title: WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.
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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Lee
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Mira
authors.initials: M
authors.lastname: Kyttälä
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Plaisier
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Marleen M J
authors.initials: MM
authors.lastname: van Greevenbroek
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusie-Luna
authors.forename: Tjerk W A
authors.initials: TW
authors.lastname: de Bruin
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Carla C J
authors.initials: CC
authors.lastname: van der Kallen
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Michel
authors.initials: M
authors.lastname: Marcil
authors.forename: Jorma S A
authors.initials: JS
authors.lastname: Viikari
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002318:Cardiovascular Diseases / Q000208:ethnology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D008076:Cholesterol, HDL / Q000096:biosynthesis*; D015331:Cohort Studies; D005260:Female; D005387:Finland; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008800:Mexico; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics* / Q000502:physiology*; D011110:Polymorphism, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D008076:Cholesterol, HDL; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human