MPO and APOEepsilon4 polymorphisms interact to increase risk for AD in Finnish males.
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.
Reynolds
W F
WF
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA. wreynolds@skcc.org
Hiltunen
M
M
Pirskanen
M
M
Mannermaa
A
A
Helisalmi
S
S
Lehtovirta
M
M
Alafuzoff
I
I
Soininen
H
H
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D005387:Finland; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics*; D006801:Humans; D007377:Interleukin-3; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012307:Risk Factors; D012737:Sex Factors
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor