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Male-specific association between a gamma-secretase polymorphism and premature coronary atherosclerosis.

van Loo KM, Dejaegere T, van Zweeden M, van Schijndel JE, Wijmenga C, Trip MD, Martens GJ - PLoS ONE (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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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Related in: MedlinePlus

γ-Secretase cleavage activity of human wild-type APH1B (Phe217) and human mutant APH1B (Leu217) stably transfected into Aph1abc−/− mouse embryonic fibroblast cells.The levels of the C-terminal fragments (CTFs) of N-cadherin, APP and syndecan 3 were analysed in cells stably transfected with human APH1B Phe217 (WT) or human APH1B Leu217 (MUT). In the MUT cells, the CTF levels of N-cadherin and APP were slightly increased (1.1-fold and 1.2-fold, respectively), but the difference failed to reach significance. The levels of syndecan-3-CTF were significantly increased (1.6-fold; p = 0.044), indicating a reduced γ-secretase cleavage activity. Bars represent quantifications of CTF signals normalized to full-length protein levels in eight stably transfected cell lines with the average level in WT cell lines set to 100%. *: p<0.05.
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pone-0003662-g002: γ-Secretase cleavage activity of human wild-type APH1B (Phe217) and human mutant APH1B (Leu217) stably transfected into Aph1abc−/− mouse embryonic fibroblast cells.The levels of the C-terminal fragments (CTFs) of N-cadherin, APP and syndecan 3 were analysed in cells stably transfected with human APH1B Phe217 (WT) or human APH1B Leu217 (MUT). In the MUT cells, the CTF levels of N-cadherin and APP were slightly increased (1.1-fold and 1.2-fold, respectively), but the difference failed to reach significance. The levels of syndecan-3-CTF were significantly increased (1.6-fold; p = 0.044), indicating a reduced γ-secretase cleavage activity. Bars represent quantifications of CTF signals normalized to full-length protein levels in eight stably transfected cell lines with the average level in WT cell lines set to 100%. *: p<0.05.

Mentions: We wondered whether the presence of a leucine instead of the conserved residue Phe217 of the APH1B protein would be of functional importance. Aph1abc−/− mouse embryonic fibroblasts were stably transfected with human APH1B Phe217 or Leu217. γ-Secretase activity was measured by quantifying the levels of different γ-secretase substrates in cell culture extracts. We observed a 1.6-fold reduction (p<0.05, n = 8) of γ-secretase activity towards one of its substrates, syndecan-3 [17], indicating a subtle influence on γ-secretase cleavage activity. The cleavages of two other substrates, N-cadherin and APP, were slightly but not significantly changed (Figure 2). Thus, in a substrate-dependent manner the Phe217Leu substitution affected γ-secretase cleavage activity.


Male-specific association between a gamma-secretase polymorphism and premature coronary atherosclerosis.

van Loo KM, Dejaegere T, van Zweeden M, van Schijndel JE, Wijmenga C, Trip MD, Martens GJ - PLoS ONE (2008)

γ-Secretase cleavage activity of human wild-type APH1B (Phe217) and human mutant APH1B (Leu217) stably transfected into Aph1abc−/− mouse embryonic fibroblast cells.The levels of the C-terminal fragments (CTFs) of N-cadherin, APP and syndecan 3 were analysed in cells stably transfected with human APH1B Phe217 (WT) or human APH1B Leu217 (MUT). In the MUT cells, the CTF levels of N-cadherin and APP were slightly increased (1.1-fold and 1.2-fold, respectively), but the difference failed to reach significance. The levels of syndecan-3-CTF were significantly increased (1.6-fold; p = 0.044), indicating a reduced γ-secretase cleavage activity. Bars represent quantifications of CTF signals normalized to full-length protein levels in eight stably transfected cell lines with the average level in WT cell lines set to 100%. *: p<0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2573958&req=5

pone-0003662-g002: γ-Secretase cleavage activity of human wild-type APH1B (Phe217) and human mutant APH1B (Leu217) stably transfected into Aph1abc−/− mouse embryonic fibroblast cells.The levels of the C-terminal fragments (CTFs) of N-cadherin, APP and syndecan 3 were analysed in cells stably transfected with human APH1B Phe217 (WT) or human APH1B Leu217 (MUT). In the MUT cells, the CTF levels of N-cadherin and APP were slightly increased (1.1-fold and 1.2-fold, respectively), but the difference failed to reach significance. The levels of syndecan-3-CTF were significantly increased (1.6-fold; p = 0.044), indicating a reduced γ-secretase cleavage activity. Bars represent quantifications of CTF signals normalized to full-length protein levels in eight stably transfected cell lines with the average level in WT cell lines set to 100%. *: p<0.05.
Mentions: We wondered whether the presence of a leucine instead of the conserved residue Phe217 of the APH1B protein would be of functional importance. Aph1abc−/− mouse embryonic fibroblasts were stably transfected with human APH1B Phe217 or Leu217. γ-Secretase activity was measured by quantifying the levels of different γ-secretase substrates in cell culture extracts. We observed a 1.6-fold reduction (p<0.05, n = 8) of γ-secretase activity towards one of its substrates, syndecan-3 [17], indicating a subtle influence on γ-secretase cleavage activity. The cleavages of two other substrates, N-cadherin and APP, were slightly but not significantly changed (Figure 2). Thus, in a substrate-dependent manner the Phe217Leu substitution affected γ-secretase cleavage activity.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus