Association of GWAS-Supported Variants rs2200733 and rs6843082 on Chromosome 4q25 with Ischemic Stroke in the Southern Chinese Han Population

Journal of Molecular Neuroscience - Genome-wide association studies (GWAS) have revealed two single-nucleotide polymorphisms (SNPs) on chromosome 4q25, rs2200733, and rs6843082, associated with...     

Genetic Variants on Chromosome 10q11.21 are Associated with Ischemic Stroke in the Northern Chinese Han Population

Genome-wide association studies have revealed two loci (rs1746048 and rs501120) on chromosome 10q11.21 associated with atherosclerosis. The genetic variants are related to chemokine (C-X-C motif) ligand 12, which has been shown to affect atherosclerosis. This study aims to explore the associations between these loci and risk of ischemic stroke in the northern Chinese Han population. A total of 368 patients with ischemic stroke and 381 healthy controls were included in the study. The single-nucleotide polymorphisms rs501120 and rs1746048 were analyzed by polymerase chain reaction–ligation detection reaction methods. Increased risk of ischemic stroke was associated with rs1746048 in a dominant mode. The CT + TT genotype of rs1746048 was represented at an increased frequency among patients with ischemic stroke. The genotype and allele frequencies of rs501120 were similar between patients with ischemic stroke and controls. However, the rs501120 CT + CC genotype and C allele were associated with an increased risk of ischemic stroke in the male subgroup. These correlations still remained after adjusting for confounding risk factors of stroke. Here, we present a study indicating that genetic variation on chromosome 10q11.21 might contribute to stroke susceptibility.     

GWAS-Supported <Emphasis Type="Italic">CRP</Emphasis> Gene Polymorphisms and Functional Outcome of Large Artery Atherosclerotic Stroke in Han Chinese

Elevated C-reactive protein (CRP) levels increase the risk of poor functional disability in patients with ischemic stroke (IS). This study aimed to investigate the association between CRP gene polymorphisms and 3-month functional disability of large artery atherosclerotic (LAA) stroke in Han Chinese. Patients with first-ever LAA IS were prospectively enrolled in Nanjing Stroke Registry Program between August 2013 and October 2015. Five single-nucleotide polymorphisms (SNPs) (rs876537, rs2794520, rs3093059, rs7553007 and rs11265260) in CRP gene related to CRP levels in Asian by genome-wide association study were genotyped. The functional outcome at 3 months after the index stroke was assessed by the modified Rankin scale. Associations between genotypes and functional outcome of LAA IS were analyzed with logistic regression model. A total of 690 eligible patients (507 males) were evaluated. SNPs rs11265260 (multivariate-adjusted, p?=?0.022), rs2794520 (multivariate-adjusted, p?=?0.036) and rs3093059 (multivariate-adjusted, p?=?0.027) were significantly associated with elevated CRP in acute IS. Two SNPs, rs3093059 (dominant model: adjusted OR 2.49; 95% CI 1.55–4.00; recessive model: adjusted OR 3.67; 95% CI 1.22–11.03) and rs11265260 (dominant model: adjusted OR 2.51; 95% CI 1.56–4.02; recessive model: adjusted OR 4.70; 95% CI 1.63–13.56) independently predicted 3-month poor outcome of first-ever LAA IS, after adjusting for covariates. In addition, haplotype analysis indicated that haplotype GCTGC (adjusted OR 1.76; 95% CI 1.05–2.95; p?=?0.031) increased the poor outcome risk. SNPs rs3093059 and rs11265260 in CRP gene may influence the 3-month functional outcome of first-ever LAA IS in Han Chinese.     

中国汉族人群中染色体9p21.3基因多态性与阿尔茨海默病的相关性研究

目的：探讨中国汉族人群中染色体9p21.3 rs1333049基因与阿尔茨海默病（AD）的相关性。方法：采用基质辅助激光解吸电离飞行时间质谱技术检测266例AD患者（AD组）与323例非AD者（对照组）的rs1333049基因多态性分布,并通过x~2检验和Logistic回归进行疾病关联分析。结果：AD组和对照组SNP rs1333049基因型频率及等位基因频率差异均有统计学意义（P〈0.05）;调整混杂因素影响后Logistic回归分析表明,在显性模型和递加模型中,两组的分布差异仍有统计学意义（P〈0.05）,提示等位基因C增加了AD发病的易感性。结论：中国汉族人群中rs1333049基因与AD的发病存在相关性。     

Chromosome 9p21.3 Variants Are Associated with Cerebral Infarction in Chinese Population

Journal of Molecular Neuroscience - Common variants of chromosome 9p21.3 associated with coronary disease have been established, but the association of 9p21.3 and cerebral infarction (CI) is not...     

染色体9p21多态性与动脉粥样硬化性缺血性卒中易感相关性的Meta分析

目的 缺血性卒中（ischaemic stroke,IS）是一种与遗传因素密切相关的多基因疾病。以单核苷酸多态性（single nucleotide polymorphism,SNP）为遗传标记系统的全基因组关联研究（Genomewide Association Studies,GWAS）发现染色体9p21多态性是血管粥样硬化的独立危险因素,与动脉粥样硬化性缺血性卒中易感风险相关;但由于样本量较小,通过比较等位基因频率分布,显示其在病例组与对照组之间无明显差异,这突出了更大规模研究的必要性。本研究拟对目前已发表的有关染色体9p21多态性与动脉粥样硬化性缺血性卒中易感相关性的病例-对照研究严格质量控制后进行Meta分析,旨在明确染色体9p21与动脉粥样硬化性缺血性卒中易感相关性的SNP种类,并对其与疾病发生风险的大小进行评估。方法 联合检索目前已发表的全部有关染色体9p21多态性与动脉粥样硬化性缺血性卒中易感相关性的病例-对照研究,制定严格的纳入排除质量控制标准,应用国际Cochrane系统评价协作网提供的Meta分析专用软件RevMan5.0对数据进行Meta分析,用森林图（Forest Plot）展示各个研究的OR（odds ratio）值及95％可信区间（confidence interval,CI）以及合并统计的OR值及95%CI,系统评价染色体9p21与动脉粥样硬化性缺血性卒中易感相关性的SNP在病例组与对照组分布有无差异,分析得到染色体9p21多态性与动脉粥样硬化性缺血性卒中易感相关性的统计学意义。结果 进入Meta分析的资料涉及6项跨越欧洲与北美洲的多中心临床病例-对照研究。进入Meta分析的基因多态性涉及染色体9p21上的7种SNP：rs7044859、rs496892、rs564398、rs7865618、rs1537378、rs2383207及rs10757278。其中,rs564398、rs7865618、rs1537378、rs2383207和rs10757278与动脉粥样硬化性缺血性卒中相关性具有统计学意义,与动脉粥样硬化性缺血性卒中易感风险相关。而rs7044859、rs496892与动脉粥样硬化性缺血性卒中相关性无统计学意义。结论 本研究发现染色体9p21的5种SNP（rs564398、rs7865618、rs1537378、rs2383207及rs10757278）与动脉粥样硬化性缺血性卒中具有易感相关性,染色体9p21变异被认为是血管粥样硬化的危险因素,是动脉粥样硬化性缺血性卒中的候选易感基因。     

Association Study of CRP Gene and Ischemic Stroke in a Chinese Han Population

High-sensitivity C-reactive protein (hsCRP) was reported as a strong, independent predictor of future myocardial infarction and stroke. It is of importance to illustrate the conformance of CRP genetic variation, increment of plasma hsCRP and cerebral events. A case–control study including 548 patients with acute ischemic stroke and 993 age-matched controls from community-based population was conducted and four tagging SNPs (tagSNPs) were genotyped. Multiple logistic regression was applied to evaluate the association of CRP gene and stroke hsCRP elevation with adjustment for covariates. The results indicated that rs3093059 and rs3091244 presented statistical associations with ischemic stroke. Odds ratios (ORs) (95 % confidence interval [CI]) of additive model, dominant model and minor allele at rs3093059 were 0.697 (0.528–0.921), 0.671 (0.487–0.923) and 0.811 (0.666–0.988), and ORs (95 % CI) of dominant model at rs3091244 was 0.728 (0.536–0.988), after adjusting for covariates. But there were no significant differences of genotype or allele frequencies of the four SNPs observed between hypertension (HT) and normal blood pressure (NBP) groups. Further analyses indicated the genetic variations of rs876537 and rs3093059 were positively associated with increased square root transformed hsCRP and hsCRP elevation (≥3 mg/l) in ischemic stroke patients, and rs876537 and rs3091244 were associated with hsCRP elevation in controls as well. Our finding suggests that the CRP genetic polymorphisms were associated with decreased risk of ischemic stroke and elevated plasma hsCRP and further replication study and functional research would be warranted.     

