WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.
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.
Lee
Jenny C
JC
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Weissglas-Volkov
Daphna
D
Kyttälä
Mira
M
Dastani
Zari
Z
Cantor
Rita M
RM
Sobel
Eric M
EM
Plaisier
Christopher L
CL
Engert
James C
JC
van Greevenbroek
Marleen M J
MM
Kane
John P
JP
Malloy
Mary J
MJ
Pullinger
Clive R
CR
Huertas-Vazquez
Adriana
A
Aguilar-Salinas
Carlos A
CA
Tusie-Luna
Teresa
T
de Bruin
Tjerk W A
TW
Aouizerat
Bradley E
BE
van der Kallen
Carla C J
CC
Croce
Carlo M
CM
Aqeilan
Rami I
RI
Marcil
Michel
M
Viikari
Jorma S A
JS
Lehtimäki
Terho
T
Raitakari
Olli T
OT
Kuusisto
Johanna
J
Laakso
Markku
M
Taskinen
Marja-Riitta
MR
Genest
Jacques
J
Pajukanta
Päivi
P
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
D008076:Cholesterol, HDL; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human