摘要
背景及目的溃疡性结肠炎(Ulcerative colitis, UC)是原因不明的肠道慢性非特异性疾病,对其发病机制的研究目前集中在遗传因素,环境因素和免疫调节紊乱等方面。UC是多基因疾病,目前发现与UC易感性相关的基因有二十余种,分布于1-19号染色体上。维生素D具有重要的免疫调节和抗微生物的作用,可调控上皮细胞抑菌肽的产生,参与肠道微生态的平衡,调节多种细胞的生长和分化。维生素D受体(Vitamin D receptor,VDR)基因位于第12号染色体,是维生素D发挥作用的效应基因,在人体内具有重要生理作用。VDR基因具有SNP多态性,含有多个限制性内切酶位点,如FokⅠ、BsmⅠ、ApaⅠ、TaqⅠ、poly (A)和Cdx-2等,这些SNP位点多态性与多种疾病密切相关。国外有研究表明,VDR基因多态性与UC易感性相关。由于基因多态性与种族和地域有密切关系,在我国,VDR基因多态性是否与UC易感性相关,目前还没有报道。人β-防御素(human bata-defensin,hBD)是在人肠道上皮细胞表达的抗微生物多肽,是目前研究得最多的抑菌肽,具有强大的抗菌活性,同时参与机体的先天免疫和后天免疫。在肠道组织中,p-防御素表达的改变与炎症过程的相关性还不是十分清楚。目前对肠道组织p-防御素的表达情况研究的比较多,但是同时研究VDR和β-防御素在肠道组织表达的文献很少。本课题探讨VDR基因多态性与中国北方汉族UC发病的相关性及活动性UC结肠组织中VDR mRNA和β-防御素1(hBD-1) mRNA、β-防御素2 (hBD-2) mRNA的表达,为进一步揭示UC的发病机制提供依据。
材料与方法应用PCR-限制性片段长度多态性(PCR-RFLP)方法,检测218例中国北方汉族人群UC患者和251例汉族健康对照者的VDR基因四个(ApaⅠ、TaqⅠ、BsmⅠ和Fok I)限制性内切酶位点的多态性。应用实时荧光定量PCR (Real-time PCR)方法检测30例活动性UC患者和32例正常对照者的肠道上皮组织中VDR mRNA、hBD-1 mRNA和hBD-2 mRNA的表达。
结果VDR基因在中国北方汉族人群中具有多态性,四个位点基因型均符合Hardy-Weinberg平衡,表明本研究所纳入样本能够代表总体基因型分布规律。在VDR基因的四个多态性位点中,只有BamⅠ位点与UC易感性相关。与对照组相比,Bb基因型频率在UC组明显增加(28.4% vs.18.7%χ2=6.044, P=0.014; OR=1.739,95%CI=1.122-2.697),B等位基因频率在病例组比对照组明显增加(14.7% vs. 7.8%χ2=6.222, P=0.013; OR=1.670,95% CI= 1.113-2.506)。其余三个多态性位点(ApaⅠ、TaqⅠ和FokⅠ)各基因型及等位基因频率均与UC易感性无关。VDR基因多态性与UC临床表型无相关性。在活动性UC结肠粘膜中,VDR mRNA和hBD-2 mRNA表达均较正常粘膜升高(P<0.05), hBD-1 mRNA的表达在两组中无统计学意义。
结论在中国北方汉族人群中,VDR基因Bsm I位点多态性与UC易感性具有相关性,与UC临床表型无相关性。VDR基因可能是通过上调hBD-2 mRNA在肠道的表达而影响UC的发病。
Background and purpose
Ulcerative colitis (UC) is a chronic inflammation of the intestine. The etiopathogenesis of UC has not been clearly elucidated, however, its development is influenced by genetic, environmental and immunological factors.In its place UC is considered to be complex polygenic diseases. Several studies have demonstrated the identification of 20 gene locus located on chromosome 1-19 as a susceptibility gene in UC.
Vitamin D is an important immune system regulator and antimicrobial. Many data identify vitamin D as a key regulator of gastrointestinal homeostasis and an important player in regulation of the innate immune response.These effects of vitamin D are thought to be mediated through the Vitamin D receptor(VDR), located on chromosome 12. Several polymorphic sites were found on the VDR gene, such as Fok I, Bsm I, Apa I, Taq I, poly (A) and Cdx2. The study found that VDR gene polymorphism has been associated with increased susceptibility to UC in overseas patients, but have not study in Chinese patients.
Human bata-defensin (hBD) are antimicrobial peptides secreted by endothelial cells in intestinal tract as a component of the innate host defence. In the gastrointestinal tract, these peptides have bactericidal activity. This antimicrobial quality allows defensins to protect the host epithelium and stem cells from virulent pathogens and also help to regulate the number and composition of commensal microbiotal. The relationship between gut inflammation and the timing of defensin deficiency is unclear. There was not study about VDR and defensin at the same time. This study was designed to determine if polymorphisms of the VDR gene are associated with UC susceptibility in within north China Han people. Meanwhile, to offer the evidence of genetic mechanism in UC.
Methods A total of 218 UC patients and 251 healthy controls were genotyped for VDR gene polymorphisms (Apa I, Taq I, Bsm I and Fok I) using PCR-RFLP assay. To study of expression of VDR mRNA、hBD-1 mRNA and hBD-2 mRNA in epithelial tissue of 30 patients with active UC and 32 controls using Real-time PCR assay.
Results Among the four examined VDR gene polymorphisms, the Bsm I polymorphism showed a slightly higher distribution in our study population than that of previous studies. The increased frequency of the Bb genotype of the Bsm I VDR gene polymorphism was associated with UC as compared to healthy controls (28.4% vs.18.7%χ2=6.044, P=0.014, OR=1.739,95% CI=1.122-2.697). Moreover, Bsm I polymorphic allele (B) frequency was significantly increased in the UC cases, as compared to the healthy controls (14.7% vs.7.8%χ2=6.222, P=0.013; OR=1.670,95% CI=1.113-2.506). The other three VDR gene polymorphisms (Apa I, Taq I, and Fok I) were not associated with UC susceptibility. None of these four VDR polymorphisms had statistical association with clinicopatholgical parameters of these UC patients.The express of VDR mRNA and hBD-2 mRNA incresed in active UC mucosa compared with normal mucosa (P<0.05). However, the express of hBD-1 mRNA was not statistically significant in two groups.
Conclusion This study demonstrated a probable association of the Bsm I polymorphism of the VDR gene with ulcerative colitis susceptibility in Han Chinese. None of VDR polymorphisms had statistical association with clinicopatholgical parameters of these UC patients. The mechanism of VDR gene may be increasing the expression of hBD-2 mRNA in occurrence of UC.
引文
[1]Rivka Dresner-Pollak, Zvi Ackerman, Rami Eliakim, et al. The Bsm I Vitamin D Receptor Gene Polymorphism Is Associated with Ulcerative Colitis in Jewish Ashkenazi Patients[J].Genetic Testing.2004,8(4):417-420.
[2]Wehkamp J, Fellermann K, Herrlinger KR, et al. Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease[J]. Eur J Gastroenterol Hepatol.2002,14(7):745-752.
[3]Lorena Rodriguez-Bores, Gabriela C. Fonseca, Marco A. Villeda, et al. Novel genetic markers in infl ammatory bowel disease[J]. World J Gastroenterol.2007,13(42):5560-5570.
[4]Hugot JP, Laurent-Puig P, Gower-Rousseau C. Mapping of a susceptibility locus Crohn's disease on chromosome 16.[J]. Nature.1996,379:821-823.
[5]Ogura Y, Bonen DK, Inohara N. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.[J]. Nature.2001,411:603-606.
[6]Lesage S, Zouali H, Cezard JP, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with infl ammatory bowel disease.[J]. Am J Hum Genet.2002,70:845-857.
[7]Rosenstiel P, Fantini M, Brautigam K, et al. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD 15) gene in human intestinal epithelial cells.[J]. Gastroenterology.2003,124:1001-1009.
[8]Cavanaugh J. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set:Crohn disease and chromosome 16[J]. Am J Hum Genet.2001,68:1165-1171.
[9]Inohara N, Nunez G. The NOD:a signaling module that regulates apoptosis and host defense against pathogens.[J]. Oncogene.2001,20:6473-6481.
[10]Inohara N, Ogura Y, Chen FF. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. [J]. J Biol Chem.2001,276:2551-2554.
[11]Inohara N, Koseki T, Lin J. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways.[J]. J Biol Chem.2000,275:27823-27831.
[12]Hugot JP, Chamaillard M, Zouali H. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.[J]. Nature.2001,411:599-603.
[13]Figueroa C, Peralta A, Herrera L. NOD2/CARD15 and Till-like 4 receptor gene polymorphism in Chilean patients with inflammatory bowel disease.[J]. Eur Cytokine Netw. 2006,17(2):125-130.
[14]Leong RW, Armuzzi A, Ahmad T. NOD2/CARD15 gene polymorphism and Crohn's disease in the Chinese population.[J]. Aliment Pharmacol Ther.2003,17:1465-1470.
[15]夏冰,瞿艳,郭秋莎.NOD2基因3020insC移码突变与中国湖北汉族炎症性肠病的相关性[J].世界华人消化杂志.2004,12(5)：1208-1210.
[16]Forabosco P, Collins A, Latiana A. Combined segregation and linkage analysis of inflammatory bowel disease in the IBD1 region using severity to characterize Crohn's disease and ulcerative colitis. On behalf of the GISC.[J]. Eur J Hum Genet.2000,8:846-852.
[17]Ferraris A, Torre B, Knafelz D. Relationship between CARD15, SLC22A4/5, and DLG5 polymorphisms and early-onset inflammatory bowel disease an Italian multicentric study.[J]. Inflamm Bowel Dis.2006,12(5):355-361.
[18]Parkes M, Barmada MM, Satsangi J, et al. The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease.[J]. Am J Hum Genet.2000,67: 1605-1610.
[19]Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence [J]. Exp Biol Med.2004,229:1136-1142.
[20]Klein W, Tromm A, Folwaczny C, et al. The G2964A polymorphisms of the STAT6 gene in inflammatory bowel disease[J]. Dig Liver Dis.2005,37(3):159-161.
[21]van Heel DA, Fisher SA, Kirby A, et al. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs[J]. Hum Mol Genet. 2004,13(7):763-770.
[22]王丽英,王江滨,陈永胜.人类白细胞抗原基因多态性与炎症性肠病遗传易感关系的分析[J].中华消化杂志.2005,25(4)：247-248.
[23]郭海建,刘若丹,周向京,等.人类HLA-DP基因多态性与溃疡性结肠炎相关性研究[J].深圳中西医结合杂志.2007,17(6)：358-361.
[24]宋瑛,吴开春,张沥,等.肿瘤坏死因子基因多态性与炎症性肠病的相关性分析[J].中华消化杂志.2005,25(4)：202-206.
[25]Louis E, Franchimont D, Piron A. Tumour necrosis factor (TNF) gene polymorphism influences TNF alpha production in lipopolysaccharide(LPS) stimulated whole blood cell culture in healthy humans. [J]. Clin Exp Immunol.1998,113:401-406.
[26]袁岸龙,夏冰,侯炜,等.肿瘤坏死因子α基因多态性与炎症性肠病的相关性研究[J].中华消化杂志.2004,24(4)：243-244.
[27]项利娟,陈春晓.肿瘤坏死因子α基因多态性与炎症性肠病的关系[J].浙江医学.2006,28(4)：261-263.
[28]Koss K, Satsangi J, Fanning GC. Cytokine(TNF alpha,LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls:differential effects on production and allele frequencies.[J]. Genes Immun.2000,1:185-190.[29]陈会,左武,李艳.湖北地区汉族人群TNF基因多态性分布研究[J].微循环学杂志.2002，12：18-20.
[30]Duerr RH, Barmada MM, Zhang L, et al. High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q 11-12[J]. Am J Hum Genet.2000,66(6): 1857-1862.
[31]Vermeire S, Rutgeerts P, Van Steen K, et al. Genome wide scan in a Flemish inflammatory bowel disease population:support for the IBD4 locus, population heterogeneity, and epistasis[J]. Gut.2004,53(7):980-986.
[32]Owyang AM, Zaph C, Wilson EH, et al. Interleukin 25 regulates type 2 cytokinedependent immunity and limits chronic infl ammation in the gastrointestinal tract[J]. J Exp Med.2006,203(4):843-849.
[33]Armuzzi A, Ahmad T, Ling KL, et al. Genotypephenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31 [J]. Gut.2003,52:1133-1139.
[34]Pierik M. Vermeire S, Hlavaty T, Claessens G, et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD[J]. Gastroenterology.2005,129:1845-1853.
[35]Walters TD, Silverberg MS. Genetics of inflammatory bowel disease:current status and future directions [J]. Can J Gastroenterol.2006,20:633-639.
[36]Giallourakis C, Stoll M, Miller K, et al. IBD5 is a general risk factor for inflammatory bowel disease:replication of association with Crohn disease and identifi cation of a novel association with ulcerative colitis[J]. Am J Hum Genet.2003,73:205-211.
[37]Tosa M, Negoro K, Kinouchi Y. Lack of association between IBD5 and Crohn's disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease.[J]. Gastroenterol.2006,41(1):48-53.
[38]薛惠平,倪培华,吴洁敏,等.炎症性肠病CD14基因启动子159多态性及其意 义[J].上海交通大学学报(医学版).2007,27(9)：1127-1131.
[39]周亮,鲁继荣,勒英丽,等.细胞间黏附分子-1基因Gly241Arg多态性与儿童哮喘关系探讨[J].中国实用儿科杂志.2004,19：687-688.
[40]王银娜,李荣芬.细胞间黏附分子-1基因多态性与疾病易感性[J].国外医学遗传学分册.2004,27：165-167.
[41]Matsuzawa J, Sugimura K, Matsuda Y, et al. Association between K469E all el e of intercellular adhesion molecule 1 gene and inflammatory bowel disease in a Japanese population[J]. Gut.2003,52:75-78.
[42]Low JH, Williams FA, Yang XS, et al. Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1[J]. Inflamm Bowel Dis.2004,10:173-181.
