Mitochondrial haplogroup A is a genetic risk factor for atherothrombotic cerebral infarction in Japanese females
Introduction
Stroke is the third leading cause of death, after cancer and heart disease, in western countries and Japan. The prevalence of stroke in Japan is 1.4 million (62% ischemic stroke, 23% intracerebral hemorrhage, and 11% subarachnoid hemorrhage) with 132,799 deaths from this condition in 2005 (Ministry of Health, Labor, and Welfare of Japan). Given the importance of prevention as a strategy to reduce the overall burden of stroke, the identification of markers of stroke risk is key, both for risk prediction and for potential intervention to avert future events.
Ischemic stroke is a heterogeneous disease caused by different pathogenic mechanisms. In vascular endothelial cells, mitochondria are the major site of superoxide production; therefore the mitochondrion-derived reactive oxygen species presumably play an important role in the pathogenesis of atherosclerosis and atherothrombotic cerebral infarction. In humans, mitochondrial DNA (mtDNA) is a 16,569-bp (base pair) double-stranded circular molecule, encoding 37 genes (Anderson et al., 1981), and is exclusively transmitted from the mother. In addition, the evolutionary rate of mtDNA is reported to be much higher than that of nuclear DNA (Pakendorf and Stoneking, 2005). Consequently, the polymorphisms in the mtDNA are expected to contribute more extensively to the functional differences among individuals than those in the nuclear DNA.
Therefore, over the last several years, we have been conducting research aimed at identifying mtDNA single-nucleotide polymorphisms (mtSNPs) associated with age-related conditions such as longevity, Parkinson disease, and Alzheimer disease, and with lifestyle-related metabolic diseases such as obesity, thinness, type 2 diabetes, and atherosclerosis (Fuku et al., 2002, Guo et al., 2005, Ikebe et al., 1995, Tanaka et al., 2002, Tanaka et al., 1998). For this purpose, we sequenced the entire mtDNA molecule from 672 individuals belonging to 7 different groups, namely, centenarians, patients with Parkinson disease, patients with Alzheimer disease, young obese or non-obese males, and type 2 diabetic patients with or without severe vascular involvement (Tanaka et al., 2004). On the basis of these sequence data, we established an East Asia mtDNA phylogeny (Tanaka et al., 2004), and constructed a human mtSNP database (http://www.giib.or.jp/mtsnp/index_e.shtml). This mtSNP database has prompted us to develop a comprehensive mtSNP analysis system using fluorescent beads.
Although many studies have examined the relationship between nuclear DNA variants and ischemic stroke for the past a couple of decades, the genetic determinants of this condition remain largely unknown. The purpose of the present study was to identify mitochondrial genome haplogroups that confer susceptibility to or resistance against atherothrombotic cerebral infarction, which identification should thereby to contribute to the primary and personalized prevention of this event.
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Study population
The study population comprised 1081 unrelated Japanese individuals (641 males, 440 females) who either visited outpatient clinics of or were admitted to one of the participating hospitals (Gifu Prefectural Gifu, Tajimi, and Gero Hotspring Hospitals), between October 2002 and March 2005, as shown in Table 1. The 346 subjects (234 males, 112 females) with atherothrombotic cerebral infarction were recruited from consecutive individuals who either were admitted to the participating hospitals
Results
The characteristics of the study subjects are shown in Table 1. Age, the prevalence of hypertension, and that of type 2 diabetes were significantly higher in the subjects with atherothrombotic cerebral infarction than in the controls (P < 0.005). The female/male ratio in the subjects with the atherothrombotic cerebral infarction was significantly lower than in the controls (P = 0.0001). None of the parameter values for BMI and prevalence of smoking and hypercholesterolemia were different between
Discussion
In the present study, we examined the relationship between each of 11 major mitochondrial genome haplogroups (Table 2) and atherothrombotic cerebral infarction in an association study on 1081 unrelated Japanese individuals (Table 1). We compared the prevalence of haplogroups between control subjects and patients with atherothrombotic cerebral infarction by the chi-square test (Table 3). There were trends towards lower prevalence of atherothrombotic cerebral infarction in the haplogroups N9a and
Acknowledgements
This work was supported in part by a Grant-in-aid [A-15200051 to M.T.] from the Ministry of Education, Culture, Sports, Science, and Technology, by a grant from the Third-Term Comprehensive 10-year Strategy for Cancer Control (to M.T.), by grant 17A-10 from the program Research Grants for Nervous and Mental Disorders of the Ministry of Health, Labour, and Welfare (to M.T.), and by grants for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
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