Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Jorie Versmissen; Daniella M. Oosterveer; Mojgan Yazdanpanah; Abbas Dehghan; Hilma Holm; Jeanette Erdman; Yurii S. Aulchenko; Gudmar Thorleifsson; Heribert Schunkert; Roeland Huijgen; Ranitha Vongpromek; Andre G. Uitterlinden; Joep C. Defesche; Cornelia M. van Duijn; Monique Mulder; Tony Dadd; Hrobjartur D. Karlsson; Jose Ordovas; Iris Kindt; Amelia Jarman; Albert Hofman; Leonie van Vark-van der Zee; Adriana C. Blommesteijn-Touw; Jaap Kwekkeboom; Anho H. Liem; Frans J. van der Ouderaa; Sebastiano Calandra; Stefano Bertolini; Maurizio Averna; Gisle Langslet; Leiv Ose; Emilio Ros; Fatima Almagro; Peter W. de Leeuw; Fernando Civeira; Luis Masana; Xavier Pinto; Maarten L. Simoons; Arend F. L. Schinkel; Martin R. Green; Aeilko H. Zwinderman; Keith J. Johnson; Arne Schaefer; Andrew Neil; Jacqueline C. M. Witteman; Steve E. Humphries; John J. P. Kastelein; Eric J. G. Sijbrands

doi:10.1038/ejhg.2014.101

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Jorie Versmissen, Daniella M. Oosterveer, Mojgan Yazdanpanah, Abbas Dehghan, Hilma Holm, Jeanette Erdman, Yurii S. Aulchenko, Gudmar Thorleifsson, Heribert Schunkert, Roeland Huijgen, Ranitha Vongpromek, Andre G. Uitterlinden, Joep C. Defesche, Cornelia M. van Duijn, Monique Mulder, Tony Dadd, Hrobjartur D. Karlsson, Jose Ordovas, Iris Kindt, Amelia JarmanAlbert Hofman, Leonie van Vark-van der Zee, Adriana C. Blommesteijn-Touw, Jaap Kwekkeboom, Anho H. Liem, Frans J. van der Ouderaa, Sebastiano Calandra, Stefano Bertolini, Maurizio Averna, Gisle Langslet, Leiv Ose, Emilio Ros, Fatima Almagro, Peter W. de Leeuw, Fernando Civeira, Luis Masana, Xavier Pinto, Maarten L. Simoons, Arend F. L. Schinkel, Martin R. Green, Aeilko H. Zwinderman, Keith J. Johnson, Arne Schaefer, Andrew Neil, Jacqueline C. M. Witteman, Steve E. Humphries, John J. P. Kastelein, Eric J. G. Sijbrands^*

^*Corresponding author for this work

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

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Abstract

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P

Original language	English
Pages (from-to)	381-387
Journal	European Journal of Human Genetics
Volume	23
Issue number	3
DOIs	https://doi.org/10.1038/ejhg.2014.101
Publication status	Published - Mar 2015

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10.1038/ejhg.2014.101

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Versmissen, J., Oosterveer, D. M., Yazdanpanah, M., Dehghan, A., Holm, H., Erdman, J., Aulchenko, Y. S., Thorleifsson, G., Schunkert, H., Huijgen, R., Vongpromek, R., Uitterlinden, A. G., Defesche, J. C., van Duijn, C. M., Mulder, M., Dadd, T., Karlsson, H. D., Ordovas, J., Kindt, I., ... Sijbrands, E. J. G. (2015). Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach. European Journal of Human Genetics, 23(3), 381-387. https://doi.org/10.1038/ejhg.2014.101

