Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p

Helen M. Broadbent, John F. Peden, Stefan Lorkowski, Anuj Goel, Halit Ongen, Fiona Green, Robert Clarke, Rory Collins, Maria Grazia Franzosi, Gianni Tognoni, Udo Seedorf, Stephan Rust, Per Eriksson, Anders Hamsten, Martin Farrall, Hugh Watkins

Research output: Contribution to journalArticle

Abstract

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 = 8×10-13; 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 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.

Original languageEnglish
Pages (from-to)806-814
Number of pages9
JournalHuman Molecular Genetics
Volume17
Issue number6
DOIs
Publication statusPublished - Mar 15 2008

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Single Nucleotide Polymorphism
Coronary Artery Disease
Chromosomes
Disease Susceptibility
Haplotypes
Type 2 Diabetes Mellitus
Alleles
Myocardial Infarction
Yin-Yang
Antisense RNA
Untranslated RNA
Genome-Wide Association Study
Homocysteine
Uric Acid
Bilirubin
LDL Cholesterol
Fibrinogen
HDL Cholesterol
Genes
Case-Control Studies

ASJC Scopus subject areas

  • Genetics

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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. / Broadbent, Helen M.; Peden, John F.; Lorkowski, Stefan; Goel, Anuj; Ongen, Halit; Green, Fiona; Clarke, Robert; Collins, Rory; Franzosi, Maria Grazia; Tognoni, Gianni; Seedorf, Udo; Rust, Stephan; Eriksson, Per; Hamsten, Anders; Farrall, Martin; Watkins, Hugh.

In: Human Molecular Genetics, Vol. 17, No. 6, 15.03.2008, p. 806-814.

Research output: Contribution to journalArticle

Broadbent, HM, Peden, JF, Lorkowski, S, Goel, A, Ongen, H, Green, F, Clarke, R, Collins, R, Franzosi, MG, Tognoni, G, Seedorf, U, Rust, S, Eriksson, P, Hamsten, A, Farrall, M & Watkins, H 2008, 'Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p', Human Molecular Genetics, vol. 17, no. 6, pp. 806-814. https://doi.org/10.1093/hmg/ddm352
Broadbent, Helen M. ; Peden, John F. ; Lorkowski, Stefan ; Goel, Anuj ; Ongen, Halit ; Green, Fiona ; Clarke, Robert ; Collins, Rory ; Franzosi, Maria Grazia ; Tognoni, Gianni ; Seedorf, Udo ; Rust, Stephan ; Eriksson, Per ; Hamsten, Anders ; Farrall, Martin ; Watkins, Hugh. / Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 6. pp. 806-814.
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T1 - Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p

AU - Broadbent, Helen M.

AU - Peden, John F.

AU - Lorkowski, Stefan

AU - Goel, Anuj

AU - Ongen, Halit

AU - Green, Fiona

AU - Clarke, Robert

AU - Collins, Rory

AU - Franzosi, Maria Grazia

AU - Tognoni, Gianni

AU - Seedorf, Udo

AU - Rust, Stephan

AU - Eriksson, Per

AU - Hamsten, Anders

AU - Farrall, Martin

AU - Watkins, Hugh

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N2 - 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 = 8×10-13; 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 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.

AB - 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 = 8×10-13; 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 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.

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