[43]Hamamoto N, Maemura K, Hirata I, et al. Inhibition of dextran sulphate sodium-induced colitis in mice by intracolonically administered antibodies against adhesion molecules[J]. Clin Exp Immunol.1999,117:462-468.
[44]Labbe C, Goyette P, Lefebvre C, et al. MAST3:a novel IBD risk factor that modulates TLR4 signaling[J]. Genes Immun.2008,9(7):602-612.
[45]Rennick DM, Fort MM. Lesson from genetically engineered animal models.X Ⅱ.IL-10 deficient(IL-10(-/-)mice and intestinal inflammation[J]. Am J Physiol Gastrointest Liver Physiol.2000,278(6):G829-G833.
[46]Fernandez L, Martinez A, Mendoza TJ, et al. Interleukin-10 polymorphisms in Spanish patients with IBD[J]. Inflamm Bowel Dis.2005,11(8):739-743.
[47]KimTH, Kim BG, Shin HD, et al. Tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in Korean patients with inflammatory bowel disease[J]. Korean J Gastroenterol.2003,42(5):377-386.
[48]Cantor MJ, Nickerson P, Bernstein CN. The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease[J]. Am J Gastroenterol.2005,100(5):1134-1142.
[49]Balding J, Livingstone WJ, Conroy J, et al. Inflammatory bowel disease:the role of inflammatory cytokine gene polymorphisms[J]. Mediators Inflamm.2004,13(3):181-187.
[50]Satsangi J, Parkes M, Louis E, et al. Two stage genome-wide search in infl ammatory bowel disease provides evidence for susceptibility loci on chromosomes 3,7 and 12[J]. Nat Genet.1996,14:199-202.
[51]Rector A, Vermeire S, Thoelen I, et al. Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease[J]. Hum Genet.2001,180: 190-193.
[52]Waterhouse P, Penninger JM, Timms E. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4.[J].Science.1995,270:985-988.
[53]夏冰,蒋益.细胞毒性T淋巴细胞相关抗原4基因多态性与炎症性肠病的相关性[J].中华内科杂志.2004,43(3)：191-194.
[54]Machida H, Tsukamoto K, Wen CY. Association of polymorphic alleles of CTLA4 with inflammatory bowel disease in the Japanese.[J]. World J Gastroenterol.2005,11: 4188-4193.
[55]王琪,夏冰,郭秋莎,等.细胞毒性T淋巴细胞相关抗原4 CT60及J031基因多态性与炎症性肠病的相关性[J].中华消化杂志.2006,26(6)：422-423.
[56]周峰,夏冰,郭秋莎,等.细胞毒淋巴细胞相关抗原4基因多态性与溃疡性结肠炎[J].中华内科杂志.2006,45(6)：478-481.
[57]Hawrelak JA, Myers SP. The causes of intestinal dysbiosis:a review[J]. Altern Med Rev.2004,9:180-197.
[58]Kanauchi O, Mitsuyama K, Araki Y, et al. Modification of intestinal flora in the treatment of inflammatory bowel disease.[J]. Curr Pharm Des.2003,9:333-346.
[59]Sghir A, Gramet G, Suau A, et al. Quantification of bacterial groups within human fecal flora by oligonucleotide probe hybridization.[J]. Appl Environ Microbiol.2000,66: 2263-2266.
[60]Linskens RK, Huijsdens XW, Savelkoul PH, et al. The bacterial flora in inflammatory bowel disease:current insights in pathogenesis and the influence of antibiotics and probiotics.[J]. Scand J Gastroenterol(Suppl).2001,234:29-40.
[61]Swidsinski A, Ladhoff A, Pernthaler A, et al. Mucosal flora in inflammatory bowel disease.[J]. Gastroenterology.2002,122:44-54.
[62]Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. [J]. Gut.2003,52:237-242.
[63]Kleessen B, Kroesen AJ, Buhr HJ, et al. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. [J]. Scand J Gastroenterol.2002, 37:1034-1041.
[64]Dianda L, Hanby AM, Wright NA. T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment.[J]. Am J Pathol.1997,150(1): 91-97.
[65]Rutgeerts P, Goboes K, Peeters M. Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum.[J]. Lancet.1991,338(8770):771-774.
[66]Rutgeerts P, Hiele M, Geboes K. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection.[J]. Gastroenterology.1995,108(6): 1617-1621.
[67]Bamias G, Nyce MR, De La Rue SA, et al. New concepts in the pathophysiology of inflammatory bowel disease.[J]. Ann Intern Med.2005,143:895-904.
[68]白爱平.炎症性肠病发病机制的微生物因素[J].世界华人消化杂志.2006,14：645-649.
[69]Duchmann R, Schmitt E, Knolle P, et al. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12[J]. Eur J Immunol.1996,26:934-938.
[70]Dotan I, Rachmilewitz D. Probiotics in inflammatory bowel disease:possible mechanisms of action.[J]. Curr Opin Gastroenterol.2005,21:426-430.
[71]Mach T. Clinical usefulness of probiotics in inflammatory bowel diseases.[J]. J Physiol Pharmacol(Suppl).2006,57(9):23-33.
[72]Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases:antibiotics, probiotics, and prebiotics.[J]. Gastroenterology.2004,126: 1620-1633.
[73]Hugot JP, Alberti C, Berrebi D. Crohn's disease:the cold chain hypothesis.[J]. Lancet.2003,362:2012-2015.
[74]李晨怡,陈春晓,厉有名.克罗恩病与冷链假说[J].国际消化病杂志.2007,27(6)：438-442.
[75]何相宜,陈维雄.调节性T细胞在炎症性肠病中的研究进展[J].世界华人消化杂志.2007,15(28)：3015-3019.
[76]舒德忠,周岐新.炎症性肠病相关受体蛋白和转录调节因子的研究[J].生理科学进展.2005,36(3)：269-272.
[77]Franchimont D, Vermeire S, El Housni H, et al. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor(TLR) 4 Asp299gly polymorphism is associated with Crohn disease and Ulcerative colitis[J]. Gut.2004,53:987-992.
[78]Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease[J]. Gut.1998,42(4):477-484.
[79]Huang YC, Lee S, Stolz R, et al. Effect of hormones and development on the expression of the rat 1,25-dihyroxyvitamin D3 receptor gene.[J]. J Biol Chem.1989,264: 17454-17461.
[80]Abe E, Miyaura C, Sakagami H, et al. Differentiation of mouse myeloid leukemia cells induced by 1,25-dihydroxyvitamin D3[J]. Proc Natl Acad Sci USA.1981,78: 4990-4994.
[81]麻继臣,张晓岚,郝礼森,等.维生素D与炎症性肠病的研究进展[J].世界华人消化杂志.2008,16(23)：2637-2643.
[82]Michael F. Holick, Tai C. Chen. Vitamin D deficiency:a worldwide problem with health consequences[J]. Am J Clin Nutr.2008,87(suppl):1080S-1086S.
[83]Cantorna MT, Zhu Y, Fruicu M. Vitamin D status,1,25 dihydroxyvitamin D3, and the immune system[J]. Am J Clin Nutr.2004,80(6):1717S-1720S.
