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Genetic polymorphisms in platelet-related proteins and coronary artery disease: investigation of candidate genes, including N-acetylgalactosaminyltransferase 4 (GALNT4) and sulphotransferase 1A1/2 (SULT1A1/2)

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Abstract

Background Both platelet function and heart disease show strong genetic components, many of which remain to be elucidated. Materials and methods The roles of candidate polymorphisms in ten platelet-associated genes were compared between 1,237 Acute Coronary Syndrome (ACS) cases (with myocardial infarction and unstable angina) and 386 controls, from an Irish Caucasian population. Additionally, 361 stable angina patients were investigated. Two genes of interest were followed up in a separate Irish study of 1,484 individuals (577 with IHD and 907 unaffected). Results The GALNT4 (N-acetyl galactosaminyl transferase 4) 506I allele was significantly underrepresented in ACS (OR = 0.66, CI = 0.52–0.84; P = 0.001; P = 0.01 after correction for multiple testing), while the SULT1A1 (Sulphotransferase 1A1) 213H allele was associated with risk of ACS (OR = 1.37, CI = 1.08–1.74; P = 0.01; P = 0.1 after correction for multiple testing). Subsequent genotyping of further SNPs in GALNT4 in the family-based (IHD) group revealed that the 506I allele showed the same trend towards protecting against ACS but the haplotypic test over the four commonest haplotypes was not significant (P = 0.55). In contrast, the SULT1A1/SULT1A2 gene complex showed suggestive haplotypic association in the family-based study (P = 0.07), with the greatest increase in risk conferred by the SULT1A2 235T allele (P = 0.025). Conclusion We have identified two risk genes for cardiovascular disease, one of whose (GALNT4) effects may be on either platelet or endothelial function through modifications of PSGL1 or other important glycosylated proteins. The role of sulphotransferases (SULT1A1/2) in cardiovascular disease requires further exploration. Further validation of cardiovascular risks conferred by both genes in other populations (including gene copy number variation) is warranted.

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Acknowledgements

We thank the Irish Cardiology genetics network (ACS study) for contributing samples to this study, and Prof Desmond Fitzgerald and Prof Eoin O’Brien for assistance in establishing study populations. This research was supported by grants from the Programme for Research in Third Level Institutes administered by the Higher Education Authority (HEA), and by the Health Research Board (HRB) of Ireland.

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Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College Dublin, Dublin, 2, Ireland

    A. M. O’Halloran

  2. Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, 2, Ireland

    A. M. O’Halloran, A. Maree, R. Curtin, A. Stanton & D. C. Shields

  3. Centre for Clinical and Population Sciences, Queen’s University Belfast, Mulhouse Building, Grosvenor Road, Belfast, BT12 6BJ, Northern Ireland, UK

    C. C. Patterson & P. P. McKeown

  4. Regional Medical Cardiology Centre, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland, UK

    P. Horan & P. P. McKeown

  5. Blood Pressure Unit and ADAPT Centre, Beaumont Hospital, Dublin, 9, Ireland

    A. Stanton

  6. UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, 4, Ireland

    D. C. Shields

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  1. A. M. O’Halloran
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O’Halloran, A.M., Patterson, C.C., Horan, P. et al. Genetic polymorphisms in platelet-related proteins and coronary artery disease: investigation of candidate genes, including N-acetylgalactosaminyltransferase 4 (GALNT4) and sulphotransferase 1A1/2 (SULT1A1/2). J Thromb Thrombolysis 27, 175–184 (2009). https://doi.org/10.1007/s11239-008-0196-z

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