汉族人群Toll样受体5、9基因单核苷酸多态性与风湿性心脏病的相关性研究
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摘要
研究目的探讨Toll样受体5和9基因单核苷酸多态性与风湿性心脏病的相关性。
研究方法采集239例风湿性心脏病患者和478例健康对照者的外周静脉血标本,选取TLR5基因3个标签单核苷酸多态rs1640827、rs2353476、rs5744140及TLR9基因2个标签单核苷酸多态rs5743845、rs352139,采用微阵列杂交技术检测基因组DNA中Toll样受体5、9基因各多态性位点上的等位基因、基因型频率,同时构建单体型并进行单体型分析,统计判别风湿性心脏病患者与对照者的差异。
结果①rs5744140:病例组与对照组等位基因频率差异无统计学意义(P=0.447,OR=1.181,95%CI 0.769～1.815);病例组与对照组基因型频率差异无统计学意义(P=0.528);病例组(P=0.264)与对照组(P=0.542)基因型分布符合Hardy-Weinberg平衡。②rs1640827:病例组与对照组等位基因频率差异有统计学意义(P=0.003,OR=0.495,95%CI 0.307～0.799);病例组与对照组基因型频率差异有统计学意义(P=0.019);病例组基因型分布不符合Hardy-Weinberg平衡(P=0.0004),对照组基因型分布符合Hardy-Weinberg平衡(P=0.098)。③rs2353476:病例组与对照组等位基因频率差异有统计学意义(P=0.0008,OR=1.703,95%CI 1.244～2.332);病例组与对照组基因型频率差异有统计学意义(P=0.002);病例组(P=0.652)与对照组(P=0.065)基因型分布符合Hardy-Weinberg平衡。④rs5743845:病例组与对照组等位基因频率差异无统计学意义(P=0.413,OR=0.826,95%CI 0.522～1.307);病例组与对照组基因型频率差异无统计学意义(P=0.684);病例组(P=0.992)与对照组(P=0.602)基因型分布符合Hardy-Weinberg平衡。⑤rs352139:病例组与对照组等位基因频率差异无统计学意义(P=0.478,OR=1.083,95%CI 0.869～1.350);病例组与对照组基因型频率差异无统计学意义(P=0.746);病例组(P=0.963)与对照组(P=0.603)基因型分布符合Hardy-Weinberg平衡。⑥单体型分析显示,病例组与对照组Toll样受体5基因CGC(P=0.011)、CGT(P=0.0001)、CAC(P=0.025)单体型频率差异有统计学意义。
结论汉族人群Toll样受体5基因单核苷酸多态性与风湿性心脏病存在相关性,Toll样受体9基因rs5743845、rs352139单核苷酸多态性与风湿性心脏病不存在相关性。
Objective To investigate the association of single-nucleotide polymorphisms in toll-like receptor 5 and 9 genes and rheumatic heart disease.
Methods A group of 239 patients with rheumatic heart disease and 478 healthy controls were studied. Three tag single-nucleotide polymorphisms in toll-like receptor 5 gene(rs1640827, rs2353476, and rs5744140) and two tag single-nucleotide polymorphisms in toll-like receptor 9 gene(rs5743845, rs352139) were selected for the analysis. The single-nucleotide polymorphisms at the five sites were identified with microarray hybridization analysis.
Results①rs5744140 There were no significant differences in the distribution of alleles(P=0.447,OR=1.181,95%CI 0.769～1.815) and genotypes(P=0.528) between patients with rheumatic heart disease and controls for rs5744140.②rs1640827 The frequency of A allele was significantly higher in patients with rheumatic heart disease than that in controls(P=0.003,OR=0.495,95%CI 0.307～0.799). The frequencies of G/A and A/A genotypes was significantly higher in patients with rheumatic heart disease(P=0.019).③rs2353476 The frequency of C allele was significantly higher in patients with rheumatic heart disease(P=0.0008,OR=1.703,95%CI 1.244～2.332). And the frequency of C/C genotype was significantly higher in patients with rheumatic heart disease(P=0.002).④rs5743845 There were no significant differences in the distribution of alleles(P=0.413, OR=0.826, 95%CI 0.522～1.307) and genotypes(P=0.684) between patients with rheumatic heart disease and controls for rs5743845.⑤rs352139 There were no significant differences in the distribution of alleles(P=0.478,OR=1.083,95%CI 0.869～1.350) and genotypes(P=0.746) between patients with rheumatic heart disease and controls for rs352139.⑥Haplotype analysis showed increased frequencies of TLR5 CGC(P=0.011) and CAC(P=0.025) haplotypes in patients with rheumatic heart disease when compared to controls.
