Male-Specific Association between a c-Secretase Polymorphism and Premature Coronary Atherosclerosis

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 c-secretase pathway may be associated with atherosclerosis. Methodology/Principal Findings: We have tested for association of premature coronary atherosclerosis with a nonsynonymous single-nucleotide polymorphism (SNP) in the c-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 c-secretase activity in mouse embryonic fibroblasts, the genetic variation is likely functional. Conclusion/Significance: We conclude that, in a male-specific manner, disturbed c-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis. Citation: van Loo KMJ, Dejaegere T, van Zweeden M, van Schijndel JE, Wijmenga C, et al. (2008) Male-Specific Association between a c-Secretase Polymorphism and Premature Coronary Atherosclerosis. PLoS ONE 3(11): e3662. doi:10.1371/journal.pone.0003662 Editor: Amanda Ewart Toland, Ohio State University Medical Center, United States of America Received June 19, 2008; Accepted October 17, 2008; Published November 6, 2008 Copyright: 2008 van Loo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was performed within the framework of project T5-209 of the Dutch Top Institute Pharma. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]