Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study
Introduction
Stroke is a complex multifactorial disorder that is thought to result from an interaction between a person's genetic background and various environmental factors. It is a common and serious condition, with about 780,000 individuals having experienced a new or recurrent stroke and 150,000 deaths having occurred from stroke-related causes in the United States in 2004. The prevalence of stroke in the United States is about 5.8 million. Of all such events, 87% are ischemic stroke, 10% are intracerebral hemorrhage, and 3% are subarachnoid hemorrhage [1]. In Japan, the prevalence of stroke is about 1.4 million (61% ischemic stroke, 25% intracerebral hemorrhage, 11% subarachnoid hemorrhage, 3% others), with nearly 133,000 deaths having occurred from this condition in 2005 (Ministry of Health, Labor, and Welfare of Japan). Despite recent advances in acute stroke therapy, stroke remains the leading cause of severe disability and the third leading cause of death, after heart disease and cancer, in Western countries and Japan [2]. The identification of biomarkers for stroke risk is important both for risk prediction and for intervention to avert future events.
Although genetic epidemiological studies have implicated several genetic variants as risk factors for ischemic stroke [3], [4], [5], [6], the genetic determinants of this condition remain largely unknown. We have now performed a genome-wide association study (GWAS) for ischemic stroke with ∼520,000 single nucleotide polymorphisms (SNPs) in a total of 6341 Japanese individuals. The purpose of the present study was to identify genetic variants that confer susceptibility to ischemic stroke and thereby to contribute to the personalized prevention of this condition.
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Study subjects
A total of 6341 individuals (992 subjects with ischemic stroke and 5349 controls) from three independent populations was examined. Subject panel A comprised 266 individuals (131 subjects with ischemic stroke and 135 controls) who either visited outpatient clinics of or were admitted to participating hospitals (Gifu Prefectural General Medical Center and Gifu Prefectural Tajimi Hospital) between October 2002 and March 2004 because of various symptoms or for an annual health checkup. Subject
Results
The characteristics of the 6341 subjects enrolled in the study are shown in Table 1. In subject panel A, the frequency of men and the prevalence of hypertension and hypercholesterolemia were greater, whereas age was younger, in subjects with ischemic stroke than in controls. In subject panel B, age, the frequency of men, and the prevalence of smoking, hypertension, and diabetes mellitus were greater, whereas BMI was smaller, in subjects with ischemic stroke than in controls. In subject panel C,
Discussion
The main cause of ischemic stroke is atherothrombosis, with the principal and treatable risk factors including hypertension, diabetes mellitus, and hypercholesterolemia [11]. In addition to these conventional risk factors, genetic variants are important in the pathogenesis of ischemic stroke [12]. Prediction of the risk for ischemic stroke on the basis of genetic variants would be useful for deciding how aggressively to target the clinical risk factors that are currently amenable to treatment.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (nos. 18209023, 18018021, and 19659149 to Y.Y.).
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