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 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 journalArticle

37 Citations (Scopus)

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 × 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
Volume83
Issue number2
DOIs
StatePublished - Aug 8 2008
Externally publishedYes

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HDL Cholesterol
Oxidoreductases
Single Nucleotide Polymorphism
Alleles
Hypoalphalipoproteinemias
Electrophoretic Mobility Shift Assay
Introns
Population
Coronary Artery Disease
DNA
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Lee, J. C., Weissglas-Volkov, D., Kyttälä, M., Dastani, Z., Cantor, R. M., Sobel, E. M., ... Pajukanta, P. (2008). WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels. American Journal of Human Genetics, 83(2), 180-192. https://doi.org/10.1016/j.ajhg.2008.07.002

WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels. / Lee, Jenny C.; Weissglas-Volkov, Daphna; Kyttälä, Mira; Dastani, Zari; Cantor, Rita M.; Sobel, Eric M.; Plaisier, Christopher; 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, Vol. 83, No. 2, 08.08.2008, p. 180-192.

Research output: Contribution to journalArticle

Lee, JC, Weissglas-Volkov, D, Kyttälä, M, Dastani, Z, Cantor, RM, Sobel, EM, Plaisier, C, Engert, JC, van Greevenbroek, MMJ, Kane, JP, Malloy, MJ, Pullinger, CR, Huertas-Vazquez, A, Aguilar-Salinas, CA, Tusie-Luna, T, de Bruin, TWA, Aouizerat, BE, van der Kallen, CCJ, Croce, CM, Aqeilan, RI, Marcil, M, Viikari, JSA, Lehtimäki, T, Raitakari, OT, Kuusisto, J, Laakso, M, Taskinen, MR, Genest, J & Pajukanta, P 2008, 'WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels', American Journal of Human Genetics, vol. 83, no. 2, pp. 180-192. https://doi.org/10.1016/j.ajhg.2008.07.002
Lee JC, Weissglas-Volkov D, Kyttälä M, Dastani Z, Cantor RM, Sobel EM et al. WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels. American Journal of Human Genetics. 2008 Aug 8;83(2):180-192. https://doi.org/10.1016/j.ajhg.2008.07.002
Lee, Jenny C. ; Weissglas-Volkov, Daphna ; Kyttälä, Mira ; Dastani, Zari ; Cantor, Rita M. ; Sobel, Eric M. ; Plaisier, Christopher ; 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. / WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels. In: American Journal of Human Genetics. 2008 ; Vol. 83, No. 2. pp. 180-192.
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T1 - WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels

AU - Lee, Jenny C.

AU - Weissglas-Volkov, Daphna

AU - Kyttälä, Mira

AU - Dastani, Zari

AU - Cantor, Rita M.

AU - Sobel, Eric M.

AU - Plaisier, Christopher

AU - Engert, James C.

AU - van Greevenbroek, Marleen M.J.

AU - Kane, John P.

AU - Malloy, Mary J.

AU - Pullinger, Clive R.

AU - Huertas-Vazquez, Adriana

AU - Aguilar-Salinas, Carlos A.

AU - Tusie-Luna, Teresa

AU - de Bruin, Tjerk W.A.

AU - Aouizerat, Bradley E.

AU - van der Kallen, Carla C.J.

AU - Croce, Carlo M.

AU - Aqeilan, Rami I.

AU - Marcil, Michel

AU - Viikari, Jorma S.A.

AU - Lehtimäki, Terho

AU - Raitakari, Olli T.

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Taskinen, Marja Riitta

AU - Genest, Jacques

AU - Pajukanta, Päivi

PY - 2008/8/8

Y1 - 2008/8/8

N2 - 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.

AB - 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.

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