[84]Adorini L, Penna G, Giarratana N. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases[J]. J Cell Biochem.2003,88(2):227-233.
[85]Mahon BD, Wittke A, Weaver V. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells[J]. J Cell Biochem.2003,89(5): 922-932.
[86]Cippitelli M, Fionda C, Di Bona D. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes[J]. J Immunol.2002,168(3):1154-1166.
[87]Xu H, Soruri A, Gieseler RK.1,25 dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class Ⅱ antigen expression, accessory activity, and phagocytosis of human monocytes[J]. Scan J Immunol.1993,38(6):535-540.
[88]Penna G, Adorini L.1 Alpha,25 dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation[J]. J Immunol.2000,164(5):2405-2411.
[89]Haussler MR, Myrtle JF, Norman AW. The association of a metabolite of vitamin D3 with intestinal mucosa chromatin, in vivo[J]. J Biol Chem.1968,243:4055-4064.
[90]Myrtle JF, Haussler MR, NormanAW. Evidence for the biologically active form of cholecalciferol in the intestine[J]. J Biol Chem.1970,245:1190-1196.
[91]Norman AW, Myrtle JF, Midgett RJ, et al.1,25-Dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine[J]. Science.1971, 173:51-54.
[92]Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite.[J]. Proc Natl Acad Sci USA.1969,62:155-162.
[93]Tsai HC, Norman AW. Studies on the mode of action of calciferol. VI. Effect of 1,25-dihydroxyvitamin D3 on RNA synthesis in the intestinal mucosa[J]. Biochem Biophys Res Commun.1973,54:622-627.
[94]Norman AW. Actinomycin D and the response to vitamin D[J]. Science.1965,149: 184-186.
[95]Tsai HC, Midgett RJ, Norman AW. Studies on calciferol metabolism.VII. The effects of actinomycin D and cycloheximide on the metabolism, tissue and subcellular localization, and action of vitamin D3.[J].Arch Biochem Biophys.1973,157:339-347.
[96]Walters MR, Hunziker W, Norman AW. Unoccupied 1,25-dihydroxyvitamin D3 receptors:nuclear/cytosol ratio depends on ionic strength. [J]. J Biol Chem.1980,255: 6799-6805.
[97]Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease.[J]. New Engl J Med.1989,320:980-991.
[98]Norman AW, Roth J, Orci L. The vitamin D endocrine system:Steroid metabolism, hormone receptors and biological response (calcium binding proteins)[J]. Endocr Rev.1982, 3:331-366.
[99]Nemere 1, Dormanen MC, Hammond MW, et al. Identification of a specific binding protein for 1α,25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia.[J]. J Biol Chem.1994,269:23750-23756.
[100]Norman AW, Okamura WH, Hammond MW, et al. Comparison of 6-s-cis and 6-s-trans locked analogs of 1α,25(OH)2-vitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis nor 6-s-trans locked analogs are preferred for genomic biological responses.[J]. Mol Endocrinol.1997,11: 1518-1531.
[101]Rochel N, Wurtz JM, Mitschler A, et al. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand.[J]. Mol Cell.2000,5:173-179.
[102]Mizwicki MT, Bishop JE, Olivera CJ, et al. Evidence that annexin Ⅱ is not a putative membrane receptor for 1α,25(OH)2-vitamin D3.[J]. J Cell Biochem.2003,91: 852-863.
[103]Norman AW, Olivera CJ, Barreto Silva FR, et al. A specific binding protein/receptor for 1 a,25-dihydroxy D3 is present in an intestinal caveolae membrane fraction[J]. Biochem Biophys Res Commun.2002,298:414-419.
[104]Huhtakangas JA, Olivera CJ, Bishop JE, et al. The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1α,25(OH)2-vitamin D3 in vivo and in vitro.[J]. Mol Endocrinol.2004,18:2660-2671.
[105]Nemere I, Farach-Carson MC, Rohe B, et al. Ribozyme knockdown functionally links a la,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells.[J]. Proc Natl Acad Sci USA.2004,101:7392-7397.
[106]Nguyen TM, Lieberherr M, Fritsch J, et al. The rapid effects of 1,25-(OH)2D3 require the VDR and influence 24-hydroxylate activity:studies in human skin fibroblasts bearing vitamin D receptor mutations [J]. J Biol Chem.2004,279:7591-7597.
[107]Norman AW, Mizwicki MT, Norman DPG. Steroid hormone rapid actions, membrane receptors and a conformational ensemble model.[J]. Nat Rev Drug Discov.2004,3: 27-41.
[108]Mizwicki MT, Keidel D, Bula CM, et al. Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH)2-vitamin D3 signaling[J]. Proc Natl Acad Sci USA.2004,101:12876-12881.
[109]Zanello LP, Norman AW. Rapid modulation of osteoblast ion channel responses by 1α,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor[J]. Proc Natl Acad Sci USA.2004,101:1589-1594.
[110]Bula CM, Huhtakangas J, Olivera C, et al. Presence of a truncated form of the vitamin D receptor (VDR) in a strain of VDR-knockout mice[J]. Endocrinology.2005,146: 5581-5586.
[111]Bartik L, Whitfield GK, Kaczmarska M, et al. Curcumin:a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention [J].J Nutr Biochem.2010,21(12):1153-1161.
[112]Walters MR. Newly identified actions of the vitamin D endocrine system.[J]. Endocrinol Rev.1992,13:1-46.
[113]Taymans SE, Pack S, Pak E, et al. The human vitamin D receptor gene (VDR) is localized to region 12cen-ql2 by fluorescent in situ hybridization and radiation hybrid mapping:genetic and physical VDR map.[J]. J Bone Miner Res.1999,14:1163-1166.
[114]Miyamoto K, Kesterson RA, Yamamoto H. Structural organization of the human vitamin D receptor chromosomal gene and its promoter[J]. Mol Endocrinol.1997,11: 1165-1179.
[115]Crofts LA, Hancock MS, Morrison NA, et al. Multiple promoters direct the tissue-specific expression of novel Nterminal variant human vitamin D receptor gene transcripts.[J]. Proc Natl Acad Sci USA.1998,95:10529-10534.
[116]M. R. Haussler, C. A. Haussler, P. W. Jurutka, et al. The vitamin D hormone and its nuclear receptor:molecular actions and disease states. [J]. Journal of Endocrinology.1997, 154:S57-S73.
[117]Norman, Anthony W. Minireview:Vitamin D Receptor:New Assignments for an Already Busy Receptor[J]. Endocrinology.2006,147(12):5542-5548.
[118]Marcinkowska E. A run for a membrane vitamin D receptor[J]. Biol Signals Recept.2001,10(6):341-349.
[119]陈锦先,唐伟军,钟鸣.直肠癌旁移行粘膜维生素D受体的表达[J].上海第二医科大学学报.2001,21(2)：134-140.
[120]战军.人维生素D3受体对免疫相关基因的表达调控及其机制的初探[D].北京：中国协和医科大学,1994.
[121]Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response[J]. Science.2006,311:1770-1773.
[122]Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin Dresistant rickets.[J]. Endocrinol Rev.1999,20:156-188.
[123]Single nucleotide polymorphism data.http://www.ncbi.nlm.nih.gov/projects/SNP/. 2008.
