Abstract 5500: PDGFD Variation is Associated With Increased Susceptibility to First-ever Non-hypertensive Intracerebral Hemorrhage Whereas Predicts Decreased Risk of Recurrence
Background Platelet-derived growth factor D (PDGF-D) is a most recently discovered member of the PDGF family and plays an important role in angiogenesis, vessel remodeling and repairing in response to injury. We hypothesized that genetic variation in PDGFD gene might alter the susceptibility to stroke.
Methods We determined the genotypes of a single nucleotide polymorphism (SNP) (−858A/C, rs3809021), the only identified tag-SNP in the promoter region of PDGFD from the HapMap CHB sample, in 1484 patients with stroke (654 cerebral thrombosis, 419 lacunar infarction, 411 intracerebral hemorrhage [ICH]) and 1528 control subjects from an unrelated Chinese Han population and followed the stroke patients up for a median of 4.5 years (range 0.1 to 5.4). Functions of −858 variant were studied by using luciferase reporter assays.
Results The SNP −858A-bearing PDGFD promoter exhibited 3.78-fold increase of transcription activity than the SNP −858C-bearing promoter. Genotype analyses were conducted for both dominant and additive models. The A allele of the −858 locus showed significantly increased risk of ICH (dominant model: odds ratio [OR] 1.29, 95% confidence interval [CI] 1.00 to 1.68, P=0.05; additive model: OR 1.24, 95% CI 1.01 to 1.52, P=0.04) than wild-type genotype. Further analyses showed that −858 A allele conferred about 2-fold increase in risk of non-hypertensive ICH (dominant model: OR 2.1, 95%CI 1.34 to 3.29, P=0.001; additive model: OR 1.75, 95% CI 1.24 to 2.46, P=0.001). After a median follow-up of 4.5 years, 52 patients had a recurrent ICH. After adjusting for conventional cardiovascular risk factors, we found that −858 A allele was associated with a reduced risk of ICH recurrence (dominant model: adjusted hazard ratio [HR] 0.09, 95%CI 0.01 to 0.74, P=0.025; additive model: HR 0.21, 95% CI 0.04 to 1.16, P=0.073) in non-hypertensive patients. No association was observed between the PDGFD variant and hypertensive ICH and atherothrombotic stroke.
Conclusions The −858A allele was associated with increased first-ever non-hypertensive ICH and was a predictor of lower risk of ICH recurrence. Further studies should be conducted to reveal the role of PDGF-D at various stages of ICH development beneficial, or deleterious.