ABCB1基因多态性与中国汉族人群动脉粥样硬化性血栓性脑梗死的相关性研究

目的探讨ATP结合盒B亚家族成员1转运蛋白(ABCB1)基因多态性与中国汉族人群动脉粥样硬化性血栓性脑梗死(ATCI)患者的关系。方法选取392例ATCI患者(脑梗死组)和429例健康对照者(对照组),通过SNa Pshot方法对ABCB1基因的rs1128503和rs1045642位点进行SNP检测。比较两组的基因型和等位基因分布频率,分析基因型与临床表型的关系。结果脑梗死组rs1128503和rs1045642位点的基因型及等位基因分布频率与对照组比较,无统计学意义(P0.05)。女性ATCI患者的rs1128503位点TT基因型和CC基因型体重指数高于TC基因型(P=0.007,P=0.011)。女性ATCI患者的rs1045642位点CC基因型低密度脂蛋白-胆固醇水平高于CT基因型(P=0.030)。结论 ABCB1基因多态性与中国汉族人群ATCI的发病无明显相关性。rs1128503位点多态性可能与女性ATCI患者的体重指数有关,rs1045642位点多态性可能与女性ATCI患者的低密度脂蛋白-胆固醇水平有关。     

Association of ALOX15 Gene Polymorphism with Ischemic Stroke in Northern Chinese Han Population

Arachidonate 12/15-lipoxygenase (12/15-LOX) is a member of the lipid peroxidizing enzyme family and plays a major role in atherosclerosis. The present study aimed to evaluate whether or not the ALOX15 gene polymorphism is involved in ischemic stroke in northern Chinese Han population. Participants in a case-control study included 396 patients (239 males, 157 females) with ischemic stroke and 360 healthy subjects (211 males, 149 females). The rs7217186 polymorphism of the ALOX15 gene was analyzed by polymerase chain reaction and restriction fragment length polymorphism, while the rs2619112 polymorphism of the ALOX15 gene was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The frequencies of the CC genotype and the C allele of rs7217186 were higher in participants with ischemic stroke than in the control group [P?=?0.014 in males, P?=?0.007 in atherosclerosis ischemic stroke (ACI)]. The frequencies of the AA genotype and the A allele of rs2619112 were higher in participants with ischemic stroke than in the control group (P?=?0.011 in males, P?=?0.015 in ACI). Multiple logistic regression analysis revealed the significance of rs7217186 and rs2619112 in males and in ACI after adjustment for confounding factors. The rs7217186 and rs2619112 polymorphisms of the ALOX15 gene were associated with ischemic stroke in males and in patients with ACI in northern Chinese Han population.     

无症状性脑动脉粥样硬化与大动脉粥样硬化性卒中患者血浆微小RNA表达分析

目的 建立无症状性脑动脉粥样硬化（ath e ro s cl e ro s i s,AS）及大动脉粥样硬化（l arge arte ry atherosclerotic,LAA）性卒中患者血浆微小核糖核苷酸（microribonucleic acid,miRNA）差异表达谱。 方法 收集2013年1月～2013年2月于青岛大学医学院附属医院神经内科就诊的8名AS患者（AS组）、 LAA性卒中患者（LAA组）和对照者（control组）的空腹前臂静脉血血浆标本,应用Solexa高通量测序 技术检测每组血浆标本miRNA表达谱,筛选出差异表达的miRNA,并进行靶基因预测和功能分析,采 用实时荧光定量聚合酶链反应（polymerase chain reaction,PCR）技术对高通量检测结果进行验证。 结果 3组间比较,表达差异均具有显著性的miRNA有miR-let-7a-5p、miR-146b-5p、miR-26a-5p、 miR-23a-3p等26个;在AS组与LAA组表达一致,较对照组表达差异具有显著性的miRNA有miR-10b-5p、 miR-126-5p、miR-143-3p、miR-192-5p等41个。本研究生物信息学分析发现,差异miRNAs调控的靶基 因主要与细胞黏附、分化、增殖等生物学过程相关。实时荧光定量PCR检测miR-146b-5p、miR-23a-3p、 miR-10b-5p,结果与高通量检测结果一致。 结论 AS患者及LAA性卒中患者血浆miRNAs表达谱既有差别又有相同之处。     

Association between Histone Deacetylase 9 Gene Polymorphism and Stroke in Chinese Han Population

ObjectiveTo explore the correlation between the polymorphism of histone deacetylase 9 gene (rs1060499865, rs723296, rs957960) and ischemic stroke (IS) in Chinese Han population in Dali region. MethodsThis study included 155 IS patients and 128 healthy physical examinees. TaqMan-polymerase chain reaction technology and multivariate logistic regression were performed. ResultsIn the case group, there was no polymorphism of rs1060499865 observed in the two groups; whereas on the rs723296 locus the frequencies of C allele and TC genotype were significantly higher than that in the control group, alleles C and T were associated with a 2.158-fold increase in IS risk, and genotypes TC and TT were associated with a 2.269-fold increase in IS risk. The locus rs957960 exhibited no significant difference between the two groups. ConclusionAn association between rs723296 and the risk of IS was found in the Chinese Han population in Dali region. No significant association was found between rs1060499865, rs957960 and IS in the Chinese Han population in Dali region.     

Association of Apolipoprotein M Gene Polymorphisms with Ischemic Stroke in a Han Chinese Population

The apolipoprotein M (ApoM) gene is critical in the formation of pre-β-high-density lipoprotein (HDL) and cholesterol efflux to HDL. In this case and control study, 314 ischemic stroke patients and 389 healthy controls were analyzed for three ApoM gene single-nucleotide polymorphisms (SNPs), i.e., C-1065A, T-855C, and T-778C, using a SNaPshot Multiplex sequencing assay. The genotype and allele frequencies of the T-855C were similar in both ischemic stroke patients and the controls. But the frequency of the TC genotype, the C allele of T-778C, and the A allele of the C-1065A SNPs in ischemic stroke patients was significantly higher than that of the healthy controls. After adjusting for confounding risk factors (such as hypertension, diabetes, tobacco smoking, and alcohol consumption), the ApoM gene TC genotype, C allele of T-778C, and A allele of C-1065A were associated with a risk of ischemic stroke. Moreover, plasma levels of total cholesterol were significantly higher in patients with CC or CT genotypes of T-778C than those with TT genotype in the controls. The current data demonstrated that ApoM T-778 C and C-1065A SNPs were associated with increased risk of ischemic stroke in this Han Chinese population.     

Association Analysis Between 12 Genetic Variants of Ten Genes and Personality Traits in a Young Chinese Han Population

Some genes involved in neurotransmission synthesis and transmission have been hypothesized to affect personality traits. To investigate the possible roles of these genes in personality traits of 16 Personality Factor Questionnaire, we performed a population-based study in a young Chinese Han cohort. In the study, we selected some functional variations in ten candidate genes (COMT, DBH, DRD ₂ , DRD ₃ , DAT, MAOA, GRM ₁ , GRIN2B, 5-TH _2A , and 5-TH ₆ ) encoding components in dopamine, glutamate, and 5-hydroxytryptamine pathways. The results showed the T102C in 5-TH _2A was associated with X3 (emotional and quiet alertness) and B (reasoning) (F?=?4.71 and 6.23; p?=?0.009 and 0.002), Val158Met in COMT with E (dominance) (F?=?7.01; p?=?0.0009), while the variations in DBH, DRD ₂ , DRD ₃ , MAOA, GRM ₁ , GRIN2B, and 5-TH ₆ were not associated with any of the personality traits. This finding suggests that T102C in 5-TH _2A and Val158Met in COMT play roles in some human personality traits.     

Relative Telomere Length and Stroke Risk in a Chinese Han Population

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to stroke and investigate the association regulator of telomere elongation helicase 1 (RETL1) gene polymorphisms and RTL. RTL was measured using the real-time quantitative polymerase chain reaction (qPCR) from 300 stroke patients and 299 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform. The results indicated that stroke patients had significantly shorter median RTL than controls (P?<?0.001). Compared with the longer RTL (≥?0.766), the shorter RTL (<?0.766) was significantly increased the risk of stroke (odds ratio [OR]?=?8.44, 95% confidence interval [CI] 5.42–13.14, P?<?0.001). The RTL was categorized into tertiles, we found that the shorter RTL (0.515–1.366) (OR?=?16.27, 95% CI 7.72–34.29, P?<?0.001) and lowest RTL (<?0.515) (OR?=?30.63, 95% CI 14.27–65.75, P?<?0.001) were significantly increased stroke risk compared with the highest RTL (>?1.366). Stratified analysis showed that the shorter RTL was also significantly increased the risk of stroke compared with the longer RTL in male, age <?60 years and ≥?60 years, except the female participants. In addition, individuals with the genotypes AA (rs2297441) and GG (rs6089953) have shorter telomeres than the genotypes GG (P?=?0.031) and AA (P?=?0.032), respectively. Our results suggested that shorter RTL was associated with an increased risk of stroke. The association was found between the genotypes AA (rs2297441) and GG (rs6089953) and shorter RTL in case group. Further studies in larger sample size and biological functional assays are warranted to validate our findings.     

