Hum Genet (2008) 123:307–313 DOI 10.1007/s00439-008-0481-0 123 ORIGINAL INVESTIGATION Investigating the association between K198N coding polymorphism in EDN1 and hypertension, lipoprotein levels, the metabolic syndrome and cardiovascular disease Steven Wiltshire · Brenda L. Powell · Michelle Jennens · Pamela A. McCaskie · Kim W. Carter · Lyle J. Palmer · Peter L. Thompson · Brendan M. McQuillan · Joseph Hung · John P. Beilby Received: 26 November 2007 / Accepted: 12 February 2008 / Published online: 21 February 2008  Springer-Verlag 2008 Abstract Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identiWed associations between the coding polymorphism K198N and hypertension, sys- tolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no signiWcant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies. Introduction Cardiovascular disease, the metabolic syndrome and insulin resistance together constitute a major source of mortality and morbidity in the developed world. Together these conditions represent combined eVects of a cluster of pathological changes to normal metabolic and vascular biology, including regulation of blood pressure, altered blood lipid levels and insulin responsiveness, and impairments of the vascular endothelium (Kahn et al. 2006; Shah 2007). Understanding the genetic contribution to their aetiology will be greatly instrumental in improved diagnosis and treatment. During the past decade, endothelin-1 has attracted considerable interest from the cardiovascular community. Endothelin-1 is a potent vasoconstrictor, increases Wbroblast and macrophage activity (Luscher and Barton 2000), is present in atherosclerotic lesions, and mediates endothelial dysfunction, itself a preclinical risk factor for cardiovascular S. Wiltshire · B. L. Powell · P. A. McCaskie · K. W. Carter · L. J. Palmer Western Australian Institute for Medical Research and UWA Centre for Medical Research, University of Western Australia, Perth, Australia S. Wiltshire · L. J. Palmer · P. L. Thompson · B. M. McQuillan · J. Hung School of Medicine and Pharmacology, University of Western Australia, Perth, Australia P. A. McCaskie School of Mathematics and Statistics, University of Western Australia, Perth, Australia P. L. Thompson · B. M. McQuillan · J. Hung Sir Charles Gairdner Hospital Campus of the Heart Institute of Western Australia, Perth, Australia M. Jennens · J. P. Beilby (&) Clinical Biochemistry, PathWest, Locked Bag 2009, Nedlands, WA 6909, Australia e-mail: john.beilby@health.wa.gov.au J. P. Beilby School of Surgery and Pathology, University of Western Australia, Perth, WA, Australia