人趨化素樣因子上游啟動子區的單核苷酸多態性及其與哮喘的相關性_《中國呼吸與危重監護雜志》

作者：

章巍 ¹ , 何權瀛 ¹ , 王廣發 ² , 趙紅珊 ³ , 遲春花 ² , 趙燕妮 ² , 鄧暄 ³ , 宿利 ² , 孫遙搖 ³ , 王小迪 ³

1 北京大學人民醫院呼吸內科（北京 100044）;;
2 北京大學第一醫院呼吸內科（北京 100034）;;
3 北京大學人類疾病基因研究中心（北京 100083）;

關鍵詞：

哮喘趨化素樣因子單核苷酸多態性啟動子區基因型單倍型

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目的尋找趨化素樣因子( CKLF) 基因上游啟動子區的單核苷酸多態性( SNP) , 明確其與支氣管哮喘發病的相關性。方法提取245 例北京地區漢族人( 其中哮喘患者119 例, 健康對照126 例) 基因組DNA, 采用PCR 方法擴增CKLF 上游啟動子區1553 堿基的DNA 片段并進行直接測序, 分析發現的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病和臨床表現的相關性。結果在CKLF 上游啟動子區共發現4 個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) , 與以往報道的其他種族的結果明顯不同。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) 。哮喘組與對照組4 個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。結論北京地區漢族人群CKLF 編碼基因上游調控區的基因多態性有其獨特的分布特點及連鎖不平衡特征, 雖然與哮喘的發病無明顯相關性, 但其分布特點可能為其他疾病相關性研究提供有價值的資料。

引用本文： 章巍,何權瀛,王廣發,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子區的單核苷酸多態性及其與哮喘的相關性. 中國呼吸與危重監護雜志, 2009, 09(4): 345-350. doi: 復制

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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. 一個新的多功能細胞因子-趨化素樣因子. 上海免疫學雜志, 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 對鼠肺巨噬細胞吞噬活性的作用. 廣州醫學院學報, 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. 陜西醫學雜志, 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.	中華醫學會呼吸病學分會哮喘學組. 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 基因間的順式調控元件. 細胞與分子免疫學雜志, 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. 中國生物化學與分子生物學報, 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. 中南大學學報( 醫學版) , 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. 北京大學學報( 醫學版) , 2003, 35: 438-440.

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. 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. 一個新的多功能細胞因子-趨化素樣因子. 上海免疫學雜志, 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 對鼠肺巨噬細胞吞噬活性的作用. 廣州醫學院學報, 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. 陜西醫學雜志, 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. 中華醫學會呼吸病學分會哮喘學組. 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 基因間的順式調控元件. 細胞與分子免疫學雜志, 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. 中國生物化學與分子生物學報, 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. 中南大學學報( 醫學版) , 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. 北京大學學報( 醫學版) , 2003, 35: 438-440.

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人趨化素樣因子上游啟動子區的單核苷酸多態性及其與哮喘的相關性

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