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


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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