Association of extracellular superoxide dismutase gene with cerebral infarction in women: a haplotype‐based case‐control study

摘要

In Japan, stroke has been a major cause of death in the elderly population, with a total of 1 370 000 individuals suffering stroke each year (cerebral infarction 61%, cerebral hemorrhage 25%, subarachnoid hemorrhage 11%, other types 3%) and 130 000 dying of it (Yamada 2007). Cerebral infarction (CI) is the most common type of stroke, and it will often cause long-time disability. (Kubo et al. 2007). CI is considered a multifactorial disease that results from interaction between genetic and environmental factors (Dominiczak et al. 2000; Um et al. 2003). Arteriosclerosis, which is related to hypertension, results in blocking of the blood stream in blood vessels. Complete blockage of the blood stream in a brain vessel results in cerebral infarction. In 1988, it was reported that the risk of cardiovascular mortality increased with elevation of either systolic or diastolic blood pressure (Ueda et al. 1988). It is therefore believed that hypertension is the most important risk factor for CI.Superoxide (O2?) is among the most abundant reactive oxygen species (ROS) produced by the mitochondria, and is essential in humans for protection against bacteria and viruses (Landis and Tower 2005). However, oxidative stress injures cells in the human body when the production of ROS is higher than the reduction of ROS. It is believed that oxidative stress from surplus superoxide is a causative factor in CI and several other disorders, including cancer, leukaemia, myocardial infarction (MI) and hypertension (Fattman et al. 2003).Superoxide dismutase (SOD) is an anti-oxidative enzyme that converts superoxide to hydrogen peroxide (H2O2) (Afonso et al. 2007). SOD was characterized by McCord and Fridovich as including three distinct mammalian isoforms: copper-and-zinc-containing superoxide dismutase (CuZn-SOD: SOD1), manganese superoxide dismutase (Mn-SOD: SOD2), and extracellular superoxide dismutase (EC-SOD: SOD3) (Folz and Crapo 1994, Folz et al. 1997; Campo et al. 2005; Zhou et al. 2006). The human EC-SOD gene is located on chromosome 4p16.3-q21 and consists of three exons and two introns. Human EC-SOD, which is encoded by a gene distinct from that for CuZn-SOD, is composed of 240 amino acids and harbors an 18-amino-acid-long signal peptide targeting the protein for the extracellular compartment (Folz and Crapo 1994; Son et al. 2003). Although the function of the amino-terminal half of mature EC-SOD is unclear, amino acid residues 96-193 exhibit a high level of sequence homology to CuZn-SOD, with preservation of critical amino acids required for catalytic activity and no sequence homology to Mn-SOD. In humans, EC-SOD is present in small amounts in most tissues, but accounts for 30 to 50% of total SOD in vascular tissues (Str?lin et al. 1995; Gongora et al. 2006).In 1999, the relationship between EC-SOD and cerebral ischemia was determined using EC-SOD knock-out mice (EC-SOD?/?) (Sheng et al. 1999). In that study, it was found that the cerebral infarct size of EC-SOD?/? was significantly larger than that in wild-type mice. The human EC-SDO gene is therefore considered a susceptibility gene for CI.Although some studies have examined the relationship between EC-SOD and CI (Sheng et al. 1999; Demechenko et al. 2002; Fukui et al. 2003; Zhan and Yang 2006), no case-control studies of this relationship using haplotypes have previously been reported. Our study is the first haplotype-based case-control study of the EC-SOD gene and CI. It has been reported that EC-SOD influences both hypertension (Welch et al. 2005, 2006; Gongora et al. 2006) and cerebral ischemia (Sheng et al. 1999; Fukui et al. 2003). Since hypertension is an important risk factor for CI and cerebral ischemia, a case-control study of the EC-SOD gene is clearly worth performing.The aim of the present study was to investigate the relationship between CI and the human EC-SOD gene using single-nucleotide polymorphisms (SNPs) and haplotypes in the Japanese population.