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Published on: May 31, 2016
Male-specific association between a gamma-secretase polymorphism and premature coronary atherosclerosis
Karen M J van Loo1, Tim Dejaegere, Martine van Zweeden
1Department of Molecular Animal Physiology, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
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.
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