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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

Alignment of vertebrate and invertebrate amino acid sequences of the region within APH1 surrounding residue 217.A black background indicates identical amino acid residues; a grey background indicates a conservative amino acid change. Abbreviations: Hs, Homo sapiens; Pt, Pan troglodytes; Rn, Rattus norvegicus; Mm, Mus musculus; Xt, Xenopus tropicalis; Dr, Danio rerio; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; At, Arabidopsis thaliana. Sequences were aligned using Vector NTI (9.0) with default parameters.
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pone-0003662-g001: Alignment of vertebrate and invertebrate amino acid sequences of the region within APH1 surrounding residue 217.A black background indicates identical amino acid residues; a grey background indicates a conservative amino acid change. Abbreviations: Hs, Homo sapiens; Pt, Pan troglodytes; Rn, Rattus norvegicus; Mm, Mus musculus; Xt, Xenopus tropicalis; Dr, Danio rerio; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; At, Arabidopsis thaliana. Sequences were aligned using Vector NTI (9.0) with default parameters.

Mentions: The degree of conservation of an amino acid within a protein family is usually indicative of its importance for protein functioning. A multiple sequence alignment of members of the APH1 family (Figure 1) showed that the Phe217 residue is conserved from plant, invertebrates, lower vertebrates, rodents and primates to man. The various APH1 proteins all contain at residue 217 either a phenylalanine (F) or the conservative change to tyrosine (Y). The Support Vector Machine (SVM) score (http://www.SNPs3D.org) [16] of −1.12 for Phe217Leu indicates a likely impact of this substitution on APH1B protein function.


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)

Alignment of vertebrate and invertebrate amino acid sequences of the region within APH1 surrounding residue 217.A black background indicates identical amino acid residues; a grey background indicates a conservative amino acid change. Abbreviations: Hs, Homo sapiens; Pt, Pan troglodytes; Rn, Rattus norvegicus; Mm, Mus musculus; Xt, Xenopus tropicalis; Dr, Danio rerio; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; At, Arabidopsis thaliana. Sequences were aligned using Vector NTI (9.0) with default parameters.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2573958&req=5

pone-0003662-g001: Alignment of vertebrate and invertebrate amino acid sequences of the region within APH1 surrounding residue 217.A black background indicates identical amino acid residues; a grey background indicates a conservative amino acid change. Abbreviations: Hs, Homo sapiens; Pt, Pan troglodytes; Rn, Rattus norvegicus; Mm, Mus musculus; Xt, Xenopus tropicalis; Dr, Danio rerio; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; At, Arabidopsis thaliana. Sequences were aligned using Vector NTI (9.0) with default parameters.
Mentions: The degree of conservation of an amino acid within a protein family is usually indicative of its importance for protein functioning. A multiple sequence alignment of members of the APH1 family (Figure 1) showed that the Phe217 residue is conserved from plant, invertebrates, lower vertebrates, rodents and primates to man. The various APH1 proteins all contain at residue 217 either a phenylalanine (F) or the conservative change to tyrosine (Y). The Support Vector Machine (SVM) score (http://www.SNPs3D.org) [16] of −1.12 for Phe217Leu indicates a likely impact of this substitution on APH1B protein function.

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