Male-Specific Association between a [gamma]-Secretase Polymorphism and Premature Coronary Atherosclerosis

• Published in: PloS one 2008-11, Vol.3 (11), p.e3662
• Main Authors: van Loo, Karen M. J, Dejaegere, Tim, van Zweeden, Martine, van Schijndel, Jessica E, Wijmenga, Cisca, Trip, Mieke D, Martens, Gerard J. M
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Analysis; Atherosclerosis; Disease susceptibility; Single nucleotide polymorphisms
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0003662

Background Atherosclerosis is a common multifactorial disease resulting from an interaction between susceptibility genes and environmental factors. The causative genes that contribute to atherosclerosis are elusive. Based on recent findings with a Wistar rat model, we speculated that the [gamma]-secretase pathway may be associated with atherosclerosis. Methodology/Principal Findings We have tested for association of premature coronary atherosclerosis with a non-synonymous single-nucleotide polymorphism (SNP) in the [gamma]-secretase component APH1B (Phe217Leu; rs1047552), a SNP previously linked to Alzheimer's disease. Analysis of a Dutch Caucasian cohort (780 cases; 1414 controls) showed a higher prevalence of the risk allele in the patients (odds ratio (OR) = 1.35), albeit not statistically different from the control population. Intriguingly, after gender stratification, the difference was significant in males (OR = 1.63; p = 0.033), but not in females (OR = 0.50; p = 0.20). Since Phe217Leu-mutated APH1B showed reduced [gamma]-secretase activity in mouse embryonic fibroblasts, the genetic variation is likely functional. Conclusion/Significance We conclude that, in a male-specific manner, disturbed [gamma]-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis.