Male-Specific Association between a γ-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 γ-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 γ-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 γ-secretase activity in mouse embryonic fibroblasts, the genetic variation is likely functional. CONCLUSION/SIGNIFICANCE: We conclude that, in a male-specific manner, disturbed γ-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis.