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Male-Specific Association between a γ-Secretase Polymorphism and Premature Coronary Atherosclerosis
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Male-Specific Association between a γ-Secretase Polymorphism and Premature Coronary Atherosclerosis
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Journal Article
Male-Specific Association between a γ-Secretase Polymorphism and Premature Coronary Atherosclerosis
2008
Overview
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.
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.
We conclude that, in a male-specific manner, disturbed gamma-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Animals
/ Cardiovascular Disorders/Coronary Artery Disease
/ Coronary Artery Disease - epidemiology
/ Coronary Artery Disease - genetics
/ Embryos
/ European Continental Ancestry Group - genetics
/ Female
/ Females
/ Genes
/ Genetics
/ Genetics and Genomics/Genetics of Disease
/ Humans
/ Low density lipoprotein receptors
/ Male
/ Males
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Polymorphism, Single Nucleotide
/ Proteins
/ Recombinant Fusion Proteins - metabolism
