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Evaluation of the poly(ADP-ribose) polymerase gene in human stroke
1Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan. nkato@med.teikyo-u.ac.jp
Abstract:
Nitric oxide (NO) and its reactant product, peroxynitrite, have been implied to mediate neuronal damage following cerebral ischemia. However, the cellular targets of these compounds remain unclear. Studies using poly(ADP-ribose) polymerase (PARP) inhibitors and PARP knock-out mice have recently demonstrated that excessive activation of this nuclear enzyme plays an important role in NO-induced neurotoxicity. To evaluate the relevance of this plausible candidate gene to human stroke, we undertook a case-control study in Japanese. Participants comprised 213 cerebral infarction cases and 374 age- and sex-matched controls. As a primary investigation, we screened polymorphic sites of the PARP gene, and newly identified a total of four polymorphisms in 1230-bp 5'-flanking sequence. None of them were, however, located on the known promoter components of the gene. Two bi-allelic polymorphisms selected and a CA-repeat polymorphism were subsequently characterized in the case-control study, but none were significantly associated with cerebral infarction in the present study. Our data thus suggest that the tested PARP polymorphisms do not principally contribute to cerebral infarction, although extensive searches would be required to clarify whether the PARP gene plays an important role in the pathogenesis of human stroke.
Insights
This study investigated the role of poly(ADP-ribose) polymerase (PARP) gene variations in Japanese stroke patients. The findings suggest that tested PARP polymorphisms are not a major contributor to cerebral infarction risk.
Area of Science:
- Neuroscience
- Genetics
- Cardiovascular Research
Background:
- Nitric oxide (NO) and peroxynitrite are implicated in neuronal damage after cerebral ischemia.
- Excessive activation of poly(ADP-ribose) polymerase (PARP) is linked to NO-induced neurotoxicity.
- The specific role of PARP in human stroke pathogenesis requires further investigation.
Purpose of the Study:
- To evaluate the association between PARP gene polymorphisms and cerebral infarction in a Japanese population.
- To identify novel polymorphic sites within the PARP gene's 5'-flanking sequence.
Main Methods:
- A case-control study involving 213 cerebral infarction cases and 374 controls.
- Screening of polymorphic sites in the PARP gene, including identification of four novel polymorphisms.
- Genotyping of selected bi-allelic and CA-repeat polymorphisms.
Main Results:
- No significant association was found between the tested PARP polymorphisms and cerebral infarction.
- Identified four novel polymorphisms in the PARP 5'-flanking region, none located on known promoter components.
Conclusions:
- The investigated PARP gene polymorphisms do not appear to be principal contributors to cerebral infarction in the studied Japanese population.
- Further research is needed to definitively establish the role of the PARP gene in human stroke pathogenesis.