趋化因子CXC配体16与中国汉族动脉粥样硬化性卒中的相关性研究

目的 了解趋化因子CXC配体16（CXC ligand 16,CXCL16）181A >V多态性等位基因及基因型在中国汉族人群的分布,探讨其基因及血清水平与动脉粥样硬化性卒中的相关性。方法 采用聚合酶链反应-限制性片段长度多态性（Polymerase chain reaction-restrictive fragmentlength polymorphism,PCR-RFLP）方法,检测244例动脉粥样硬化性卒中患者（卒中组）和204例对照者（对照组）CXCL16 181A >V位点的基因型分布特点,同时比较该多态性位点在中国对照组人群、德国人群与瑞典人群间的分布差异。同时,应用ELISA方法检测卒中组与对照组的血清CXCL16水平,并进行统计学分析。结果 卒中组高血压病史、糖尿病病史、吸烟史、饮酒史、总胆固醇（total cholesterol,TC）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol,LDL-C）、血清CXCL16水平高于对照组（P均<0.01）,高密度脂蛋白胆固醇（high-density lipoprotein cholesterol,HDL-C）低于对照组（P <0.01）。CXCL16181A >V等位基因（P <0.01）及基因型分布（P =0.004）在中国组、德国组和瑞典组差异有统计学意义,而卒中组与对照组间差异无统计学意义（P =0.774,0.692）。结论 血清CXCL16水平升高与动脉粥样硬化性卒中的发生相关;CXCL16 181A >V位点基因多态性存在种族差异性,与中国汉族人群动脉粥样硬化性卒中可能无关。     

High Levels of Remnant Lipoprotein Cholesterol Is a Risk Factor for Large Artery Atherosclerotic Stroke

Background and Purpose

Remnant lipoproteins (RLPs) are products of partially catabolized chylomicrons and very-low-density lipoprotein, from which some triglycerides have been removed. These particles are smaller and denser than the parent particles and are believed to be strongly atherogenic. We explored the association between RLP cholesterol (RLP-C) and ischemic stroke, including stroke subtypes.

Methods

A cohort of 142 ischemic stroke patients (90 men and 52 women; age, 65.2±12.8 years, mean±SD) was enrolled; all had acute infarcts confirmed by diffusion-weighted MRI, and had fasting lipograms. A full stroke-related evaluation was conducted on each patient. An outpatient population of 88 subjects without a history of cerebrovascular or cardiovascular disease served as a control group. Serum RLP fractions were isolated using an immunoaffinity gel containing specific antiapolipoprotein (anti-apo)B-100 and anti-apoA-I antibodies. RLP-C values were considered to be high when they were in the highest quartile of all values in the study.

Results

High RLP-C values were more common in stroke patients than in control patients (31.0% vs. 14.8%, p=0.01), when 5.6 mg/dL (>75th percentile) was used as the cutoff value. Multivariable analyses indicated that RLP-C was a risk factor for stroke, with an odds ratio of 2.54 (p=0.045). The RLP-C level was higher in the large artery atherosclerosis subgroup (5.7±3.9 mg/dL) than in any other stroke subgroup (small vessel occlusion, 4.9±5.9 mg/dL; cardioembolism, 1.8±2.3 mg/dL; stroke of undetermined etiology, 3.1±2.9 mg/dL).

Conclusions

We have found an association between high RLP-C levels and ischemic stroke, and in particular large artery atherosclerotic stroke.     

COMT基因rs4680位点与中国汉族人群帕金森病遗传易患性关联性分析

目的 探讨儿茶酚胺氧位甲基转移酶(COMT)基因rs4680位点Val158Met多态性与帕金森病遗传易患性的相关性.方法 采用聚合酶链反应-连接酶检测反应(polymerase chain reaction-ligase detection reaction,PCR-LDR)基因多态性测序方法,分析COMT rs4680位点基因型及等位基因频率在帕金森病患者(437例)和健康对照者(530人)间的分布差异.结果 帕金森病患者G等位基因频率为77.2％,A等位基因频率为22.8％,而在健康对照者分别为74.7％、25.3％,两组间COMTrs4680位点Val158Met等位基因频率分布差异没有统计学意义(P =0.199).各基因型频率在帕金森病患者分别为G/G型57.4％、G/A型39.6％、A/A型3.0％,在健康对照者分别为54.9％、39.6％、5.5％,两组间基因型频率分布差异无统计学意义(P=0.156).在校正性别、年龄混杂因素后经二元Logistic回归分析,COMT rs4680位点各基因型与帕金森病发病风险之间仍无相关性.结论 COMT基因r4680位点Val158Met多态性与中国汉族人群帕金森病易患性可能无关,进一步扩大样本量及在其他不同种族中的研究能更好地确定COMT rs4680位点Val158Met多态性在帕金森病发病风险中的作用.