Haptoglobin genotype is a major determinant of the amount of iron in the human atherosclerotic plaque.
OBJECTIVE
We sought to test the hypothesis that haptoglobin (Hp) genotype is a determinant of the amount of iron in the atherosclerotic plaque.


BACKGROUND
In atherosclerotic lesions, intraplaque hemorrhage releases free hemoglobin (Hb), whose incorporated iron can act as an oxidant and inflammatory stimulus. These effects are antagonized by Hp, which binds free Hb and facilitates its clearance from the plaque. The Hp gene has 2 alleles (1 and 2), giving rise to 3 genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. We previously hypothesized that Hp 2-2 individuals with diabetes mellitus (DM) have impaired clearance of Hb and its iron cargo from the plaque.


METHODS
We identified the presence or absence of Perl's iron stain in 189 plaques obtained from 37 decedents at autopsy.


RESULTS
Among DM, the prevalence of Perl's iron stain was increased in Hp 2-2 compared with that seen in Hp 1-1 or 2-1 (46.2% vs. 11.8%). After accounting for the within-decedent correlation of plaques, the prevalence ratio of Perl's iron stain associated with Hp 2-2 was 3.97 (95% confidence interval: 1.38 to 11.5; p = 0.025). In non-DM plaques, there was a nonsignificant trend towards a higher prevalence of iron staining in Hp 2-2 compared with that in Hp 1-1 or 2-1 (26.8% vs. 11.1%; prevalence ratio =2.40 [95% confidence interval: 0.81 to 7.09]; p = 0.114).


CONCLUSIONS
These data support an impaired clearance of Hb from plaques in Hp 2-2 individuals, particularly in DM. The higher prevalence of plaque iron in Hp 2-2 DM individuals may contribute to the increased incidence of atherothrombotic events in these patients.
Department of Medicine (Cardiology), Mount Sinai Medical Center, New York, New York, USA.
Pedro R
PR
Moreno
K Raman
KR
Purushothaman
Meera
M
Purushothaman
Paul
P
Muntner
Nina S
NS
Levy
Valentin
V
Fuster
John T
JT
Fallon
Patrick A
PA
Lento
Aaron
A
Winterstern
Andrew P
AP
Levy
D001013:Aorta, Thoracic / Q000378:metabolism*; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D004396:Coloring Agents; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D005295:Ferrocyanides; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male
D004396:Coloring Agents; D005295:Ferrocyanides; D006242:Haptoglobins; D007501:Iron; C000170:ferric ferrocyanide