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 journalArticleAcademicpeer-review

12 Citations (Web of Science)


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 languageEnglish
Pages (from-to)381-387
JournalEuropean Journal of Human Genetics
Issue number3
Publication statusPublished - Mar 2015

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