Conclusion The genetic variants of toll-like receptor 5 gene might be associated with rheumatic heart disease in Chinese Han population, while single-nucleotide polymorphisms rs5743845 and rs352139 in toll-like receptor 9 gene have no association with rheumatic heart disease in Chinese Han population.
研究方法采集239例风湿性心脏病患者和478例健康对照者的外周静脉血标本,选取TLR5基因3个标签单核苷酸多态rs1640827、rs2353476、rs5744140及TLR9基因2个标签单核苷酸多态rs5743845、rs352139,采用微阵列杂交技术检测基因组DNA中Toll样受体5、9基因各多态性位点上的等位基因、基因型频率,同时构建单体型并进行单体型分析,统计判别风湿性心脏病患者与对照者的差异。
结果①rs5744140:病例组与对照组等位基因频率差异无统计学意义(P=0.447,OR=1.181,95%CI 0.769～1.815);病例组与对照组基因型频率差异无统计学意义(P=0.528);病例组(P=0.264)与对照组(P=0.542)基因型分布符合Hardy-Weinberg平衡。②rs1640827:病例组与对照组等位基因频率差异有统计学意义(P=0.003,OR=0.495,95%CI 0.307～0.799);病例组与对照组基因型频率差异有统计学意义(P=0.019);病例组基因型分布不符合Hardy-Weinberg平衡(P=0.0004),对照组基因型分布符合Hardy-Weinberg平衡(P=0.098)。③rs2353476:病例组与对照组等位基因频率差异有统计学意义(P=0.0008,OR=1.703,95%CI 1.244～2.332);病例组与对照组基因型频率差异有统计学意义(P=0.002);病例组(P=0.652)与对照组(P=0.065)基因型分布符合Hardy-Weinberg平衡。④rs5743845:病例组与对照组等位基因频率差异无统计学意义(P=0.413,OR=0.826,95%CI 0.522～1.307);病例组与对照组基因型频率差异无统计学意义(P=0.684);病例组(P=0.992)与对照组(P=0.602)基因型分布符合Hardy-Weinberg平衡。⑤rs352139:病例组与对照组等位基因频率差异无统计学意义(P=0.478,OR=1.083,95%CI 0.869～1.350);病例组与对照组基因型频率差异无统计学意义(P=0.746);病例组(P=0.963)与对照组(P=0.603)基因型分布符合Hardy-Weinberg平衡。⑥单体型分析显示,病例组与对照组Toll样受体5基因CGC(P=0.011)、CGT(P=0.0001)、CAC(P=0.025)单体型频率差异有统计学意义。
结论汉族人群Toll样受体5基因单核苷酸多态性与风湿性心脏病存在相关性,Toll样受体9基因rs5743845、rs352139单核苷酸多态性与风湿性心脏病不存在相关性。
Objective To investigate the association of single-nucleotide polymorphisms in toll-like receptor 5 and 9 genes and rheumatic heart disease.
Methods A group of 239 patients with rheumatic heart disease and 478 healthy controls were studied. Three tag single-nucleotide polymorphisms in toll-like receptor 5 gene(rs1640827, rs2353476, and rs5744140) and two tag single-nucleotide polymorphisms in toll-like receptor 9 gene(rs5743845, rs352139) were selected for the analysis. The single-nucleotide polymorphisms at the five sites were identified with microarray hybridization analysis.
Results①rs5744140 There were no significant differences in the distribution of alleles(P=0.447,OR=1.181,95%CI 0.769～1.815) and genotypes(P=0.528) between patients with rheumatic heart disease and controls for rs5744140.②rs1640827 The frequency of A allele was significantly higher in patients with rheumatic heart disease than that in controls(P=0.003,OR=0.495,95%CI 0.307～0.799). The frequencies of G/A and A/A genotypes was significantly higher in patients with rheumatic heart disease(P=0.019).③rs2353476 The frequency of C allele was significantly higher in patients with rheumatic heart disease(P=0.0008,OR=1.703,95%CI 1.244～2.332). And the frequency of C/C genotype was significantly higher in patients with rheumatic heart disease(P=0.002).④rs5743845 There were no significant differences in the distribution of alleles(P=0.413, OR=0.826, 95%CI 0.522～1.307) and genotypes(P=0.684) between patients with rheumatic heart disease and controls for rs5743845.⑤rs352139 There were no significant differences in the distribution of alleles(P=0.478,OR=1.083,95%CI 0.869～1.350) and genotypes(P=0.746) between patients with rheumatic heart disease and controls for rs352139.⑥Haplotype analysis showed increased frequencies of TLR5 CGC(P=0.011) and CAC(P=0.025) haplotypes in patients with rheumatic heart disease when compared to controls.
