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MPO and APOEepsilon4 polymorphisms interact to increase risk for AD in Finnish males
W F Reynolds1, M Hiltunen, M Pirskanen
1Sidney Kimmel Cancer Center, San Diego, CA 92121, USA. wreynolds@skcc.org
Background:
Myeloperoxidase (MPO) is present in senile plaques and surrounding reactive microglia, but not in normal brain parenchyma. MPO in plaques is highest in APOE epsilon4 carriers, suggesting a functional interaction. An MPO promoter polymorphism (-463G/A) linked to increased MPO expression has been associated with increased risk of AD.
Methods:
To further define the possible interaction of MPO and APOE epsilon4, we examined 127 patients with AD and 174 controls from a genetically homogeneous Finnish population.
Results:
A significantly higher percentage of male patients with AD carried the MPO A and APOE epsilon4 alleles relative to men carrying neither allele (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE epsilon4 carriers lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), indicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower in men carrying the MPO A and APOE epsilon4 alleles (Kaplan-Meier survival analysis; p = 0.01). Also, the MPO AA genotype was associated with selective mortality in men, but not in women. AA genotypes were absent from 159 male patients with AD and controls, representing the expected 5% to 6% in women and male controls younger than age 20. The -463A creates an estrogen receptor binding site that may contribute to these gender differences.
Conclusions:
MPO A and APOE epsilon4 alleles interact to increase the risk of AD in men but not in women in this Finnish cohort.
Insights
Myeloperoxidase (MPO) A and APOE epsilon4 alleles interact to significantly increase Alzheimer's disease (AD) risk in men. This genetic interaction was not observed in women, suggesting gender-specific effects in AD.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Myeloperoxidase (MPO) is found in Alzheimer's disease (AD) senile plaques and reactive microglia.
- MPO levels are highest in APOE epsilon4 carriers, suggesting a functional interaction.
- An MPO promoter polymorphism (-463G/A) is linked to increased MPO expression and AD risk.
Purpose of the Study:
- To investigate the interaction between MPO and APOE epsilon4 in Alzheimer's disease (AD).
- To examine the influence of MPO and APOE epsilon4 alleles on AD risk and onset in a Finnish cohort.
Main Methods:
- Examined 127 AD patients and 174 controls from a genetically homogeneous Finnish population.
- Analyzed MPO and APOE epsilon4 allele frequencies and their association with AD.
- Utilized Kaplan-Meier survival analysis to assess age at onset and mortality.
Main Results:
- A significantly higher percentage of male AD patients carried both MPO A and APOE epsilon4 alleles (OR, 11.4).
- MPO A allele enhances AD risk by 3.8-fold in male APOE epsilon4 carriers.
- The MPO AA genotype was associated with selective mortality in men, with earlier onset in men carrying both MPO A and APOE epsilon4 alleles.
Conclusions:
- MPO A and APOE epsilon4 alleles interact to increase Alzheimer's disease (AD) risk in men.
- This interaction was not observed in women, suggesting gender-specific effects.
- The -463A polymorphism may create an estrogen receptor binding site, potentially explaining gender differences.