WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels by 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 in American journal of human genetics (2008). PubMed

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 x 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 x 10(-4) to 2 x 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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