[124]Vitamin D receptor data. http://egp.gs.washington.edu/data/vdr/.2008.
[125]Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases[J]. Clin Chim Acta.2006,371:1-12.
[126]Hawa NS, Cockerill FJ, Vadher S, et al. Identification of a novel mutation in hereditary vitamin D-resistant rickets causing exon skipping.[J]. Clin Endocrinol.1996,45: 85-92.
[127]Cockerill FJ, Hawa NS, Yousaf N, et al. Mutations in the vitamin D receptor gene in three kindreds associated with hereditary vitamin D resistant rickets.[J]. J Clin Endocrinol Metab.1997,82:3156-3160.
[128]Gross C, Eccleshall TR, Malloy PJ, et al. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women.[J]. J Bone Miner Res.1996,11: 1850-1855.
[129]Arai H, Miyamoto K, Taketani Y, et al. A vitamin D receptor gene polymorphism in the translation initiation codon:effect on protein activity and relation to bone mineral density in Japanese women.[J].J Bone Miner Res.1997,12:915-921.
[130]Eccleshall TR, Garnero P, Gross C, et al. Lack of correlation between start codon polymorphism of the vitamin D receptor gene and bone mineral density in premenopausal French women:the OFELY Study[J]. J Bone Miner Res.1998,13:31-35.
[131]王果,李宝群,周宏灏.中国人结直肠瘤与维生素D受体基因Fok Ⅰ多态的相关性[J].中南大学学报(医学版).2008,33(5)：399-403.
[132]Nejentsev S, Godfrey L, Snook H. Comparative highresolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene.[J]. Hum Mol Genet.2004,13:1633-1639.
[133]Haussler MR, Whitfield GK, Haussler CA. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed[J]. J Bone Miner Res.1998,13: 325-349.
[134]Zmuda JM, Cauley JA, Danielson ME, et al. Vitamin D receptor translation initiation codon polymorphism and markers of osteoporotic risk in older African-American women.[J]. Osteoporos Int.1999,9:214-219.
[135]Ferrari S, Rizzoli R, Manen D, et al. Vitamin D receptor gene start codon polymorphisms (Fok 1) and bone mineral density:interaction with age, dietary calcium, and 3'-end region polymorphisms.[J]. J Bone Miner Res.1998,13:925-930.
[136]Morrison NA, Qi JC, Tokita A. Prediction of bone density from vitamin D receptor alleles.[Z].1994:367,284-287.
[137]Ingles SA, Haile RW, Henderson BE. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups:implications for association studies.[J]. Cancer Epidemiol Biomarkers Prev.1997,6:93-98.
[138]Zmuda JM, Cauley JA, Ferrell RE. Molecular epidemiology of vitamin D receptor gene variants[J]. Epidemiol Rev.2000,22:203-217.
[139]Whitfield GK, Remus LS, Jurutka PW. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene[J]. Mol Cell Endocrinol.2001,177:145-159.
[140]Carling T, Rastad J, Akerstrom G. Vitamin D receptor(VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors.[J]. J Clin Endocrinol Metab.1998,83:2255-2259.
[141]Cooper GS, Umbach DM. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis.[J].J Bone Miner Res.1996,11:1841-1849.
[142]Akifumi Tokita, Hiroshi Matsumot, Nigel A. Morrison, et al. Vitamin D Receptor Alleles, Bone Mineral Density and Turnover in Premenopausal Japanese Women[J]. Journal Of Bone And Mineral Research.1996,11(7):1003-1009.
[143]Jorgensen HL, Scholler J, Sand JC, et al. Relation of common allelic variation at vitamin D receptor locus to bone mineral density and postmenopausal bone loss: cross-sectional and longitudinal population study.[J]. BMJ.1996,313:586-590.
[144]Zmuda JM, Cauley JA, Danielson ME, et al. Vitamin D receptor gene polymorphisms, bone turnover, and rates of bone loss in older African-American women.[J]. J Bone Miner Res.1997,12:1446-1452.
[145]张红红,陶国枢,高宇红,等.我国四种,民族维生素D受体基因多态性分布的研究[J].中国骨质疏松杂志.2006,12(1)：1-3.
[146]Lim SK, Park YS, Park JM, et al. Lack of association between vitamin D receptor genotypes and osteoporosis in Koreans.[J]. J Clin Endocrinol Metab.1995,80(12): 3677-3681.
[147]Hustmyer FG, DeLuca HF, Peacock M. Apa I, Bsm I, EcoRV and Taq I polymorphisms at the human vitamin D receptor gene locus in Caucasians, Blacks and Asians[J]. Hum Mol Genet.1993,2:487.
[148]Garnero P, Borel O, Sorney-Rendu E. Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy Japanese woman.[J]. J Bone Miner Res. 1995,10:1283-1288.
[149]Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from vitamin D receptor alleles.[J]. Nature.1994,367(6460):284-287.
[150]Morrison NA, Yeoman R, Kelly PJ, et al. Contribution of trans-acting factor alleles to normal physiological variability:vitamin D receptor gene polymorphism and circulating osteocalcin.[J]. Proc Natl Acad Sci USA.1992,89:6665-6669.
[151]Schug J, Overton GC. Modeling transcription factor binding sites with Gibbs Sampling and minimum description length encoding.[J]. Proc Int Conf Intell Syst Mol Biol. 1997,5:268-271.
[152]Rengarajan J, Szabo SJ, Glimcher LH. Transcriptional regulation of Th1/Th2 polarization.[J]. Immunol Today.2000,21:479-483.
[153]Moccllin S, Nitti D. Therapeutics targeting tumor immune escape:towards the development of new generation anticancer vaccines. [J]. Med Res Rev.2008,28:413-444.
[154]Remus LS, Whitfield GK, Jurutka PW. Functional evaluation of endogenous VDR alleles in human fibroblast cell lines:relative contribution of F/f and L/S genotypes to 1,25(OH)2D3-elicited VDR transactivation ability.[J]. Bone.1998,23(Suppl.):S198.
[155]Ingles SA, Haile RW, Henderson B. Loci in the 5' and 3'regions of the vitamin D receptor gene interact to influence breast cancer risk[J]. Am J Hum Genet.1997,61:A201.
[156]孙赞,周园,邵宏伟,等.老年人维生素D受体基因启动子Cdx-2结合位点多态性研究[J].中国冶金工业医学杂志.2008,25(5)：529-530.
[157]Yue Fang, Joyce BJ, Van Meurs. Cdx-2 Polymorphism in the Promoter Region of the Human Vitamin D receptor gene determines susceptibility to fracture in the elderly.[J]. J Bone Miner Res.2003,18(9):1632-1641.
[158]Arai H, Miyamoto KI, Yoshida M, et al. The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene.[J]. J Bone Miner Res.2001,16:1256-1264.
[159]Yamamoto H, Miyamoto K, Li B, et al. The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine.[J]. J Bone Miner Res.1999,14:240-247.
[160]Suh E, Chen L, Taylor J, et al. A homeodomain protein related to caudal regulates intestine-specific gene transcription.[J]. Mol Cell Biol.1994,14:7340-7351.
