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 L. 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. Aqeilan; Michel Marcil; Jorma S.A. Viikari; Terho Lehtimäki; Olli T. Raitakari; Johanna Kuusisto; Markku Laakso; Marja Riitta Taskinen; Jacques Genest; Päivi Pajukanta

doi:10.1016/j.ajhg.2008.07.002

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 L. 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^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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 language	English
Pages (from-to)	180-192
Number of pages	13
Journal	American Journal of Human Genetics
Volume	83
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2008.07.002
State	Published - 8 Aug 2008

Bibliographical note

Funding Information:
We thank the patients and family members for their participation in this study. We thank L. Peltonen, K. Porkka, and I. Nuotio for sample collection; E. Nikkola, M. Lupsakko, L. Riba, and I. Ruel for laboratory technical assistance; and N. Zanesi and T. Palumbo for their contribution. This research was supported by National Institutes of Health grants HL-28481 and HL082762, the AHA grant 0430180N, the Kimmel Scholar Award, The Fondation Leducq, California Discovery Grant 02-10251, and the Dhanem Foundation. D.W.-V. is supported by National Human Genome Research Institute grant T32 HG02536; M.K. by a grant from the Academy of Finland; A.H.-V. by the American Hearth Association grant 072523Y; B.E.A by the American Hearth Association grant 0465005Y; abd R.I.A by Ohio Cancer Research Associates. M.-R.T. is supported by the Clinical Research Institute, Helsinki University Central Hospital and the Finnish Heart Foundation, and T.L. is supported by the Tampere University Hospital Medical Fund. The Young Finns Study is supported by the Academy of Finland grants 77841 and 210283. J.G, M.M., and J.C.E are supported by grant CIHR MOP 62834 from the Canadian Institutes of Health Research; J.G. holds the McGill University-Novartis Chair in Medicine; M.M. and J.C.E. are recipients of a Fonds de la recherche en santé du Québec (FRSQ) research scholarship. The authors have no competing financial interests to disclose. T.W.A.d.B. has been employed by GlaxoSmithKline. GlaxoSmithKline did not provide any financial support for this study.

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10.1016/j.ajhg.2008.07.002

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Lee, J. C., Weissglas-Volkov, D., Kyttälä, M., Dastani, Z., Cantor, R. M., Sobel, E. M., Plaisier, C. L., Engert, J. C., van Greevenbroek, M. M. J., Kane, J. P., Malloy, M. J., Pullinger, C. R., Huertas-Vazquez, A., Aguilar-Salinas, C. A., Tusie-Luna, T., de Bruin, T. W. A., Aouizerat, B. E., van der Kallen, C. C. J., Croce, C. 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

@article{28fd2e7d320241bbabc84ce63c2a78df,

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 × 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.",

author = "Lee, {Jenny C.} and Daphna Weissglas-Volkov and Mira Kytt{\"a}l{\"a} and Zari Dastani and Cantor, {Rita M.} and Sobel, {Eric M.} and Plaisier, {Christopher L.} and Engert, {James C.} and {van Greevenbroek}, {Marleen M.J.} and Kane, {John P.} and Malloy, {Mary J.} and Pullinger, {Clive R.} and Adriana Huertas-Vazquez and Aguilar-Salinas, {Carlos A.} and Teresa Tusie-Luna and {de Bruin}, {Tjerk W.A.} and Aouizerat, {Bradley E.} and {van der Kallen}, {Carla C.J.} and Croce, {Carlo M.} and Aqeilan, {Rami I.} and Michel Marcil and Viikari, {Jorma S.A.} and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Johanna Kuusisto and Markku Laakso and Taskinen, {Marja Riitta} and Jacques Genest and P{\"a}ivi Pajukanta",

note = "Funding Information: We thank the patients and family members for their participation in this study. We thank L. Peltonen, K. Porkka, and I. Nuotio for sample collection; E. Nikkola, M. Lupsakko, L. Riba, and I. Ruel for laboratory technical assistance; and N. Zanesi and T. Palumbo for their contribution. This research was supported by National Institutes of Health grants HL-28481 and HL082762, the AHA grant 0430180N, the Kimmel Scholar Award, The Fondation Leducq, California Discovery Grant 02-10251, and the Dhanem Foundation. D.W.-V. is supported by National Human Genome Research Institute grant T32 HG02536; M.K. by a grant from the Academy of Finland; A.H.-V. by the American Hearth Association grant 072523Y; B.E.A by the American Hearth Association grant 0465005Y; abd R.I.A by Ohio Cancer Research Associates. M.-R.T. is supported by the Clinical Research Institute, Helsinki University Central Hospital and the Finnish Heart Foundation, and T.L. is supported by the Tampere University Hospital Medical Fund. The Young Finns Study is supported by the Academy of Finland grants 77841 and 210283. J.G, M.M., and J.C.E are supported by grant CIHR MOP 62834 from the Canadian Institutes of Health Research; J.G. holds the McGill University-Novartis Chair in Medicine; M.M. and J.C.E. are recipients of a Fonds de la recherche en sant{\'e} du Qu{\'e}bec (FRSQ) research scholarship. The authors have no competing financial interests to disclose. T.W.A.d.B. has been employed by GlaxoSmithKline. GlaxoSmithKline did not provide any financial support for this study. ",

year = "2008",

month = aug,

day = "8",

doi = "10.1016/j.ajhg.2008.07.002",

language = "אנגלית",

volume = "83",

pages = "180--192",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

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number = "2",

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Lee, JC, Weissglas-Volkov, D, Kyttälä, M, Dastani, Z, Cantor, RM, Sobel, EM, Plaisier, CL, 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

TY - JOUR

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 L.

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

N1 - Funding Information: We thank the patients and family members for their participation in this study. We thank L. Peltonen, K. Porkka, and I. Nuotio for sample collection; E. Nikkola, M. Lupsakko, L. Riba, and I. Ruel for laboratory technical assistance; and N. Zanesi and T. Palumbo for their contribution. This research was supported by National Institutes of Health grants HL-28481 and HL082762, the AHA grant 0430180N, the Kimmel Scholar Award, The Fondation Leducq, California Discovery Grant 02-10251, and the Dhanem Foundation. D.W.-V. is supported by National Human Genome Research Institute grant T32 HG02536; M.K. by a grant from the Academy of Finland; A.H.-V. by the American Hearth Association grant 072523Y; B.E.A by the American Hearth Association grant 0465005Y; abd R.I.A by Ohio Cancer Research Associates. M.-R.T. is supported by the Clinical Research Institute, Helsinki University Central Hospital and the Finnish Heart Foundation, and T.L. is supported by the Tampere University Hospital Medical Fund. The Young Finns Study is supported by the Academy of Finland grants 77841 and 210283. J.G, M.M., and J.C.E are supported by grant CIHR MOP 62834 from the Canadian Institutes of Health Research; J.G. holds the McGill University-Novartis Chair in Medicine; M.M. and J.C.E. are recipients of a Fonds de la recherche en santé du Québec (FRSQ) research scholarship. The authors have no competing financial interests to disclose. T.W.A.d.B. has been employed by GlaxoSmithKline. GlaxoSmithKline did not provide any financial support for this study.

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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U2 - 10.1016/j.ajhg.2008.07.002

DO - 10.1016/j.ajhg.2008.07.002

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C2 - 18674750

AN - SCOPUS:48349120779

SN - 0002-9297

VL - 83

SP - 180

EP - 192

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

WW-Domain-Containing Oxidoreductase Is Associated with Low Plasma HDL-C Levels

Abstract

Bibliographical note

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