Conclusion The genetic variants of toll-like receptor 5 gene might be associated with rheumatic heart disease in Chinese Han population, while single-nucleotide polymorphisms rs5743845 and rs352139 in toll-like receptor 9 gene have no association with rheumatic heart disease in Chinese Han population.
引文
[1] Shastry BS. SNP alleles in human disease and evolution. J Hum Genet, 2002, 47(11): 561-566.
[2] Stephens JC, Schneider JA, Tanguay DA, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science, 2001, 293(5529): 489-493.
[3] Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet, 2001, 69(1): 1-14.
[4] Carlson CS, Eberle MA, Rieder MJ, et al. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet, 2003, 33(4): 518-521.
[5] Zhang K, Calabrese P, Nordborg M, et al. Haplotype block structure and its applications in association studies: power and study designs. Am J Hum Genet, 2002, 71(6): 1386-1394.
[6] The International HapMap Consortium. The International HapMap project. Nature, 2003, 426(6968): 789-796.
[7] Adib-ConquyM, Cavaillon JM. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett, 2007, 581(19): 3723-3733.
[8] Lorenz E, Mira JP, Frees KL, et a1. Relevance of mutations in the TLR4 receptors in patients with gram-negative septic shock. Arch Intern Med, 2002, 162(9): 1028-1032.
[9] Michel O, Levan TD, Stern D, et a1. Systemic responsiveness to Lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Chin Immunol, 2003, 112(5): 923-929.
[10] Lorenz E, Mira JP, Frees KL, et a1. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect immun, 2000, 68(11): 6398-640l.
[11] Pifie FJ, Pegoraro IL, Motala AA, et a1. Toll-like receptor 3 gene polymorphisms in South AfricanBlacks with type 1 diabetes. Tissue Antigens, 2005, 66(2): 125-130.
[12]张合喜,邹立君,王友洁.用PCR-SSCP方法检测TLR9基因多态性.新乡医学院学报, 2006, 23( 3): 217-219.
[13] 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(2): 97-98.
[14] Marta M, Daniela B, Nadia P, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol, 2000, 164(11): 5998-6004.
[15] Szabo C. Role of flagellin in the pathogenesis of shock and acute respiratory distress syndrome: therapeutic opportunities. Crit Care Med, 2003, 31(1 Suppl): S39-45.
[16] Liaudet L, Murthy KG, Mabley JG, et al. Comparison of inflammation, organ damage, and oxidant stress induced by salmonella enterica Serovar Muenchen flagellin and serovar Enteritidis lipopolysaccharide. Infect Immun, 2002, 70(1): 192-198.
[17] Liaudet L, Szabo C, Evgenov OV, et al. Flagellin from Gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis. Shock, 2003, 19(2): 131-137.
[18] Xin Z, Jorge AG, Alfredo GT, et al. Flagellin of enteropathogenic Escherichia coli stimulates interleukin-8 production in T84 cells. Infect Immun, 2003, 71(4): 2120-2129.
[19]Steven BM, Pillip W, Roy RH. Identification of a sequence in human Toll-like receptors 5 required for the binding of Gram-negative flagellin. J Biol Chem, 2003, 278(26): 23624-23629.
[20] Siezen CL, Bont L, Hodemaekers HM, et al. Genetic Susceptibility to Respiratory Syncytial Virus Bronchiolitis in Preterm Children Is Associated With Airway Remodeling Genes and Innate Immune Genes[J]. Pediatr Infect Dis J, 2009, 28(4): 333-335.
[21] Xu J, Lowey J, Wiklund F, et al. The interaction of four genes in the inflammation pathwaysignificantly predicts prostate cancer risk. Cancer Epidemiol Biomarkers Prev, 2005, 14(11 Pt 1): 2563-2568.
[22] Gewirtz AT, Vijay-Kumar M, Brant SR, et al. Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. Am J Physiol Gastrointest Liver Physiol, 2006, 290(6): G1157-1163.
[23] Hawn TR, Wu H, Grossman JM, et al. A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci U S A, 2005, 102(30): 10593-10597.
[24] Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature, 2000, 408(6813): 740-745.