[161]Lambert M, Colnot S, Suh ER, et al. Cis-acting elements and transcription factors involved in the intestinal specific expression of the rat calbindin-D9k:Binding of the intestinal-specific transcription factor Cdx-2 to the TATA box.[J]. Eur J Biochem.1996,236: 778-788.
[162]Troelsen JT, Michelmore C, Spodsberg N, et al. Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2.[J]. Biochem J. 1997,322:833-838.
[163]Suh E, Traber PG. An intestine-specific homeobox gene regulates proliferation and differentiation.[J]. Mol Cell Biol.1996,16:619-625.
[164]Traber PG, Silberg DG. Intestinal specific gene transcription.[J].Annu Rev Physiol.1996,58:275-297.
[165]German MS, Wang J, Chadwick RB, et al. Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein:Building a functional insulin minienhancer complex.[J]. Genes Dev.1992,6:2165-2176.
[166]Jin T, Drucker DJ. Activation of proglucagon gene transcription through a novel promoter element by the caudalrelated homeodomain protein cdx-2/3.[J]. Mol Cell Biol.1996, 16:19-28.
[167]Jin T, Trinh DKY, Wang F, et al. The caudal homeobox protein cdx-2/3 activates endogenous proglucagon gene expression in InRl-G9 islet cells. [J]. Mol Endocrinol.1997, 11:203-209.
[168]Gennari C, Agnusdei D, Nardi P, et al. Estrogen preserves a normal intestinal responsiveness to 1,25-dihydroxyvitamin D3 in oophorectomized women.[J]. J Clin Endocrinol Metab.1990,71:1288-1293.
[169]Civitelli R, Agnusdei D, Nardi P, et al. Effects of one-year treatment with estrogens on bone mass, intestinal calcium absorption, and 25 hydroxyvitamin D-1 alpha-hydroxylase reserve in postmenopausal women.[J]. Calcif Tissue Int.1988,42:77-86.
[170]Liel Y, Shany S, Smirnoff P, et al. Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa.[J]. Endocrinology.1999, 140:280-285.
[171]Beaumont M, Bennett AJ, White DA. Allelic differences in the 3' untranslated region of the vitamin D receptor gene affect mRNA levels in bone cells.[J]. Osteoporos Int. 1998,8:37.
[172]Durrin LK, Haile RW, Ingles SA, et al. Vitamin D receptor 3'-untranslated region polymorphisms:lack of effect on mRNA stability.[J]. Biochim Biophys Acta.1999,1453: 311-320.
[173]Rook GA, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes.[J].Immunology.1986,57: 159-163.
[174]Bellamy R, Ruwende C, Corrah T, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.[J]. J Infect Dis.1999,179: 721-724.
[175]Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London:a casecontrol study.[J]. Lancet.2000,355:618-621.
[176]Roy S, Frodsham A, Saha B, et al. Association of vitamin D receptor genotype and leprosy type.[J]. J Infect Dis.1999,179:187-191.
[177]Adorini L. Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases[J]. Int Immunopharmacol.2002,2(7):1017-1028.
[178]Cantorna MT. Vitamin D and its role in immunology:multiple sclerosis, and inflammatory bowel disease[J]. Prog Biophys Mol Biol.2006,92:60-64.
[179]Monica Froicu, Margherita T. Cantorna. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury[J]. BMC Immunology. 2007,8:5.
[180]Yu S, Bruce D, Froicu M, et al. Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice.[J]. Proc Natl Acad Sci U S A.2008,105(52):20834-20839.
[181]Monica Froicu, Veronika Weaver, Thomas A. Wynn, et al. A crucial role for the vitamin D receptor in experimental Inflammatory Bowel Diseases[J]. Mol Endocrinol.2003, 17(12):2386-2392.
[182]Juan Kong, Zhongyi Zhang, Mark W. Musch, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier [J]. Am J Physiol Gastrointest Liver Physiol.2008,294:G208-G216.
[183]Ara C, Devirgiliis LC, Massimi M. Influence of retinoic acid on adhesion complexes in human hepatoma cells:a clue to its antiproliferative effects [J]. Cell Commun Adhes.2004,11:13-23.
[184]Simmons JD, Mullighan C, Welsh KI, et al. Vitamin D receptor gene polymorphism:association with Crohn's disease susceptibility [J]. Gut.2000,47:211-214.
[185]Osborne JE, Hutchinson PE. Vitamin D and systemic cancer:is this relevant to malignant melanoma?[J]. Br J Dermatol.2002,147:197-213.
[186]McKay JD, McCullough ML, Ziegler RG, et al. Vitamin D receptor polymorphisms and breast cancer risk:results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.[J]. Cancer Epidemiol Biomarkers Prev.2009,18(1): 297-305.
[187]Chakraborty A, Mishra AK, Soni A, et al. Vitamin D receptor gene polymorphism(s) and breast cancer risk in north Indians.[J]. Cancer Detect Prev.2009, 32(5-6):386-394.
[188]Marc Sinotte, Francois Rousseau, Pierre Ayotte, et al. Vitamin D receptor polymorphisms (Fokl, BsmI) and breast cancer risk:association replication in two case-control studies within French Canadian population[J]. Endocrine-Related Cancer.2008,15: 975-983.
[189]Jack A. Taylor, An Hirvonen, Mary Watson, et al. Association of Prostate Cancer with Vitamin D Receptor Gene Polymorphism[J]. Cancer Research.1996,56(15):4108-4110.
[190]Ochs-Balcom HM, Cicek MS, Thompson CL, et al. Association of vitamin D receptor gene variants, adiposity and colon cancer.[J]. Carcinogenesis.2008,29(9): 1788-1793.
[191]Li C, Li Y, Gao LB, et al. Vitamin D receptor gene polymorphisms and the risk of colorectal cancer in a Chinese population.[J]. Dig Dis Sci.2009,54(3):634-639.
[192]Fliigge J, Laschinski G, Roots I, et al. Vitamin D receptor poly(A) microsatellite and colorectal cancer risk in Caucasians [J]. Int J Colorectal Dis.2009,24(2):171-175.
[193]Lee YH, Woo JH, Choi SJ, et al. Vitamin D receptor TaqI, BsmI and ApaI polymorphisms and osteoarthritis susceptibility:a meta-analysis[J]. Joint Bone Spine.2009, 76(2):156-161.
[194]Dogan I, Onen HI, Yurdakul AS, et al. Polymorphisms in the vitamin D receptor gene and risk of lung cancer.[J]. Med Sci Monit.2009,15(8):R232-R242.
[195]Smolders J, Peelen E, Thewissen M, et al. The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis[J]. Autoimmun Rev.2009, 8(7):621-626.
[196]Randerson Moor JA, Taylor JC, Elliott F, et al. Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma:UK case-control comparisons and a meta-analysis of published VDR data[J]. Eur J Cancer.2009,45(18): 3271-3281.
[197]Simone M, Donato N. Vitamin D receptor polymorphisms and the risk of cutaneous melanoma A systematic review and Meta-analysis[J]. Cancer.2008,113: 2398-2407.
[198]Ingles SA, Ross RK, Yu MC, et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor.[J]. J Natl Cancer Inst.1997,89: 166-170.
[199]Ingles SA, Coetzee GA, Ross RK, et al. Association of prostate cancer with vitamin D receptor haplotypes in African-Americans.[J]. Cancer Res.1998,58:1620-1623.
[200]Ma J, Stampfer MJ, Gann PH, et al. Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians.[J]. Cancer Epidemiol Biomarkers Prev.1998,7:385-390.
[201]Miller GJ. Vitamin D and prostate cancer:biologic interactions and clinical potentials.[J]. Cancer Metastasis Rev.1999,17:353-360.
[202]Habuchi T, Suzuki T, Sasaki R, et al. Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population.[J]. Cancer Res.2000,60:305-308.
[203]Yamagata Z, Zhang Y, Asaka A. Association of breast cancer with vitamin D receptor gene polymorphism[J]. Am J Hum Genet.1997,61:A388.
[204]Curran JE, Vaughan T, Lea RA, et al. Association of a vitamin D receptor polymorphism with sporadic breast cancer development.[J]. Int J Cancer.1999,83:723-726.
[205]Ingles SA, Garcia DG, Wang W, et al. Vitamin D receptor genotype and breast cancer in Latinas (United States)[J]. Cancer Causes Control.2000,11:25-30.
[206]Ruggiero M, Pacini S, Aterini S, et al. Vitamin D receptor gene polymorphism is associated with metastatic breast cancer.[J]. Oncol Res.1998,10:43-46.
[207]Lundin AC, Soderkvist P, Eriksson B, et al. Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group.[J]. Cancer Res.1999,59:2332-2334.
[208]Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis[J]. Hepatol.2002,35: 126-131.
[209]Correa P, Rastad J, Schwarz P, et al. The vitamin D receptor (VDR) start codon polymorphism in primary hyperparathyroidism and parathyroid VDR messenger ribonucleic acid levels.[J]. J Clin Endocrinol Metab.1999,84(5):1690-1694.
[210]Carling T, Ridefelt P, Hellman P, et al. Vitamin D receptor gene polymorphism and parathyroid calcium sensor protein (CAS/gp330) expression in primary hyperparathyroidism. [J]. World J Surg.1998,22(7):700-706.
[211]Zhou H, Xu C, Gu M. Vitamin D receptor gene polymorphisms and Graves' disease:a meta-analysis[J]. Clin Endocrinol (Oxf).2009,70(6):945-983.
[212]Panierakis C, Goulielmos G, Mamoulakis D, et al. Vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Crete, Greece.[J]. Clin Immunol.2009, 133(2):276-281.
[213]Stio M, Martinesi M, Bruni S, et al. The Vitamin D analogue TX 527 blocks NF-kappaB activation in peripheral blood mononuclear cells of patients with Crohn's disease[J]. J Steroid Biochem Mol Biol.2007,103:51-60.
[214]Daniel C, Radeke HH, Sartory NA, et al. The new low calcemic vitamin D analog 22-ene-25-oxa-vitamin D prominently ameliorates T helper cell type 1-mediated colitis in mice[J]. J Pharmacol Exp Ther.2006,319:622-631.
[215]Laverny G, Penna G, Uskokovic M, et al. Synthesis and anti-inflammatory properties of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a hypocalcemic, stable metabolite of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-vitamin D3[J]. J Med Chem. 2009,52:2204-2213.
[216]Schneider JJ, Unholzer A, Schaller M, et al. Human defensins[J]. J Mol Med.2005, 83(8):587-595.
[217]DANN SM, ECKMANN L. Innate immune defenses in the intestinal tract[J]. Curr Opin Gastroentrol.2007,23(2):115-120.
[218]Cunliffe RN. Alpha-defensins in the gastrointestinal tract [J]. Mol Immunol.2003, 40(4):463-467.
[219]ECKMANN L. Sensor molecules in intestinal innate immunity against bacterial infections[J]. Curr Opin Gastroenterol.2006,22(2):95-101.
[220]Cunliffe RN, Mahida YR. Antimicrobial peptides in innate intestinal host defence[J]. Gut.2000,47:16-17.
[221]Braff MH, Gallo RL. Antimicrobial peptides:an essential component of the skindefensive barrier[J]. Curr Top Microbiol Immunol.2006,306:91-110.
[222]Ganz T. Defensins:antimierodial peptides of innate immunity[J]. Nat Rev Immunol. 2003,3:710-720.
[223]Yang D, Biragyn A, Hoover DM, et al. Multiple roles of antimicrobial defensins,cathelicidins,and eosinophil-derived neurotoxin in host defense[J]. Annu Rev Immunol.2004,22:181-215.
[224]Pazgier M, Hoover DM, Yang D, et al. Human beta-defensins[J]. Cell Mol Lire Sci.2006,63:1294-1313.
[225]Harder J, Bartels J, Christophers E, et al. A peptide antibiotic from human skin[J]. Nature.1997,387(6636):861-862.
[226]Linzmeier RM, Ganz T. Human defensin gene copy number polymorphisms:compre-hensive analysis of independent variation in alpha-and beta-defensin regions at 8p22-p23[J]. Genomics.2005,86:423-430.
[227]Liu L, Wang L, Jia HP, et al. Structure and mapping of the human β defensin HBD-2 gene and its expression at sites of inflammation[J]. Gene.1998,222:237-244.
[228]Wehkamp K, Schwichtenberg L, Schroder JM, et al. Pseudomonas aeruginosa-and IL-1 beta-mediated induction of human beta-defensin-2 in keratinocytes is controlled by NF kappa B and AP-1[J]. J Invest Dermatol.2006,126:121-127.
[229]Mineshiba J, Myokai F, Mineshiba F, et al. Transc riptional regulation of beta-defensin 2 by lipopolysaccharide in cultured human cervical carcinoma(HeLa)cells[J]. FEMS Immunol Med Microbiol.2005,45:37-44.
[230]姚国鹏,智发朝,张迎春,等.克罗恩病相关的NOD2及β-防御素-2基因多态性对β-防御素-2表达的影响[J].中华消化内镜杂志.2009,26(11)：584-588.
[231]Oren A, Ganz T, Liu L, et al. In human epidermis,β-defensin 2 is packaged in lamellar bodies[J]. Exp Molec Pathol.2003,74:180-182.
[232]Harder J, Bartels J, Christophers E, et al. Isolation and characterization of human beta-defensin-3, a novel human indueible peptide antibiotic[J]. Biol Chem.2001,276(8): 5707-5713.
[233]Schibli DJ, Hunter HN, Aseyev V, et al. The solution structures of the human beta-defensins lead to a better understanding of the potent bactericidal activity of hBD-3 against staphylococcus aureus[J]. Biol Chem.2002,277(10):8279-8289.
[234]Jia HP, Schutte BC, Schudy A, et al. Discovery of new human beta-defensins using a genomics-based approach[J]. Gene.2001,263(1-2):211-218.
[235]Menzies BE, Kenoyer A. Signal transduction and nuclear responses in staphylococcus anreus-induced expression of human β-defensin-3 in skin keratinocytes [J]. Infect humun.2006,74(12):6847-6854.
[236]Garcia JR, Krause A, Schulz S, et al. Human beta-defensin 4:a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity [J]. FASEB J.2001,15: 1819-1821.
