期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 49, 页码 19707-19712出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1117137108
关键词
subarachnoid hemorrhage; stroke; genetic risk loci
资金
- Yale Center for Human Genetics and Genomics
- Yale Program on Neurogenetics
- National Institutes of Health [R01NS057756, R01NS067023]
- The Howard Hughes Medical Institute
- European Commission [IST-FP6-027703]
- German Federal Ministry of Education and Research [01GI9907]
- Grants-in-Aid for Scientific Research [22241049] Funding Source: KAKEN
The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 x 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 x 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 x 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.
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