| BackgroundIschemic stroke refers to the sudden reduction/decrease or interrupt of local brain arterial blood supply and perfusion completely, which stops pumping blood and supplying oxygen and glucose to the brain, and then results in the histolysis and damage of the local brain tissues. It is a multifactorial disease, caused by the interactions of genetic agents and environmental factors. It features high incidence and mortality, high disability and recurrence rate, many complications and so on.In china, ischemic stroke composes three quarters of the total stroke. According to the WHO investigations, the incidence of stroke in China is the highest in the world. In the recent twenty years, the incidence of cerebrovascular diseases increase continuously, the value ranging from 109.7 up to 217 per then thousand; and the cerebrovascular disease is the third death cause of the country residents. Stroke is one of the main public health problems that harm the people's health seriously. It not only threatens the public health, but also brings heavy burden to the society. To explore the pathogenesis and look for the etiology and effective preventions have become an urgent task.Ischemic stroke is a complex disease affected by genetic factors, environmental factors and the interactions of them two. So far, many environmental risk factors have been identified, such as smoking, consuming too much alcohol, hypertension, diabetes mellirus, dyslipidemia, overweight and obesity. Meanwhile, the studies of genetic predisposition have also made a lot of progress. There is a long list of stroke related genes, and most of them involve in rennin-angiotensin-aldosterone systems, lipid metabolism, coagulation system, fibrinolytic system, and so on. A recent genome-wide association study discovered two novel SNPs related to ischemic stroke in four large cohorts, which were rs12425791 and rs 11833579, located in chromosome 12p13 and beside the gene NINJ2. The strong association between rsl2425791 and stroke were replicated in two independent samples:North American black persons and Dutch white persons. There were also strong linkage disequilibrium between both SNPs, and between both SNPs and some SNPs in NINJ2 gene. Although the definite functions of gene NINJ2 are not known well, the gene NINJ2 is an important candidate gene of stroke, especially ischemic stroke.Our study investigated the ischemic stroke patients in the Chao Yang hospital in Beijing. A small mount of expected tag SNPs were selected from the giant gene data release by Hapmap to cover large segments of gene NINJ2. By analyzing the association between the tag SNPs and the ischemic stroke, we can learn the association between the gene NJNJ2 and the disease.ObjectionsA hospital based case-control study was set up to investigate the association of polymorphisms of NINJ2 gene with first onset nonfatal ischemic stroke, and its risk factors. Besides, we aim to assess the interaction effect between NINJ2 gene and other risk factors in order to have a better comprehension of the nosogenesis and to provide affective protective strategies to ischemic stroke.Subjects and MethodsIn the hospital based case control study, we selected eight tag SNPs of NINJ2 gene to analyze the association between gene NINJ2 and the ischemic stroke.The group of first onset nonfatal ischemic stroke was recruited in the Department of Neurology of Beijing Chao Yang Hospital, between April,2007 and November 2009. Brain CT and/or brain MRI, and electrocardiography were performed for all patients. All patients were diagnosed by the professional doctors according to the criteria which named "the diagnosis points of various cerebrovascular diseases 1995", revised in the fourth national cerebrovascular disease conference of the neurological committee. The patients, whose second onset ischemic stroke were caused by blood disease, tumor, cerebrovascular malformation or aneurysms, autoimmune disease and so on, were eliminated. The control subjects were hospitalized in the departments of traumatic surgery, urinary surgery, hepatobiliary surgery, oral surgery, ophthalmology, or otorhinolaryngology during the same period as the patient group. People with history of stroke, blood disease, tumor, cerebrovascular malformation or aneurysm, autoimmune disease, were all exclude. All the subjects were Chinese Han.Blood were taken and anticoagulated by ACD. Genomic DNA was extracted by phenol-chloroform extraction method. All selected SNPs were genotyped by the Taqman technology platform (Applied Biosystems, Foster City). Multiple logistic regressions were employed to adjust for the confounding factors. Association study of haplotypes of the tag SNPs was also performed by Haploview4.2. The interactions between genetic polymorphisms and environmental factors were explored by stratified analysis and the case only study.ResultsThe average age, BMI, cholesterol, triglyceride, low density lipoprotein, and fasting blood-glucose of case group were all higher than that of the control. And the ischemic stroke group had higher percentage of smokers and alcohol drinkers, and higher percentage of patients with hypertension, diabetes and hyperlipidaemia. The common risk factors with ischemic stroke, sorted by the risk from high to low, were respectively hypertension with OR=2.165(1.632,2.873), diabetes with OR=2.052(1.531,2.752), alcohol consume with OR=1.940(1.376,2.737), age(OR1.808(1.399,2.337)) and hyperlipidaemia (OR= 1.452(1.115,1.892)).None of the selected tag SNPs was deviated from Hardy-Weinberg equilibrium. The frequencies of genotypes and alleles of rs 10849373 were both significant different between the case and the control. And in dominant model, individuals with AA/GA genotype of this loci had a higher risk (OR=1.384(1.067,1.729)) of ischemic stroke contrast to the individuals with GG genotype; and the risk of AA and GA were respectively 1.902(1.056,3.428) and 1.316(1.002,1.729). The TT+CT genotype of rs2535393 was a strong protective factor (OR=0.268(0.081,0.893)) to triglyceride, as well as the AA+GA genotype of rs11063794 to diabetes (OR=0.786(0.623,0.991)). But the TT+CT genotype of rs10849373 was a risk genetic factor to hyperlipidaemia, with the OR=1.270 (1.023,1.578).There were interactions between smoking and the loci of rs 10849373 (OR=3.101). Smoking might interact with rs10849373 on some levels and promote rsl0849373 induce the ischemic stroke. The interaction could double the risk of ischemic stroke. Besides, in the case only study, the interaction between alcohol consume and rs10849373 was indicated with the OR=1.434(1.028,2.002). Also we found the negative interaction between both rs2535398 and rs2245918 and rs10849373 (P<0.0001); rs2535398 (OR=0.286) and rs2245918 (OR=0.205) could interact with rs10849373 and reduce the risk of ischemic stroke for rs10849373. But both rs11063806 (OR=2.727) and rs2607926 (OR=1.710) had positive interaction with rs10849373, and both of them could increase the risk of ischemic stroke.ConclusionsRs10849373 in gene NINJ2 was strongly associated with ischemic stroke of Chinese Han population, and was associated with hyperlipidaemia. Rs2535393 and rs11063794 were respectively related with triglyceride levels and diabetes. There was a positive interaction between rs10849373 and smoking which increased the risk of ischemic stroke. The negative interactions between both rs2535393 and rs2245918 and rs10849373, and the positive interactions between rsl 1063806 and rs2607926 and rs10849373 were indicated in case only study. We could conclude that gene NINJ2 was associated with ischemic stroke in Chinese Han population. |
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