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WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels |
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| Authors: | Lee Jenny C Weissglas-Volkov Daphna Kyttälä Mira Dastani Zari Cantor Rita M Sobel Eric M Plaisier Christopher L Engert James C van Greevenbroek Marleen M J Kane John P Malloy Mary J Pullinger Clive R Huertas-Vazquez Adriana Aguilar-Salinas Carlos A Tusie-Luna Teresa de Bruin Tjerk W A Aouizerat Bradley E van der Kallen Carla C J Croce Carlo M Aqeilan Rami I Marcil Michel Viikari Jorma S A Lehtimäki Terho Raitakari Olli T Kuusisto Johanna Laakso Markku Taskinen Marja-Riitta Genest Jacques Pajukanta Päivi |
| Affiliation: | 1 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA 2 Cardiovascular Genetics Laboratory, Division of Cardiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada 3 Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada 4 Department of Internal Medicine and the Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6200MD, The Netherlands 5 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA 6 Department of Physiological Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA 94143, USA 7 Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran 14000, México 8 Molecular Biology and Genomic Medicine Unit, Instituto de Investigaciones Biomédicas de la UNAM, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran 62210, México 9 Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA 10 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA 11 Department of Medicine, University of Turku, Turku FIN-20520, Finland 12 Department of Clinical Physiology, University of Turku, Turku FIN-20520, Finland 13 Department of Clinical Chemistry, Tampere University Hospital and Medical School, University of Tampere, Tampere FIN-33014, Finland 14 Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio 70210, Finland 15 Helsinki University Central Hospital, University of Helsinki, Helsinki FIN-00290, Finland 16 The Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel |
| Abstract: | Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 × 10−7). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 × 10−4 to 2 × 10−5. Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function. |
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