Haptoglobin 2 allele associates with unstable carotid plaque and major cardiovascular events.
OBJECTIVE
Intraplaque hemorrhages (IPH) may predispose to unstable atherosclerotic disease and its atherothrombotic complications, ischemic stroke and coronary syndromes. However, the discriminative value of IPH has been limited in histological and imaging studies suggesting that confounding factors modulate the response to IPH. We studied whether common variants of haptoglobin (Hp), which facilitates the removal of free hemoglobin and protects tissues from heme-iron induced oxidative damage, would modify the inflammatory response to IPH and the risk of unstable carotid stenosis (CS) and major cardiovascular diseases.


METHODS
We genotyped Hp polymorphism in 91 patients with a high-grade CS from Helsinki Carotid Endarterectomy Study (HeCES) and in 1417 individuals from Health 2000, a Finnish epidemiological cross-sectional health survey, and determined heme oxygenase-1 (HO1) expression in relation to Hp genotypes in carotid plaques.


RESULTS
In the Health 2000 cohort, Hp genotype frequencies were 0.143 (hp1-1), 0.486 (hp1-2) and 0.371 (hp2-2) consistent with Hardy-Weinberg equilibrium and those reported from other Caucasian populations. Among patients with unstable CS, the frequency of hp2-2 genotype was higher than in the control population (0.516 vs. 0.371, P = 0.025). Hp genotypes correlated with HO1 expression in the plaque (r = 0.47, P = 0.027). In the Health 2000 cohort, hp2 allele was associated with an increased risk of major cardiovascular diseases (ischemic stroke, TIA, myocardial infarction, coronary heart disease) with an adjusted OR of 1.46 (95% CI 1.03-2.06).


CONCLUSIONS
Common haptoglobin variants modulate the inflammatory response to IPH and associate with the risk of unstable carotid stenosis and major ischemic cardiovascular events.
Department of Neurology, Helsinki University Central Hospital, Finland; Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki and Department of Clinical Neurosciences, University of Helsinki, Finland. Electronic address: petra.ijas@hus.fi.
Petra
P
Ijäs
Jani
J
Saksi
Lauri
L
Soinne
Jarno
J
Tuimala
Matti
M
Jauhiainen
Antti
A
Jula
Mika
M
Kähönen
Y Antero
YA
Kesäniemi
Petri T
PT
Kovanen
Markku
M
Kaste
Perttu J
PJ
Lindsberg
D000368:Aged; D000483:Alleles; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D002339:Carotid Arteries / Q000473:pathology*; D016893:Carotid Stenosis / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016894:Endarterectomy, Carotid; D005260:Female; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D012306:Risk; D020521:Stroke / Q000175:diagnosis / Q000235:genetics
D006242:Haptoglobins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
Carotid stenoses; Intraplaque hemorrhage; Myocardial infarction; Stroke