[237]Garcia JR, Jaumann F, Schulz S, et al. Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction[J]. Cell Tissue Res.2001,306(2):257-264.
[238]Maisetta G, Di Luca M, Esin S, et al. Evaluation of the inhibitory effects of human serum components on bactericidal activity of human beta-defensin-3[J]. Peptides.2008,29(1):1-6.
[239]Schroder JM. Epithelial peptide antibiotics[J]. Biochem Pharmacol.1999,57(2): 121-134.
[240]宫霞,施用晖,乐国伟.抗菌活性肽与细菌染色体DNA的相互作用机理[J].自然科学进展.2004,14(5)：509-513.
[241]Epand RM, Vogel HJ. Diversity of antimiembial peptides and their mechanisms of action[J]. Biochim Biophys Aeta.1999,1462(1-2):11-28.
[242]Chertov O, Michiel DF, Xu L, et al. Identification of defensin-1,defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils[J]. J Biol Chem.1996,271(6):2935-2940.
[243]Lillard JW Jr, Boyaka PN, Chertov O, et al. Mechanisms for induction of acquired host immunity:by neutrophil peptide defensins[J]. Proc Natl Acad USA.1999,96(2): 651-656.
[244]Bats R. Epithelial antimierobial peptides in host defense agaillst infection[J]. Respir Res.2000,1(3):141-150.
[245]Yang D, Chertov O, Bykovskaia SN, et al. Beta-defensins:linking innate and adaptive immunity through dendritic and T cell CCR6[J]. Science.1999,286:525-528.
[246]Niyonsaba F, Iwabuchi K, Matsuda H, et al. Epithelial cell derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway[J].Int Immunol.2002,14(4):421-426.
[247]O'Neil DA, Porter EM, Elewaut D, et al. Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium [J]. J Immunol.1999,163(12): 6718-6724.
[248]Funderburg N, Lederman MM, Feng Z, et al. Human-defensin-3 activates professional antigen-presenting cells via Toll-like receptots 1 and 2[J]. Proc Natl Aead Sci USA.2007,104(47):18631-18635.
[249]Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota:a hypothesis on intimate interplay at the intestinal mucosa[J]. Semin Immunol.2007,19(2):70-83.
[250]Cunliffe RN, Kamal M, Rose FR, et al. Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa[J]. J Clin Pathol. 2002,55(4):298-304.
[251]Cunliffe RN, Rose FR, Keyte J, et al. Human defensin 5 is stored in precursor form in normal Paneth cells and isexpressed by some villous epithelial cells and by metaplastic Paneth cells in thecolon in inflammatory bowel disease[J]. Gut.2001,48(2):176-185.
[252]Yamaguchi N, Isomoto H, Mukae H, et al. Concentrations of alpha- and beta-defensins in plasma of patients withinflammatory bowel disease[J]. Inflamm Res.2009, 58(4):192-197.
[253]Bentley RW, Pearson J, Gearry RB, et al. Association of higher DEFB4 genomic copy number with Crohn's disease[J]. Am J Gastroenterol.2010,105(2):354-359.
[254]Lakatos PL, Altorjay I, Mandi Y, et al. Interaction between seroreactivity to microbial antigens and genetics in Crohn's disease:is there a role for defensins?[J]. Tissue Antigens.2008,71(6):552-559.
[255]Ferguson LR, Browning BL, Huebner C, et al. Single nucleotide polymorphisms in human Paneth cell defensin A5 may confer susceptibility to inflammatory bowel disease in a New Zealand Caucasian population[J]. Dig Liver Dis.2008,40(9):723-730.
[256]Zou H, Harrington JJ, Sugumar A, et al. Detection of colorectal disease by stool defensin assay:an exploratory study[J]. Clin Gastroenterol Hepatol.2007,5(7):865-868.
[257]Wehkamp J. Wang G. A, Kays RJ, Fellermann K, et al. The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4[J]. J Immunol. 2007,179:3109-3118.
[258]常玉英,欧阳钦.克罗恩病与防御素缺陷[J].临床消化病杂志.2005,17(5)：261-263.
[259]Wehkamp J, Schmid M, Fellermann K, et al. Defensin deficiency,intestinal microbes,and the clinical phenotypes of Crohn's disease[J]. J Leukoc Biol.2005,77:460-465.
[260]Lichtenstein A, Ganz T, Selsted ME, et al. In vitro tumor cell cytolysis mediated by peptide ddeusins of human and rabbit granulocytes[J]. Blood.1986,68(6):1407-1410.
[261]Kesting MR, Loeffelbein DJ, Hasler RJ, et al. Expression profile of human beta-defensin 3 in oral squamous cell carcinoma[J]. Cancer Invest.2009,27(5):575-581.
[262]Ibrahim HR, Sugimoto Y, Aoki T. Ovotransferrin antimicrobial peptide (OTAP-92) kills bacteria through a membrane damage mechanism[J]. Biochim Biophys Acta.2000, 1523(2-3):196-205.
[263]Chen Y, Xu X, Hong S, et al. RGD-Tachyplesin inhibits tumor growth[J]. Cancer Res.2001,61(6):2434-2438.
[264]贾洪武,张双全,戴祝英.家蚕抗菌肽对K562癌细胞的杀伤作用及对细胞超微结构的影响[J].蚕业科学.1996,22(4)：62.
[265]王芳,张双全.K563癌细胞单细胞凝胶电泳抗菌肽CM4组分的K562癌细胞染色质DNA断裂作用的SCGE研究[J].生物化学与生物物理进展.1998,25(1)：64-67.
[266]Ganz T. Defensin and host defense[J]. Science.1999,286(5439):420-421.
[267]Varoga D, Pufe T, Harder J, et al. Human β-defensin-3 mediates tissue remodeling processes in articular cartilage by increasing levels of metalloproteinases and reducing levels of their endogenous inhibitars[J]. Arthritis Rheum.2005,52(6):1736-1745.
[268]Feng Z, Dubyak GR, Lederman MM, et al. Cutting edge:human β defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4[J]. J Immunol.2006,177(2):782-786.
[269]中华医学会消化病分会炎症性肠病协作组.对我国炎症性肠病诊断治疗规范的共识意见[J].中华消化杂志.2007,12：488-495.
[270]冷曙光,宋文佳,王雅文,等.538名中国汉族人口维生素D受体基因多态性分析[J].中华预防医学杂志.2002,36(5)：314.
[271]Nosratollah Naderi, Alma Farnood, Manijeh Habibi, et al. Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease[J]. Journal of Gastroenterology and Hepatology.2008,23:1816-1822.
[272]Martin K, Radlmayr M, Borchers R, et al. Candidate genes colocalized to linkage regions in inflammatory bowel disease[J]. Digestion.2002,66:121-126.
[273]Voss E, Wehkamp J, Wehkamp K, et al. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2[J]. J Biol Chem.2006,281:2005-2011.
[274]Wehkamp J, Harder J, Weichenthal M. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis[J]. Inflamm Bowel.2003, 9:215-223.
[275]Ouellette AJ, Bevins CL. Paneth cell defensins and innate immunity of the small bowel [J]. Inflamm Bowel Dis.2001,7:43-50.