Wnk1基因多态性与汉族人缺血性卒中的关联分析
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摘要
目的:探索赖氨酸缺乏蛋白激酶1(Wnk1)基因单核苷酸多态性(SNP)与中国汉族人群缺血性卒中的关系。方法:收集2008年1月~2009年12月新疆5所医院294例汉族缺血性卒中患者(病例组)和同期外科系统住院治疗的其他无脑梗死疾病的汉族患者314例(对照组)进行病例对照研究。用标签SNP(tSNP)策略选择Wnk1基因10个SNP位点(rs3858703、rs11611246、rs7305065、rs1990021、rs34408667、rs12309274、rs1012729、rs956868、rs12828016、rs953361)。SNP基因分型检测采用多重SNaPshot平台。用t检验、卡方检验和logistic回归分析对数据进行统计分析,用Haploview软件进行连锁不平衡分析和单倍型分析。结果:病例组饮酒(37.1%)、高血压病(62.9%)、糖尿病(18.0%)、高脂血症(36.4%)患者比例均高于对照组(均P<0.01),而吸烟者比例在两组间差异无统计学意义(P>0.05)。所有位点基因分型缺失率均在1%以下。除rs34408667位点外,其余tSNP均通过Hardy-Weinberg平衡检验。Wnk1基因第四内含子rs11611246位点与汉族缺血性卒中相关。T等位基因在病例组中的分布频率低于对照组(30.3%与35.7%,P=0.046)。进行性别分层后发现,rs11611246 T等位基因是汉族男性缺血性卒中发病的保护因子。GT基因型及TT基因型在病例组男性中的分布频率分别为43.3%及7.2%,而在对照组男性中的分布频率分别为43.1%及15.2%(P=0.038)。加性遗传模型显示T等位基因携带者发生缺血性卒中的风险是对照组的0.702倍(95%CI:0.517~0.953,P=0.023)。调整年龄后差异仍然存在(P=0.022),进一步调整年龄、体质量指数、吸烟、饮酒、高血压、糖尿病、高脂血症等混杂因素后,差异仍然存在(P=0.008)。未发现Wnk1基因其余9个SNP位点与汉族人脑梗死相关。结论:Wnk1基因第四内含子rs11611246多态性影响中国人缺血性卒中的发生。rs11611246位点T等位基因可能是汉族男性发生缺血性卒中的保护因素。
Objective: To investigate the association between single nucleotide polymorphisms( SNPs) in Wnk1 gene and ischemic stroke in Chinese Han population. Methods: A hospital-based case-control study was carried out. The ischemic stroke group included 294 Chinese Han subjects,who were admitted with non-fatal ischemic stroke in departments of neurology of 5 hospitals in Xinjiang during January 2008 through December 2009. Control group included 314 age and sex-matched Han subjects without an inquired history of stroke,hospitalized in departments of surgery of these 5 hospitals. Ten tagging SNPs( tSNPs) of the Wnk1 gene were genotyped,and the association between these tSNPs and ischemic stroke were evaluated. The tSNPs( rs3858703,rs11611246,rs7305065,rs1990021,rs34408667,rs12309274,rs1012729,rs956868,rs12828016 and rs953361) were determined by the Multiplex SNaPshot platform. The data were analyzed by using t-test,χ2-test and logistic regression. Linkage disequilibrium and haplotype were analyzed by Haploview software. Results: The rates of alcohol drinking,hypertension,diabetes and hyperlipidemia in ischemic stroke group were higher than those in control group( 37. 1% vs 21. 0%,62. 9% vs 36. 6%,18. 0% vs 6. 1% and 36. 4% vs 17. 5%,respectively,all P < 0. 01). No significant difference in smoking rate was found between two groups. The genotyping loss rates of all sites were less than 1%. All the tSNPs were examined by Hardy-Weinberg equilibrium test except rs34408667. tSNP rs11611246 in the 4th intron of the Wnk1 gene was significantly associated with ischemic stroke. The distribution frequency of T allele in cases was significantly lower than that in male controls( 30. 3% vs 35. 7%,P = 0. 046). When the samples were further stratified according to gender,rs11611246 was found to be associated with a reduced risk of ischemic stroke in male cases than in controls. GT and TT genotype frequencies were 43. 3% and 7. 2% in male cases,43. 1% and 15. 2% in male controls,respectively( P = 0. 038). The T allele was associated with a reduced risk of ischemic stroke,with a per-allele OR of 0. 702( 95% CI: 0. 517-0. 953,P = 0. 023) in male cases than in male controls. The significance remained after adjusting the covariates of age( P = 0. 022),or the covariates of age,BMI,cigarette smoking,alcohol drinking,hypertension,diabetes and hyperlipidemia( P = 0. 008). No association between other 9 tSNPs and ischemic stroke was noted in Chinese Han subjects. Conclusion: The polymorphism of rs11611246 on the 4th intron of Wnk1 gene is associated with a reduced risk of ischemic stroke in Chinese Han population and the T allele might be a protective factor for ischemic stroke in male Chinese Hans.
