The Studies Of ALOX5AP Gene、H6PD Gene And1p13.3Single-nucleotide Polymorphisms Associated With Ischemic Stroke And Its Subtypes In The East China

Stroke is an important health problem worldwide, and it is still a leading cause ofmortality and morbidity in Chinese. It has been established that the underlyingpathogenesis is likely to be mediated by both genetic and environmental risk factors.Atherosclerosis is a chronic inflammatory disease that underlies the pathogenesisof cardiovascular disease and stroke. Through the development of SNPs in high-passdetection technology is rapidly maturing, a large study found the association betweenALOX5AP gene, H6PD gene, chromosome1p13.3single-nucleotide polymorphismand atherosclerosis.The human ALOX5AP gene is mapped to chromosome13q12.3and consists offive exons. Based on its important physiological functions, ALOX5AP can beconsidered a good candidate gene for cardiovascular disease and stroke risk. Becausethe thickness of the intima and media of the carotid artery (carotid intima-medialthickness, CIMT) is associated with cardiovascular disease and stroke.The studyfound that H6DP gene could be considered a good candidate gene for increasing thethickness of CIMT. Through the development of GWAS, there are many researchesfound the associations between the1p13.3and cardiovascular disease. However, to date, the association between genetic variations in the H6DP gene、1p13.3and risk ofischemic stroke in Eastern Chinese population has not been reported.In the present study, we selected4SNPs from the data for Chinese in the HapMap,two in ALOX5AP gene, one in H6PD gene, and one in1p13.3, to investigate theassociation between common genetic variants and risk of ischemic stroke in ourongoing hospital-based case-control study in an Eastern Chinese Han population.[Objective] The aim of the present study is to investigate the association between theALOX5AP gene、H6PD gene、1p13.3polymorphism and the risk of ischemic strokeand its subtypes in Eastern Chinese population.[Methods] We recruited only patients with1of2subtypes of ischemic stroke inTOAST: large-artery atherosclerosis (LAA), small-artery occlusion or lacune (SAO).Those cases who had other types of stroke (transient ischemic attack, subarachnoidhemorrhage, embolic brain infarction, brain tumors, and cerebrovascularmalformation) and severe systemic diseases (collagenosis, endocrine, and metabolicdisease (except for diabetes mellitus, DM), inflammation, neoplastic, or renal diseases)were excluded. Diagnosis of ischemic stroke was based on the results of strictneurological examination—CT, MRI, or both—according to the InternationalClassification of Diseases, Ninth Revision (ICD-10). Controls were selectedsimultaneously from the same demographic area and frequency-matched to the casesby age, sex. We conducted a comprehensive association study of326sichemic strokepatients and326controls to assess the associations between the single-nucleotidepolymorphisms (SNPs) of the ALOX5AP gene、H6DP gene、1p13.3with the risk ofischemic stroke and its subtypes. Genotyping was performed by using the PCR-RFLPassay andTaqman-PCR. [Results]1．Basic characteristics of the subjectsThe mean age was67.17±9.07years for the cases and66.74±8.84years for thecontrols (P=1.000);(52.5%) cases and (52.8%) controls were male (P=0.541). Therewas no significant difference in the distribution of age and sex between the cases andcontrols. As expected, cases had a higher prevalence of conventional risk factors forvascular disease, including BMI, family history of CVD, self-history of CAD,hypertension, DM, and transient ischemic attack (TIA), higher blood pressure,glucose, TG, TC, higher level of LDL cholesterol and lower level of HDL cholesterol.However, some risk factors did not differ. For example, smoking and alcohol intakewere not statistically significant (P=0.419and P=0.055, respectively) between ourtwo groups.2．Individual SNP association analysis and TOAST analysisRs17368528and rs599839had significant different allele frequencies between thecases and controls. The genotype distributions of the SNPs in cases and controls aresummarized in Table. The analysis indicated that the genotype frequencies ofrs17368528in H6DP gene and rs599839in1p13.3were significantly differentbetween the overall cases and controls (P=0.001and P=0.002), however there are nodifferences in ALOX5AP gene.Multivariate logistic regression analyses revealed that the genotype frequencies ofTG and TG/GG of the SNPs rs17222919located in the promoter of ALOX5AP genewere significantly higher in ischemic stroke patients than controls (adjustedOR=1.47,95%CI=1.05-2.07and adjusted OR=1.4,95%CI=1.04-2.00), especially inischemic stroke caused by SAO. In H6DP gene compared with the wildtype CC, asignificant increased risk was associated with the TC genotype (adjusted OR=1.49;95%CI=1.07-2.08), the TT genotype (adjusted OR=2.37;95%CI=1.43-3.94), and the TC/TT genotype (adjusted OR=1.67;95%CI=1.22-2.28). We also found that thethree genotypes in H6DP gene could increase the risk of LAA and SAO. In1p13.3,the genotype frequencies of AG the SNPs rs599839had a significant decreased riskof ischemic stroke compared with the wildtype AA (adjusted OR=0.34;95%CI=0.17-0.67). The genotype frequencies of AG the SNPs rs599839were associatedwith the low risk of LAA and SAO.3．1p13.3rs599839and LDL-cCompared to AA genotype, LDL serum concentration of rs599839AGgenotype was significantly decreased. But there was no differ between case andcomtrol in AA genotype or AG genotype.[Conclusion] The present study suggests that sequence variants in theALOX5AP gene、H6DP gene and1p13.3are significantly associated with ischemicstroke. Rs17222919in ALOX5AP gene may take part in pathogenesis of SAO.However, rs17368528in H6PD genes and rs599839in1p13.3may be associated withSAO and LAA. Larger studies and functional studies are needed to confirm ourfindings.