Introduction: Haptoglobin (Hb) is an acute phase plasma protein which binds free hemoglobin and protects tissues from heme-iron induced oxidative damage. Hp gene exists in two variant alleles, Hp1 and Hp2 giving rise to three protein isoforms, hp1-1, hp1-2 and hp2-2, which differ in their efficiency to limit oxidative stress. Previously, Hp variants have been associated with the risk of ischemic stroke subtypes, Hp1 variant with lacunar stroke and Hp2 with large-artery atherosclerotic stroke.
Hypothesis: Our aim was to scrutinize previous associations to stroke subtypes and, further, to test association of Hp variants with the extent of white matter lesions (WML) and incidence of cardiovascular death after first-ever ischemic stroke.
Methods: Hp was genotyped by PCR and gel electrophoresis in Helsinki Stroke Aging Memory Study (SAM, n=378 with DNA) and Cardiovascular diseases -subcohort of Health 2000 Survey (n=1426), who served as population controls.
Results: Hp genotype frequencies were 15.6% (Hp1-1), 44.2% (Hp1-2) and 40.2% (Hp2-2), within Hardy-Weinberg equilibrium and equal to those described in other Caucasian populations. There were no significant differences in Hp genotypes between stroke subtypes classified according to TOAST within SAM or compared to population controls. Hp alleles did not associate with the extent of WML. In follow-up, the carriers of Hp2 allele (Hp1-2 and Hp2-2) had substantially higher rate of cardiac deaths (24.5% vs 8.5%, P=0.006) and a trend towards more fatal strokes (23.5% vs 13.6%, P=0.122). The combined risk of ischemic cardiovascular death was 2.4-fold increased in Hp2 carriers (95%CI 1.28-4.43) even after adjustment for major cardiovascular risk factors (age, gender, hypertension, diabetes, atrial fibrillation, smoking, high LDL cholesterol).
Conclusions: Hp2 allele is associated with increased risk of ischemic cardiovascular death after first-ever ischemic stroke. This may result from the impaired capacity of Hp2-containing protein isoforms to alleviate oxidative stress in the vasculopathic arterial tree.