[25] He B, Qiao X, Cerutti A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol. 2004, 173(7): 4479-4491.
[26] Hong J, Leung E, Fraser AG, et al. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J Gastroenterol Hepatol, 2007, 22(11): 1760-1766.
[27] Lachheb J, Dhifallah IB, Chelbi H, et al. Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children. Tissue Antigens, 2008, 71(5): 417-425.
[28] Kauffmann F, Demenais F, Pin I, et al. CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults. Am J Respir Crit Care Med, 2009, 179(5):363-368.
[29] Suzuki H, Suzuki Y, Narita I, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol, 2008, 19(12): 2384-2395.
[30] Tao K, Fujii M, Tsukumo S, et al. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis, 2007, 66(7): 905-909.
[1] Hernandez-Pacheco G., Aguilar-Garcia J, Flores-Dominguez C, et al. MHC classⅡalleles in Mexican patients with rheumatic heart disease[J]. Int J Cardiol, 2003, 92(1): 49-54.
[2] Rehman S, Akhtar N, Ahmad W, et al. Human Leukocyte Antigen(HLA)classⅡassociation with rheumatic heart disease in Pakistan[J]. J Heart Valve Dis, 2007, 16(3): 300-304.
[3] Gündogdu F, Islamoglu Y, Pirim I, et al. Human Leukocyte Antigen(HLA) classⅠandⅡalleles in Turkish patients with rheumatic heart disease[J]. J Heart Valve Dis, 2007, 16(3): 293-299.
[4] Hsiang-Tai Chou, Chien-Hsiun Chen, Jan-Yow Chen, et al. Association of HLA DRB1-DQA1-DQB1 haplotypes with rheumatic heart disease in Taiwan[J]. Int J Cardiol, 2008, 128(3): 434-435.
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[6] Guadalupe Hernández-Pacheco, Carmina Flores-Domínguez, JoséManuel Rodríguez-Pérez. Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease[J]. J Autoimmun, 2003, Volume 21(1): 59-63.
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[8] Ramasawmy R, Spina GS, Fae KC. Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology[J]. Clin Vaccine Immunol, 2008, 15(6): 932-936.
[9]金振晓,纪宗玲.甘露糖结合凝集素基因点突变与风湿性心脏病易感性的关系[J].中华医学杂志, 2001, 81(21): 1284-1286.
[10]李娟,范雪云.转化生长因子-β及基因多态性与纤维化的关系[J].中华劳动卫生职业病杂志, 2004, 22(5): 382-385.
[11] Hsiang-Tai Chou, Chien-Hsiun Chen, Chang-Hai Tsai, Fuu-Jen Tsai. Association between transforming growth factor-β1 gene C-509T and T869C polymorphisms and rheumatic heart disease[J]. Am Heart J, 2004, 148(1): 181-186.
[12]李晓丹,董天皞,倪红. IL-10基因单核苷酸多态性与疾病易感性的研究进展[J].国际遗传学杂志, 2006, 29(5): 368-371.
[13] Snieder H, Van Doornen LJP, Boomsma DI. Age-dependency of gene expression for plasma lipids, lipoproteins and apolipoproteins[J]. Am J Hum Genet, 1997, 60(3): 638-650.
[14] Settin A, Abdel-Hady H, El-Baz R, et al. Gene polymorphisms of TNF-α-308, IL-10-1082, IL-6-174, and IL-1RaVNTR related to susceptibility and severity of rheumatic heart disease[J]. Pediatr Cardiol, 2007, 28(5): 363-371.
[2] Stephens JC, Schneider JA, Tanguay DA, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science, 2001, 293(5529): 489-493.
[3] Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet, 2001, 69(1): 1-14.
[4] Carlson CS, Eberle MA, Rieder MJ, et al. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet, 2003, 33(4): 518-521.
[5] Zhang K, Calabrese P, Nordborg M, et al. Haplotype block structure and its applications in association studies: power and study designs. Am J Hum Genet, 2002, 71(6): 1386-1394.
[6] The International HapMap Consortium. The International HapMap project. Nature, 2003, 426(6968): 789-796.
[7] Adib-ConquyM, Cavaillon JM. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett, 2007, 581(19): 3723-3733.
[8] Lorenz E, Mira JP, Frees KL, et a1. Relevance of mutations in the TLR4 receptors in patients with gram-negative septic shock. Arch Intern Med, 2002, 162(9): 1028-1032.
[9] Michel O, Levan TD, Stern D, et a1. Systemic responsiveness to Lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Chin Immunol, 2003, 112(5): 923-929.
