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

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 languageEnglish (US)
Pages (from-to)180-192
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 8 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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