authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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