Objective: To investigate the association between single nucleotide polymorphisms( SNPs) in Wnk1 gene and ischemic stroke in Chinese Han population. Methods: A hospital-based case-control study was carried out. The ischemic stroke group included 294 Chinese Han subjects,who were admitted with non-fatal ischemic stroke in departments of neurology of 5 hospitals in Xinjiang during January 2008 through December 2009. Control group included 314 age and sex-matched Han subjects without an inquired history of stroke,hospitalized in departments of surgery of these 5 hospitals. Ten tagging SNPs( tSNPs) of the Wnk1 gene were genotyped,and the association between these tSNPs and ischemic stroke were evaluated. The tSNPs( rs3858703,rs11611246,rs7305065,rs1990021,rs34408667,rs12309274,rs1012729,rs956868,rs12828016 and rs953361) were determined by the Multiplex SNaPshot platform. The data were analyzed by using t-test,χ2-test and logistic regression. Linkage disequilibrium and haplotype were analyzed by Haploview software. Results: The rates of alcohol drinking,hypertension,diabetes and hyperlipidemia in ischemic stroke group were higher than those in control group( 37. 1% vs 21. 0%,62. 9% vs 36. 6%,18. 0% vs 6. 1% and 36. 4% vs 17. 5%,respectively,all P < 0. 01). No significant difference in smoking rate was found between two groups. The genotyping loss rates of all sites were less than 1%. All the tSNPs were examined by Hardy-Weinberg equilibrium test except rs34408667. tSNP rs11611246 in the 4th intron of the Wnk1 gene was significantly associated with ischemic stroke. The distribution frequency of T allele in cases was significantly lower than that in male controls( 30. 3% vs 35. 7%,P = 0. 046). When the samples were further stratified according to gender,rs11611246 was found to be associated with a reduced risk of ischemic stroke in male cases than in controls. GT and TT genotype frequencies were 43. 3% and 7. 2% in male cases,43. 1% and 15. 2% in male controls,respectively( P = 0. 038). The T allele was associated with a reduced risk of ischemic stroke,with a per-allele OR of 0. 702( 95% CI: 0. 517-0. 953,P = 0. 023) in male cases than in male controls. The significance remained after adjusting the covariates of age( P = 0. 022),or the covariates of age,BMI,cigarette smoking,alcohol drinking,hypertension,diabetes and hyperlipidemia( P = 0. 008). No association between other 9 tSNPs and ischemic stroke was noted in Chinese Han subjects. Conclusion: The polymorphism of rs11611246 on the 4th intron of Wnk1 gene is associated with a reduced risk of ischemic stroke in Chinese Han population and the T allele might be a protective factor for ischemic stroke in male Chinese Hans.
引文
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[13]VERSSIMO F,JORDAN P.WNK kinases,a novel protein kinase subfamily in multi-cellular organisms[J].Oncogene,2001,20(39):5562-5569.
[14]SHEKARABI M,GIRARD N,RIVIRE J B,et al.Mutations in the nervous system—specific HSN2 exon of WNK1 cause hereditary sensory neuropathy typeⅡ[J].J Clin Invest,2008,118(7):2496-2505.
[15]DISSE-NICODME S,ACHARD J M,DESITTER I,et al.A new locus on chromosome 12p13.3 for pseudohypoaldosteronism typeⅡ,an autosomal dominant form of hypertension[J].Am J Hum Genet,2000,67(2):302-310.
[16]COEN K,PAREYSON D,AUER-GRUMBACH M,et al.Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy typeⅡ[J].Neurology,2006,66(5):748-751.
[17]NEWHOUSE S J,WALLACE C,DOBSON R,et al.Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study[J].Human Molecular Genetics,2005,14(13):1805-1814.
[18]TOBIN M D,RALEIGH S M,NEWHOUSE S,et al.Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population[J].Circulation,2005,112(22):3423-3429.
[19]NEWHOUSE S,FARRALL M,WALLACE C,et al.Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion[J].PLoS One,2009,4(4):e5003.
[20]CUN Y,LI J,TANG W,et al.Association of WNK1exon 1 polymorphisms with essential hypertension in Hani and Yi minorities of China[J].J Genet Genomics,2011,38(4):165-171.
[21]TOBIN M D,TIMPSON N J,WAIN L V,et al.Common variation in the WNK1 gene and blood pressure in childhood:the Avon Longitudinal Study of Parents and Children[J].Hypertension,2008,52(5):974-979.
[2]FLOSSMANN E,SCHULZ U G,ROTHWELL P M.Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke[J].Stroke,2004,35(1):212-227.
[3]XU B E,LEE B H,MIN X,et al.WNK1:analysis of protein kinase structure,downstream targets and potential roles in hypertension[J].Cell Res,2005,15(1):6-10.
[4]DELALOY C,HADCHOUEL J,IMBERT-TEBOUL M,et al.Cardiovascular expression of the mouse WNK1gene during development and adulthood revealed by a BAC reporter assay[J].Am J Pathol,2006,169(1):105-118.
[5]WILSON F H,DISSE-NICODME S,CHOATE K A,et al.Human hypertension caused by mutations in WNK kinases[J].Science,2001,293(5532):1107-1112.
[6]VISSCHER P M,MCEVOY B,YANG J.From Galton to GWAS:quantitative genetics of human height[J].Genet Res(Camb),2010,92(5-6):371-379.
[7]IKRAM M A,SESHADRI S,BIS J C,et al.Genome wide association studies of stroke[J].N Engl J Med,2009,360(17):1718-1728.
[8]中华医学会神经病学分会.中国脑血管病防治指南[S].北京:人民卫生出版社,2007.Chinese Society of Neurology.China guideline for cerebrovascular disease prevention and treatment[S].Beijing:People's Health Publishing House,2007.(in Chinese)
[9]《中国高血压防治指南》修改委员会.中国高血压防治指南[S].北京:人民卫生出版社,2006.Amendments Committee.The guidelines for prevention and control of hypertension[S].Beijing:People's Health Publishing House,2006.(in Chinese)
[10]World Health Organization.Definition diagnosis and classification of diabetes mellitus and its complications:report of a WHO consultation.Part 1:diagnosis and classification of diabetes Mellitus[EB/OL].(1999).Geneva:World Health Organization.
[11]中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南[J].中华心血管病杂志,2007,35(5):390-419.Joint committee for developing Chinese guidelines on prevention and treatment of dyslipidemia in adults.Chinese guidelines on prevention and treatment of dyslipidemia in adults[J].Chinese Journal of Cardiology,2007,35(5):390-419.(in Chinese)
[12]JOHNSON G C,ESPOSITO L,BARRATT B J,et al.Haplotype tagging for the identification of common disease genes[J].Nat Genet,2001,29(2):233-237.
[13]VERSSIMO F,JORDAN P.WNK kinases,a novel protein kinase subfamily in multi-cellular organisms[J].Oncogene,2001,20(39):5562-5569.
[14]SHEKARABI M,GIRARD N,RIVIRE J B,et al.Mutations in the nervous system—specific HSN2 exon of WNK1 cause hereditary sensory neuropathy typeⅡ[J].J Clin Invest,2008,118(7):2496-2505.
[15]DISSE-NICODME S,ACHARD J M,DESITTER I,et al.A new locus on chromosome 12p13.3 for pseudohypoaldosteronism typeⅡ,an autosomal dominant form of hypertension[J].Am J Hum Genet,2000,67(2):302-310.
[16]COEN K,PAREYSON D,AUER-GRUMBACH M,et al.Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy typeⅡ[J].Neurology,2006,66(5):748-751.
[17]NEWHOUSE S J,WALLACE C,DOBSON R,et al.Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study[J].Human Molecular Genetics,2005,14(13):1805-1814.
[18]TOBIN M D,RALEIGH S M,NEWHOUSE S,et al.Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population[J].Circulation,2005,112(22):3423-3429.
[19]NEWHOUSE S,FARRALL M,WALLACE C,et al.Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion[J].PLoS One,2009,4(4):e5003.
[20]CUN Y,LI J,TANG W,et al.Association of WNK1exon 1 polymorphisms with essential hypertension in Hani and Yi minorities of China[J].J Genet Genomics,2011,38(4):165-171.
[21]TOBIN M D,TIMPSON N J,WAIN L V,et al.Common variation in the WNK1 gene and blood pressure in childhood:the Avon Longitudinal Study of Parents and Children[J].Hypertension,2008,52(5):974-979.