期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 83, 期 2, 页码 180-192出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2008.07.002
关键词
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资金
- National Institutes of Health [HL-28481, HL082762]
- AHA [0430180N]
- Kimmel Scholar Award
- The Fondation Leducq
- California Discovery Grant [02-10251]
- Dhanem Foundation
- National Human Genome Research Institute [T32 HG02536]
- Academy of Finland
- American Hearth Association [072523Y, 0465005Y]
- Ohio Cancer Research Associates
- Clinical Research Institute
- Helsinki University Central Hospital
- University Hospital Medical Fund
- Academy of Finland [77841, 210283]
- Canadian Institutes of Health Research [CIHR MOP 62834]
- Fonds de la recherche en sante du Quebec (FRSQ)
- Tampere University Hospital Medical Fund
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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