@article{f30e3fe865494336b77a0a0811e8d96b,

title = "Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach",

abstract = "Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P",

author = "Jorie Versmissen and Oosterveer, {Daniella M.} and Mojgan Yazdanpanah and Abbas Dehghan and Hilma Holm and Jeanette Erdman and Aulchenko, {Yurii S.} and Gudmar Thorleifsson and Heribert Schunkert and Roeland Huijgen and Ranitha Vongpromek and Uitterlinden, {Andre G.} and Defesche, {Joep C.} and {van Duijn}, {Cornelia M.} and Monique Mulder and Tony Dadd and Karlsson, {Hrobjartur D.} and Jose Ordovas and Iris Kindt and Amelia Jarman and Albert Hofman and {van Vark-van der Zee}, Leonie and Blommesteijn-Touw, {Adriana C.} and Jaap Kwekkeboom and Liem, {Anho H.} and {van der Ouderaa}, {Frans J.} and Sebastiano Calandra and Stefano Bertolini and Maurizio Averna and Gisle Langslet and Leiv Ose and Emilio Ros and Fatima Almagro and {de Leeuw}, {Peter W.} and Fernando Civeira and Luis Masana and Xavier Pinto and Simoons, {Maarten L.} and Schinkel, {Arend F. L.} and Green, {Martin R.} and Zwinderman, {Aeilko H.} and Johnson, {Keith J.} and Arne Schaefer and Andrew Neil and Witteman, {Jacqueline C. M.} and Humphries, {Steve E.} and Kastelein, {John J. P.} and Sijbrands, {Eric J. G.}",

year = "2015",

month = mar,

doi = "10.1038/ejhg.2014.101",

language = "English",

volume = "23",

pages = "381--387",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "3",

}

Versmissen, J, Oosterveer, DM, Yazdanpanah, M, Dehghan, A, Holm, H, Erdman, J, Aulchenko, YS, Thorleifsson, G, Schunkert, H, Huijgen, R, Vongpromek, R, Uitterlinden, AG, Defesche, JC, van Duijn, CM, Mulder, M, Dadd, T, Karlsson, HD, Ordovas, J, Kindt, I, Jarman, A, Hofman, A, van Vark-van der Zee, L, Blommesteijn-Touw, AC, Kwekkeboom, J, Liem, AH, van der Ouderaa, FJ, Calandra, S, Bertolini, S, Averna, M, Langslet, G, Ose, L, Ros, E, Almagro, F, de Leeuw, PW, Civeira, F, Masana, L, Pinto, X, Simoons, ML, Schinkel, AFL, Green, MR, Zwinderman, AH, Johnson, KJ, Schaefer, A, Neil, A, Witteman, JCM, Humphries, SE, Kastelein, JJP & Sijbrands, EJG 2015, 'Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach', European Journal of Human Genetics, vol. 23, no. 3, pp. 381-387. https://doi.org/10.1038/ejhg.2014.101

TY - JOUR

T1 - Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

AU - Versmissen, Jorie

AU - Oosterveer, Daniella M.

AU - Yazdanpanah, Mojgan

AU - Dehghan, Abbas

AU - Holm, Hilma

AU - Erdman, Jeanette

AU - Aulchenko, Yurii S.

AU - Thorleifsson, Gudmar

AU - Schunkert, Heribert

AU - Huijgen, Roeland

AU - Vongpromek, Ranitha

AU - Uitterlinden, Andre G.

AU - Defesche, Joep C.

AU - van Duijn, Cornelia M.

AU - Mulder, Monique

AU - Dadd, Tony

AU - Karlsson, Hrobjartur D.

AU - Ordovas, Jose

AU - Kindt, Iris

AU - Jarman, Amelia

AU - Hofman, Albert

AU - van Vark-van der Zee, Leonie

AU - Blommesteijn-Touw, Adriana C.

AU - Kwekkeboom, Jaap

AU - Liem, Anho H.

AU - van der Ouderaa, Frans J.

AU - Calandra, Sebastiano

AU - Bertolini, Stefano

AU - Averna, Maurizio

AU - Langslet, Gisle

AU - Ose, Leiv

AU - Ros, Emilio

AU - Almagro, Fatima

AU - de Leeuw, Peter W.

AU - Civeira, Fernando

AU - Masana, Luis

AU - Pinto, Xavier

AU - Simoons, Maarten L.

AU - Schinkel, Arend F. L.

AU - Green, Martin R.

AU - Zwinderman, Aeilko H.

AU - Johnson, Keith J.

AU - Schaefer, Arne

AU - Neil, Andrew

AU - Witteman, Jacqueline C. M.

AU - Humphries, Steve E.

AU - Kastelein, John J. P.

AU - Sijbrands, Eric J. G.

PY - 2015/3

Y1 - 2015/3

N2 - Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P

AB - Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P

U2 - 10.1038/ejhg.2014.101

DO - 10.1038/ejhg.2014.101

M3 - Article

C2 - 24916650

VL - 23

SP - 381

EP - 387

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 3

ER -