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The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol

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Abstract

Through genome-wide association studies, we have recently identified seven novel loci that confer a substantial increase in risk for coronary artery disease (CAD). Elucidating the mechanisms by which these loci affect CAD risk could have important clinical utility. Here, we investigated whether these loci act through mechanisms involving traditional cardiovascular risk factors. We genotyped 2,037 adult individuals from 520 nuclear families characterised for body mass index, waist-hip ratio, 24-h ambulatory blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose for the lead single nucleotide polymorphisms (SNPs) in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The CAD-associated risk allele A of rs599839 (allele frequency 0.78) was associated with a 0.17-mmol/l (95% CI 0.10 to 0.24 mmol/l) higher serum cholesterol level per allele copy (P = 3.84 × 10−6). The association of the A allele with higher total cholesterol was confirmed in an independent cohort (n = 847) of healthy adults (P = 1.0 × 10−4) and related to an effect on low-density lipoprotein (LDL) cholesterol (P = 8.56 × 10−5). An association of rs599839 with LDL cholesterol was also shown in 1,090 cases with myocardial infarction (P = 0.0026). None of the other variants showed a strong association with the measured cardiovascular risk factors, suggesting that these loci act through other mechanisms. However, the novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. The findings support further investigation of the role of these genes in cholesterol metabolism and coronary risk.

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Acknowledgments

We thank all the participants, collaborating general practitioners, research nurses and laboratory staff who contributed to the GRAPHIC and German Studies.

Funding

The GRAPHIC Study was funded by the British Heart Foundation. Genotyping was funded by the CARDIOGENICS project of the European Union. NJS holds a Chair supported by the British Heart Foundation, CH holds an MRC Training Fellowship and MDT holds a Medical Research Council (MRC) Clinician Scientist Fellowship.

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Authors and Affiliations

  1. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

    Nilesh J. Samani, Peter S. Braund, Maciej Tomaszewski & Massimo Mangino

  2. Department of Health Sciences and Genetics, University of Leicester, Leicester, UK

    Cother Hajat, Paul R. Burton & Martin D. Tobin

  3. Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany

    Jeanette Erdmann, Patrick Linsel-Nitschke & Heribert Schunkert

  4. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany

    Anika Götz & Andreas Ziegler

  5. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany

    Christian Hengstenberg & Klaus Stark

  6. Pharmacology and The Genome Centre, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, UK

    Mark Caulfield

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  1. Nilesh J. Samani
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Corresponding author

Correspondence to Nilesh J. Samani.

Additional information

Nilesh J. Samani, Peter S. Braund and Jeanette Erdmann contributed equally to this work.

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Table S1

Distribution of serum lipid levels in the German MI Cases and stratified by lipid lowering medication (DOC 38.5 KB)

Table S2

Association findings for all quantitative traits in the GRAPHIC Study for the seven analysed SNPs (DOC 163 KB)

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Samani, N.J., Braund, P.S., Erdmann, J. et al. The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol. J Mol Med 86, 1233–1241 (2008). https://doi.org/10.1007/s00109-008-0387-2

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  • DOI: https://doi.org/10.1007/s00109-008-0387-2

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