Common genetic variants do not associate with CAD in familial hypercholesterolemia.
In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.
1] Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands [2] Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
Erik P A
EP
van Iperen
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
Suthesh
S
Sivapalaratnam
1] Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands [2] Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
S Matthijs
SM
Boekholdt
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
G Kees
GK
Hovingh
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
Stephanie
S
Maiwald
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
Michael W
MW
Tanck
Human Genetics, Welcome Trust Sanger Institute, Hinxton, UK.
Nicole
0000000310953852
N
Soranzo
1] Department of Haematology, University of Cambridge, Cambridge, UK [2] National Health Service Blood and Transplant, Cambridge, UK.
Jonathan C
JC
Stephens
1] Department of Haematology, University of Cambridge, Cambridge, UK [2] National Health Service Blood and Transplant, Cambridge, UK.
Jennifer G
JG
Sambrook
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
Marcel
M
Levi
1] Human Genetics, Welcome Trust Sanger Institute, Hinxton, UK [2] Department of Haematology, University of Cambridge, Cambridge, UK [3] National Health Service Blood and Transplant, Cambridge, UK.
Willem H
WH
Ouwehand
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
John Jp
JJ
Kastelein
Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
Mieke D
MD
Trip
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
Aeilko H
AH
Zwinderman
D000368:Aged; D003324:Coronary Artery Disease / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics
D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases