• 1 北京大學(xué)人民醫(yī)院呼吸內(nèi)科（北京 100044）;;
  • 2 北京大學(xué)第一醫(yī)院呼吸內(nèi)科（北京 100034）;;
  • 3 北京大學(xué)人類疾病基因研究中心（北京 100083）;

目的  尋找趨化素樣因子( CKLF) 基因上游啟動(dòng)子區(qū)的單核苷酸多態(tài)性( SNP) , 明確其與支氣管哮喘發(fā)病的相關(guān)性。方法  提取245 例北京地區(qū)漢族人( 其中哮喘患者119 例, 健康對(duì)照126 例) 基因組DNA, 采用PCR 方法擴(kuò)增CKLF 上游啟動(dòng)子區(qū)1553 堿基的DNA 片段并進(jìn)行直接測(cè)序, 分析發(fā)現(xiàn)的SNPs 的等位基因頻率、基因型頻率和單倍型分布頻率及其與哮喘的發(fā)病和臨床表現(xiàn)的相關(guān)性。結(jié)果  在CKLF 上游啟動(dòng)子區(qū)共發(fā)現(xiàn)4 個(gè)SNPs: SNP88( T  gt; C) 、SNP196( T  gt; C) 、SNP568( C gt;G) 、SNP1047( C  gt; G) 。其等位基因頻率分別為0. 168 ( SNP88C) 、0. 168 ( SNP196C) 、0. 352( SNP568G) 和0. 167( SNP1047G) , 與以往報(bào)道的其他種族的結(jié)果明顯不同。SNP88 與SNP196 之間、SNP88 與SNP1047 之間, 以及SNP196 與SNP1047 之間存在完全連鎖不平衡( D′= 1. 000, r2 = 1. 000) ,SNP568 與SNP88、SNP196 及SNP1047 間存在連鎖不平衡( r2 = 0. 366) 。哮喘組與對(duì)照組4 個(gè)SNPs 的等位基因頻率、基因型頻率和單倍型頻率差異無顯著性。結(jié)論  北京地區(qū)漢族人群CKLF 編碼基因上游調(diào)控區(qū)的基因多態(tài)性有其獨(dú)特的分布特點(diǎn)及連鎖不平衡特征, 雖然與哮喘的發(fā)病無明顯相關(guān)性, 但其分布特點(diǎn)可能為其他疾病相關(guān)性研究提供有價(jià)值的資料。

引用本文： 章巍,何權(quán)瀛,王廣發(fā),趙紅珊,遲春花,趙燕妮,鄧暄,宿利,孫遙搖,王小迪. 人趨化素樣因子上游啟動(dòng)子區(qū)的單核苷酸多態(tài)性及其與哮喘的相關(guān)性. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2009, 09(4): 345-350. doi: 復(fù)制

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2. Vercelli D. Advances in asthma and allergy genetics in 2007. J Allergy Clin Immunol, 2008, 122: 267-271.
3. Warrier MR, Hershey GK. Asthma genetics: personalizing medicine. J Asthma, 2008, 45: 257-264.
4. Denham S, Koppelman GH, Blakey J, et al. Meta-analysis of genome-wide linkage studies of asthma and related traits. Respir Res, 2008 , 9: 38 .
5. 韓文玲, 馬大龍. 一個(gè)新的多功能細(xì)胞因子-趨化素樣因子. 上海免疫學(xué)雜志, 2002, 22: 217-219.
6. McLeish S, Turner SW. Gene-environment interactions in asthma.Arch Dis Child, 2007, 92: 1032-1035.
7. Colobran R, Pujol-Borrell R, Armengol MP, et al. The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility. Clin Exp Immunol, 2007, 150: 1-12.
8. Ober C. Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol, 2005, 116: 274-278.
9. Han W, Lou Y, Tang J, et al. Molecular cloning and characterization of chemokine-like factor 1 ( CKLF1 ) , a novel human cytokine with unique structure and potential chemotactic activity. Biochem J,2001, 357: 127-135.
10. 譚亞夏, 鐘南山. 趨化素樣因子1 在支氣管肺損傷與重建中的作用. 中華結(jié)核和呼吸雜志, 2002, 25: 433.
11. 譚亞夏, 葉楓, 莫紅纓, 等. 趨化素樣因子1 對(duì)鼠肺巨噬細(xì)胞吞噬活性的作用. 廣州醫(yī)學(xué)院學(xué)報(bào), 2007, 35: 24-26.
12. 楊小瓊, 鄧述愷, 黃忠碧, 等. 大鼠趨化素樣因子1mRNA 在哮喘大鼠肺組織中的表達(dá). 陜西醫(yī)學(xué)雜志, 2007, 36: 14-17.
13. Tan YX, Han WL, Chen YY, et al. Chemokine-like factor 1, a novel cytokine, contributes to airway damage, remodeling and pulmonary fibrosis. Chin Med J( Engl) , 2004, 117: 1123-1129.
14. National center for biotechnology information. Single nucleotide polymorphism database [ DB /OL] . http: / / www. ncbi. nlm. nih.gov/ sites/ entrez? db = snp&cmd = search&term = cklf, 2008-06-29.
15. Programs for genomic applications. SeattleSNPs [ DB/OL ] .http: / / pga. gs. washington. edu/data/cklf / , 2008-08-07.
16. International HapMap Project. HapMap data phase III [ DB/ OL] .http: / / www. hapmap. org / cgi-perl / gbrowse /hapmap3 B36/,2008-08-29.
17. 中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)哮喘學(xué)組. 支氣管哮喘防治指南( 支氣管哮喘的定義、診斷、治療及教育和管理方案) . 中華內(nèi)科雜志, 2003, 42: 817-822.
18. Gustincich S, Manfioletti G, Del Sal G, et al. A fast method for high-quality genomic DNA extraction from whole human blood.Biotechniques, 1991, 11: 298-300, 302.
19. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res, 2005, 15: 97 -98 .
20. Braman SS. The global burden of asthma. Chest, 2006, 130 ( 1Suppl) : 4S-12S.
21. Ma X, Ruan G, Wang Y, et al. Two single-nucleotide polymorphisms with linkage disequilibrium in the human programmed cell death 5 gene 5′regulatory region affect promoter activity and the susceptibility of chronic myelogenous leukemia in Chinese population. Clin Cancer Res, 2005, 11: 8592-8599.
22. Lech-Maranda E, Baseggio L, Bienvenu J, et al. Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood, 2004, 103: 3529-3534.
23. Gonzalez P, Diez-Juan A, Coto E, et al. A single-nucleotide polymorphism in the human p27kip1 gene ( -838C > A ) affects basal promoter activity and the risk of myocardial infarction. BMC Biol, 2004, 2: 5.
24. Skoog T, van’t Hooft FM, Kallin B, et al. A common functional polymorphism ( C→A substitution at position -863) in the promoter region of the tumour necrosis factor-α( TNF-α) gene sociated with reduced circulating levels of TNF-α. Hum Mol Genet, 1999, 8:1443-1449.
25. Zhang J, Jin X, Fang S, et al. The functional SNP in the matrix metalloproteinase-3 promoter modifies susceptibility and lymphatic metastases in esophageal squamous cell carcinoma but not in gastric cardiac adenocarcinoma. Carcinogenesis, 2004 , 25 : 2519-2524.
26. 徐明旭, 賴茂毅, 夏東嵐, 等. CKLF 基因與CKLFSF1 基因間的順式調(diào)控元件. 細(xì)胞與分子免疫學(xué)雜志, 2003, 19: 276-278.
27. 徐明旭, 程寧, 楊松樺, 等. CKLFSF1 基因與CKLFSF2 基因間存在的順式作用元件. 中國(guó)生物化學(xué)與分子生物學(xué)報(bào), 2003, 19:349-353.
28. Chowdhury MH, Nagai A, Terashima M, et al. Chemokine-like factor expression in the idiopathic inflammatory myopathies. Acta Neurol Scand, 2008, 118: 106-114.
29. 季迎, 張浩, 袁洪, 等. 趨化素樣因子-1 在狼瘡性腎炎患者腎組織中的表達(dá). 中南大學(xué)學(xué)報(bào)( 醫(yī)學(xué)版) , 2007, 32: 490-493.
30. 龔艷君, 洪濤, 蔣捷, 等. 大鼠趨化素樣因子2 mRNA 在心肌梗死大鼠心臟中的表達(dá). 北京大學(xué)學(xué)報(bào)( 醫(yī)學(xué)版) , 2003, 35: 438-440.
  1. 1. NHLBI/WHO. Workshop Report: Global Strategy for Asthma Management and Prevention [ DB /OL] . http: / / www. ginasthma.org /Guidelineitem. asp?? l1 =2&l2 = 1&intId = 60.
  2. 2. Vercelli D. Advances in asthma and allergy genetics in 2007. J Allergy Clin Immunol, 2008, 122: 267-271.
  3. 3. Warrier MR, Hershey GK. Asthma genetics: personalizing medicine. J Asthma, 2008, 45: 257-264.
  4. 4. Denham S, Koppelman GH, Blakey J, et al. Meta-analysis of genome-wide linkage studies of asthma and related traits. Respir Res, 2008 , 9: 38 .
  5. 5. 韓文玲, 馬大龍. 一個(gè)新的多功能細(xì)胞因子-趨化素樣因子. 上海免疫學(xué)雜志, 2002, 22: 217-219.
  6. 6. McLeish S, Turner SW. Gene-environment interactions in asthma.Arch Dis Child, 2007, 92: 1032-1035.
  7. 7. Colobran R, Pujol-Borrell R, Armengol MP, et al. The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility. Clin Exp Immunol, 2007, 150: 1-12.
  8. 8. Ober C. Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol, 2005, 116: 274-278.
