title: Complement Factor H Y402H polymorphism is associated with an increased risk of mortality after intracerebral hemorrhage.
abstract: Intracerebral hemorrhage (ICH) accounts for 10% to 15% of all strokes and is a major cause of morbidity and mortality. Despite advances in management, numerous clinical trials have failed to demonstrate significant benefit of medical and surgical interventions, underscoring the need for the identification of novel therapeutic targets based on improved understanding of ICH pathophysiology and optimal risk stratification based on reliable and effective prognosticators. The alternative complement cascade has been implicated as an important contributor to neurological injury after ICH. Therefore, common, functionally relevant genetic variants in the key components of this pathway have been associated with greater inflammation post-ictus, further cerebral damage, and ultimately, a worse outcome. We investigated the affects of single-nucleotide polymorphisms (SNP) on mortality in complement component 3 C3 (rs2230199), complement component 5 C5 (rs17611), and Complement Factor H (CFH; rs1061170) genes, which are associated with the onset and progression of several neurological diseases, in a prospective cohort of patients with spontaneous ICH. From February 2009 through May 2010, adult patients with spontaneous ICH were admitted to the Columbia University Neurological Intensive Care Unit and enrolled in the Intracerebral Hemorrhage Outcomes Project. Demographic, clinical, radiographic, and treatment data were prospectively collected. Buccal swabs were obtained, and isolated cells were sequenced for the aforementioned SNP. A total of 103 patients were admitted with ICH, and of these, 82 consented for genetic testing and were included in the analysis. The median age was 61 years and 39% were females. The median Glasgow Coma Scale score on admission was 11.5. The CFH SNP was significantly associated with both discharge (p = 0.01) and 6-month mortality (p = 0.02), while no such association was observed for C3 (p = 0.545 and p = 0.830) or C5 (p = 0.983 and p = 0.536) SNP. Additionally, after controlling for pertinent variables identified in the univariate analysis, the CFH genotype independently predicted mortality at discharge (p = 0.019, odds ratio [OR] 7.62, 95% confidence interval [CI] 1.40-41.6) and at 6 months (p = 0.041, OR 1.822, 95% CI 1.025-3.239). The CFH genotype was also independently predictive of survival duration (p = 0.041, OR 1.822, 95% CI 1.025-3.239). We concluded that CFH Y402H polymorphism independently predicts mortality at discharge and 6-months and survival duration after spontaneous ICH.
authors.affiliation: Cerebrovascular Research Laboratory, Columbia University, College of Physicians and Surgeons, Neurological Institute of New York, New York, NY 10032, USA. ga2294@columbia.edu
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Appelboom
authors.forename: Matthew
authors.initials: M
authors.lastname: Piazza
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Hwang
authors.forename: Samuel
authors.initials: S
authors.lastname: Bruce
authors.forename: Steve
authors.initials: S
authors.lastname: Smith
authors.forename: Alexander
authors.initials: A
authors.lastname: Bratt
authors.forename: Emilia
authors.initials: E
authors.lastname: Bagiella
authors.forename: Neeraj
authors.initials: N
authors.lastname: Badjatia
authors.forename: Stephan
authors.initials: S
authors.lastname: Mayer
authors.forename: E
authors.initials: E
authors.lastname: Sander Connolly
mesh_terms: D000368:Aged; D000483:Alleles; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000401:mortality*; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012306:Risk
chemical_list: D017242:Complement Factor H