中国北方汉族抗中性粒细胞胞浆抗体相关性小血管炎与TLR2/9基因多态性的相关性

Association of Toll-like receptor 2 and 9 polymorphisms with antineutrophil cytoplasmic autoantibodies-associated vasculitides in northern Han Chinese

目的探讨Toll样受体2／9（Tolllikereceptor2／9，TLR2／9）基因单核苷酸多态性（singlenucleotidepolymorphisms，SNP）与中国北方汉族人群抗中性粒细胞胞浆抗体（anti．neutrophilcytoplamicautoantibody，ANCA）相关性小血管炎（ANCA．associatedvasculitis，AAV）易感性的相关性。方法采用回顾性病例对照设计。随机收集2011年11月至2012年12月北京协和医院门诊和住院的176例AAV患者，包括肉芽肿性多血管炎（granulomatosiswithpolyangiitis，GPA）100例、显微镜下多血管炎（microscopicpolyangitis，MPA）76例，以及485名健康人，针对其TLR2／9基因标签SNP（taggerSNP）位点，用基质辅助激光解析电离飞行时间质谱（Matrix assisted laser desorpfion ionization time of flight masss pectrometry，MALDI-TOF-MS）进行TLR2／9基因分型。对检测数据先进行Hardy．Weinberg和基因型（HWE）平衡检验；然后，对等位基因频率和基因型频率进行关联分析：并比较各SNP位点在各组中等位基因频率：同时进行单体型分析。结果Rs3804100（TLR2）的C等位基因频率在MPA组[39．5％（60／76）]和健康对照组[27．9％（271／485）]的差异有统计学意义（Pc=O．026，OR1．68，95％CI1．18～2．40）；而在GPA组[26．5％（53／100）]和健康对照组的差异无统计学意义（x2=0．17，pc〉0．05l在单体型分析中，区域2的CC单体型频率在MPA组较健康对照组显著升高[39．5％（60／76）比27．6％（134／485）]，且差异有统计学意义（x2=8．74，Pc=O．022）。AAV组rs352139和rsl87084（TLR9）与健康对照组的等位基因频率比较，差异均无统计学意义（矿分别为0．29、o．05，Pc均〉0．05）。结论首次发现TLR2rs3804100位点与中国北方汉族人群MPA的易感性相关，而与GPA可能不相关。TLR9（rs352139、rsl87084）可能与中国北方汉族人群的AAV（GPA和MPA）均不相关。

Objective To investigate the role of the Toll-like receptor 2/9 （TLR2/9） single nucleotide polymorphisms（SNPs） in conferring susceptibility to the ANCA-associated vasculitis （AAV）. Methods A retrospective grouped case-control design was applied. Matrix assisted laser desorption ionization time of flight mass spectrometry （MALDI-TOF-MS） was used to genotype the SNPs of TLR2/9 in 176 Chinese Hart patients with AAV [100 cases of granulomatosis with polyangiitis （GPA）, 76 cases of microscopic polyangitis （MPA）] and 485 ethnically matched healthy controls randomly collected in inpatient/ outpatient department of Beijing Union Medical College Hospital from November 2011 to December 2012. The allele and genotype frequencies were used for association analysis. The distributions of genotype frequencies in each group were compared and haplotype frequencies were analyzed. Results A synonymous SNPs inthe exon of TLR2 （rs3804100） was closely associated with the risk of MPA, and the frequencies of allele C in MPA patients and healthy controls were 39.5%（60/76） and 27.9%（271/485）, respectively （Pc=0.026, 0R1.68, 95%CI 1.18-2.40）. But the frequency of allele C in GPA patients was 26.5%（53/100） and was not associated with GPA （x2=0.17, Pc 〉 0.05）. Haplotype analysis showed CC haplotype frequencies in the region of 2 MPA groups were significantly higher than in the control group [39.5%（60/76） vs 27.6%（134/485）], and the differences were statistically significant （3（2=8.74, Pc=0.022）. Also, there were no significant differences in the distribution of two TLR9 SNPs（rs352139, rs187084） between patients and healthy controls （Z2=0.29, 0.05, all of Pc 〉 0.05 respectively）. Conclusion These results suggested that rs3804100 （TLR2） is closely associated with MPA but not GPA for the first time, while TLR9 SNPs （rs352139, rs 187084） may be not associated with AAV, GPA or MPA.