[10] Lorenz E, Mira JP, Frees KL, et a1. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect immun, 2000, 68(11): 6398-640l.
[11] Pifie FJ, Pegoraro IL, Motala AA, et a1. Toll-like receptor 3 gene polymorphisms in South AfricanBlacks with type 1 diabetes. Tissue Antigens, 2005, 66(2): 125-130.
[12]张合喜,邹立君,王友洁.用PCR-SSCP方法检测TLR9基因多态性.新乡医学院学报, 2006, 23( 3): 217-219.
[13] 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(2): 97-98.
[14] Marta M, Daniela B, Nadia P, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol, 2000, 164(11): 5998-6004.
[15] Szabo C. Role of flagellin in the pathogenesis of shock and acute respiratory distress syndrome: therapeutic opportunities. Crit Care Med, 2003, 31(1 Suppl): S39-45.
[16] Liaudet L, Murthy KG, Mabley JG, et al. Comparison of inflammation, organ damage, and oxidant stress induced by salmonella enterica Serovar Muenchen flagellin and serovar Enteritidis lipopolysaccharide. Infect Immun, 2002, 70(1): 192-198.
[17] Liaudet L, Szabo C, Evgenov OV, et al. Flagellin from Gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis. Shock, 2003, 19(2): 131-137.
[18] Xin Z, Jorge AG, Alfredo GT, et al. Flagellin of enteropathogenic Escherichia coli stimulates interleukin-8 production in T84 cells. Infect Immun, 2003, 71(4): 2120-2129.
[19]Steven BM, Pillip W, Roy RH. Identification of a sequence in human Toll-like receptors 5 required for the binding of Gram-negative flagellin. J Biol Chem, 2003, 278(26): 23624-23629.
[20] Siezen CL, Bont L, Hodemaekers HM, et al. Genetic Susceptibility to Respiratory Syncytial Virus Bronchiolitis in Preterm Children Is Associated With Airway Remodeling Genes and Innate Immune Genes[J]. Pediatr Infect Dis J, 2009, 28(4): 333-335.
[21] Xu J, Lowey J, Wiklund F, et al. The interaction of four genes in the inflammation pathwaysignificantly predicts prostate cancer risk. Cancer Epidemiol Biomarkers Prev, 2005, 14(11 Pt 1): 2563-2568.
[22] Gewirtz AT, Vijay-Kumar M, Brant SR, et al. Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. Am J Physiol Gastrointest Liver Physiol, 2006, 290(6): G1157-1163.
[23] Hawn TR, Wu H, Grossman JM, et al. A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci U S A, 2005, 102(30): 10593-10597.
[24] Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature, 2000, 408(6813): 740-745.
[25] He B, Qiao X, Cerutti A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol. 2004, 173(7): 4479-4491.
[26] Hong J, Leung E, Fraser AG, et al. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J Gastroenterol Hepatol, 2007, 22(11): 1760-1766.
[27] Lachheb J, Dhifallah IB, Chelbi H, et al. Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children. Tissue Antigens, 2008, 71(5): 417-425.
[28] Kauffmann F, Demenais F, Pin I, et al. CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults. Am J Respir Crit Care Med, 2009, 179(5):363-368.
[29] Suzuki H, Suzuki Y, Narita I, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol, 2008, 19(12): 2384-2395.
[30] Tao K, Fujii M, Tsukumo S, et al. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis, 2007, 66(7): 905-909.
[1] Hernandez-Pacheco G., Aguilar-Garcia J, Flores-Dominguez C, et al. MHC classⅡalleles in Mexican patients with rheumatic heart disease[J]. Int J Cardiol, 2003, 92(1): 49-54.
[2] Rehman S, Akhtar N, Ahmad W, et al. Human Leukocyte Antigen(HLA)classⅡassociation with rheumatic heart disease in Pakistan[J]. J Heart Valve Dis, 2007, 16(3): 300-304.
[3] Gündogdu F, Islamoglu Y, Pirim I, et al. Human Leukocyte Antigen(HLA) classⅠandⅡalleles in Turkish patients with rheumatic heart disease[J]. J Heart Valve Dis, 2007, 16(3): 293-299.
[4] Hsiang-Tai Chou, Chien-Hsiun Chen, Jan-Yow Chen, et al. Association of HLA DRB1-DQA1-DQB1 haplotypes with rheumatic heart disease in Taiwan[J]. Int J Cardiol, 2008, 128(3): 434-435.
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