  9. 9. Han W, Lou Y, Tang J, et al. Molecular cloning and characterization of chemokine-like factor 1 ( CKLF1 ) , a novel human cytokine with unique structure and potential chemotactic activity. Biochem J,2001, 357: 127-135.
  10. 10. 譚亞夏, 鐘南山. 趨化素樣因子1 在支氣管肺損傷與重建中的作用. 中華結(jié)核和呼吸雜志, 2002, 25: 433.
  11. 11. 譚亞夏, 葉楓, 莫紅纓, 等. 趨化素樣因子1 對(duì)鼠肺巨噬細(xì)胞吞噬活性的作用. 廣州醫(yī)學(xué)院學(xué)報(bào), 2007, 35: 24-26.
  12. 12. 楊小瓊, 鄧述愷, 黃忠碧, 等. 大鼠趨化素樣因子1mRNA 在哮喘大鼠肺組織中的表達(dá). 陜西醫(yī)學(xué)雜志, 2007, 36: 14-17.
  13. 13. Tan YX, Han WL, Chen YY, et al. Chemokine-like factor 1, a novel cytokine, contributes to airway damage, remodeling and pulmonary fibrosis. Chin Med J( Engl) , 2004, 117: 1123-1129.
  14. 14. National center for biotechnology information. Single nucleotide polymorphism database [ DB /OL] . http: / / www. ncbi. nlm. nih.gov/ sites/ entrez? db = snp&cmd = search&term = cklf, 2008-06-29.
  15. 15. Programs for genomic applications. SeattleSNPs [ DB/OL ] .http: / / pga. gs. washington. edu/data/cklf / , 2008-08-07.
  16. 16. International HapMap Project. HapMap data phase III [ DB/ OL] .http: / / www. hapmap. org / cgi-perl / gbrowse /hapmap3 B36/,2008-08-29.
  17. 17. 中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)哮喘學(xué)組. 支氣管哮喘防治指南( 支氣管哮喘的定義、診斷、治療及教育和管理方案) . 中華內(nèi)科雜志, 2003, 42: 817-822.
  18. 18. Gustincich S, Manfioletti G, Del Sal G, et al. A fast method for high-quality genomic DNA extraction from whole human blood.Biotechniques, 1991, 11: 298-300, 302.
  19. 19. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res, 2005, 15: 97 -98 .
  20. 20. Braman SS. The global burden of asthma. Chest, 2006, 130 ( 1Suppl) : 4S-12S.
  21. 21. Ma X, Ruan G, Wang Y, et al. Two single-nucleotide polymorphisms with linkage disequilibrium in the human programmed cell death 5 gene 5′regulatory region affect promoter activity and the susceptibility of chronic myelogenous leukemia in Chinese population. Clin Cancer Res, 2005, 11: 8592-8599.
  22. 22. Lech-Maranda E, Baseggio L, Bienvenu J, et al. Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood, 2004, 103: 3529-3534.
  23. 23. Gonzalez P, Diez-Juan A, Coto E, et al. A single-nucleotide polymorphism in the human p27kip1 gene ( -838C > A ) affects basal promoter activity and the risk of myocardial infarction. BMC Biol, 2004, 2: 5.
  24. 24. Skoog T, van’t Hooft FM, Kallin B, et al. A common functional polymorphism ( C→A substitution at position -863) in the promoter region of the tumour necrosis factor-α( TNF-α) gene sociated with reduced circulating levels of TNF-α. Hum Mol Genet, 1999, 8:1443-1449.
  25. 25. Zhang J, Jin X, Fang S, et al. The functional SNP in the matrix metalloproteinase-3 promoter modifies susceptibility and lymphatic metastases in esophageal squamous cell carcinoma but not in gastric cardiac adenocarcinoma. Carcinogenesis, 2004 , 25 : 2519-2524.
  26. 26. 徐明旭, 賴茂毅, 夏東嵐, 等. CKLF 基因與CKLFSF1 基因間的順式調(diào)控元件. 細(xì)胞與分子免疫學(xué)雜志, 2003, 19: 276-278.
  27. 27. 徐明旭, 程寧, 楊松樺, 等. CKLFSF1 基因與CKLFSF2 基因間存在的順式作用元件. 中國(guó)生物化學(xué)與分子生物學(xué)報(bào), 2003, 19:349-353.
  28. 28. Chowdhury MH, Nagai A, Terashima M, et al. Chemokine-like factor expression in the idiopathic inflammatory myopathies. Acta Neurol Scand, 2008, 118: 106-114.
  29. 29. 季迎, 張浩, 袁洪, 等. 趨化素樣因子-1 在狼瘡性腎炎患者腎組織中的表達(dá). 中南大學(xué)學(xué)報(bào)( 醫(yī)學(xué)版) , 2007, 32: 490-493.
  30. 30. 龔艷君, 洪濤, 蔣捷, 等. 大鼠趨化素樣因子2 mRNA 在心肌梗死大鼠心臟中的表達(dá). 北京大學(xué)學(xué)報(bào)( 醫(yī)學(xué)版) , 2003, 35: 438-440.

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