Male-specific association between a gamma-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 gamma-secretase pathway may be associated with atherosclerosis.


RESULTS
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.


CONCLUSIONS
We conclude that, in a male-specific manner, disturbed gamma-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis.
van Loo
Karen M J
KM
Department of Molecular Animal Physiology, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Dejaegere
Tim
T
van Zweeden
Martine
M
van Schijndel
Jessica E
JE
Wijmenga
Cisca
C
Trip
Mieke D
MD
Martens
Gerard J M
GJ
D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D010450:Endopeptidases; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010447:Peptide Hydrolases; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012307:Risk Factors; D017678:Sex Distribution; D012737:Sex Factors; D013379:Substrate Specificity; D044465:White People / Q000235:genetics
D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D005340:Fibrinogen; C475154:APH1A protein, human; D010450:Endopeptidases; D010447:Peptide Hydrolases