WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels

Jenny C. Lee, Daphna Weissglas-Volkov, Mira Kyttälä, Zari Dastani, Rita M. Cantor, Eric M. Sobel, Christopher L. Plaisier, James C. Engert, Marleen M.J. van Greevenbroek, John P. Kane, Mary J. Malloy, Clive R. Pullinger, Adriana Huertas-Vazquez, Carlos A. Aguilar-Salinas, Teresa Tusie-Luna, Tjerk W.A. de Bruin, Bradley E. Aouizerat, Carla C.J. van der Kallen, Carlo M. Croce, Rami I. AqeilanMichel Marcil, Jorma S.A. Viikari, Terho Lehtimäki, Olli T. Raitakari, Johanna Kuusisto, Markku Laakso, Marja Riitta Taskinen, Jacques Genest, Päivi Pajukanta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageAmerican English
Pages (from-to)180-192
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - 8 Aug 2008

Bibliographical note

Funding Information:
We thank the patients and family members for their participation in this study. We thank L. Peltonen, K. Porkka, and I. Nuotio for sample collection; E. Nikkola, M. Lupsakko, L. Riba, and I. Ruel for laboratory technical assistance; and N. Zanesi and T. Palumbo for their contribution. This research was supported by National Institutes of Health grants HL-28481 and HL082762, the AHA grant 0430180N, the Kimmel Scholar Award, The Fondation Leducq, California Discovery Grant 02-10251, and the Dhanem Foundation. D.W.-V. is supported by National Human Genome Research Institute grant T32 HG02536; M.K. by a grant from the Academy of Finland; A.H.-V. by the American Hearth Association grant 072523Y; B.E.A by the American Hearth Association grant 0465005Y; abd R.I.A by Ohio Cancer Research Associates. M.-R.T. is supported by the Clinical Research Institute, Helsinki University Central Hospital and the Finnish Heart Foundation, and T.L. is supported by the Tampere University Hospital Medical Fund. The Young Finns Study is supported by the Academy of Finland grants 77841 and 210283. J.G, M.M., and J.C.E are supported by grant CIHR MOP 62834 from the Canadian Institutes of Health Research; J.G. holds the McGill University-Novartis Chair in Medicine; M.M. and J.C.E. are recipients of a Fonds de la recherche en santé du Québec (FRSQ) research scholarship. The authors have no competing financial interests to disclose. T.W.A.d.B. has been employed by GlaxoSmithKline. GlaxoSmithKline did not provide any financial support for this study.


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