肿瘤坏死因子-α受体基因多态性与强直性脊柱炎相关性研究

Association of tumor necrosis factor-α receptor gene single nucleotide polymorphism in patients with ankylosing spondylitis

目的探讨肿瘤坏死因子（TNF）-α受体基因单核苷酸多态性（sNP）对强直性脊柱炎（AS）患者易感性、临床表现型和抗TNF-α拮抗剂治疗近期、远期疗效的影响。方法采用连接酶检测聚合酶链反应（LDR—PeR）法检测215例AS患者和216名健康者TNFRSF1A基因＋36A／G（rs767455）位点和-383A／C（r52234649）位点、TNFRSF1B基因＋196T／G（rs1061622）位点SNP。采用t检验V检验和方差分析进行统计学分析。结果①As患者和健康对照人群中TNFRSF1A基因rs767455位点A等位基因分布频率（86．8％，91．5％）和G等位基因分布频率（13．2％，8．5％）的分布不同（X^2=4．627，P=-0．0315）；纯合型在As组和对照组中分布频率为74．6％（150／201）和83．9％（177／211），杂合型为25．4％（51／201）和16．1％（34／211），差异有统计学意义舒=5．390，P=0．020）。TNFRSF1A基因rs2234649位点和TNFRSF1B基因rs1061622位点SNP在AS和对照组间差异均无统计学意义（P〉0．05）。单倍体型rs1061622T．rs2234649A-rs 767455G携带者）使AS的易感性明显增加（11．5％与6．9％）（OR=1．753，95％CI：1．078～2．852，P=-0．022）。②方差分析结果显示：AS患者中TNFRSFIB基因rs1061622位点3个基因型组间在晨僵持续时间（F=3．168，P=0．044）和外周关节压痛数（F=4．598，P=-0．011）上差异有统计学意义。AS患者中TNFRSF1A基因rs2234649位点3个基因型组间在疾病功能指数上差异有统计学意义（F=5．783，P=0．004）。AS患者中TNFRSFIA基因rs767455位点各基因型间上述指标差异均无统计学意义（P〉0．05）。③44例AS患者采用抗TNF-α拮抗剂治疗，TNFRSF1A基因和TNFRSF1B基因SNP与生物制剂治疗的3个月及12个月时疗效均无关（P〉0，05）。结论安徽籍汉族人群TNFRSF1A基因rs767455位点SNP与AS易感性有关；单倍体型（rs1061622T-rs2234649A-rs767455G）可能增加疾病的易感性。TNFRSFIB基因rs1061622位点SNP与AS疾病活动性有关；TNFRSF1A基因r52234649位点SNP与AS疾病功能指数有关。TNFRSF1A和TNFRSF1B基因SNP与TNF-α拮抗剂疗效无关。

Objective To investigate the value of tumor necrosis factor （TNF）-α receptor gene, TNFRSF1A ＋36A/G （rs767455） and -383A/C （rs2234649）, TNFRSF1B ＋ 196T/G （rs 1061622 ） single nucleotide polymorphism （SNP） for the susceptibility to ankylosing spondylitis （AS） and the relationship between SNP and AS. T test, Chi-square test, and ANOVA were used for statististical analysis. Methods Two hundred and fifteen patients who had definite diagnosis of AS and 216 healthy blood donors were involved in this study. SNPs of TNF-ot receptor gene： TNFRSF1A ＋36A/G（rs767455）, -383A/C （rs2234649） and TNFRSF1B＋196T/ G （rs1061622） were detected with the ligase detection reaction （LDR-PCR） method. Results （1） Distribution frequencies of A alleles （86.8%, 91.5% ） and G alleles （ 13.2%, 8.5% ） of TNFRSF1A （rs767455） in AS and controls were significantly different with each other （X2=4.627, P=0.0315）, while the distribution frequency in group of homozygotes （AA or GG genotype） in AS and controls were 74.6%（150/201） and 85.9%（177/211）,the frequencies in group of heterozygotes （AG） were 25.4% （51/201） and 16.1%（34/211）0（2= 5.390, P= 0.020）. Frequency of alleles and the genotypes of TNFRSF1A （rs2234649） and TNFRSF1B （rs1061622） between AS and control group were similar（P〉0.05 ）. It also demonstrated that TNF-ot receptor gene haplotype （rs1061622T-rs2234649A-rs767455G） carriers apparently increased the susceptibility to AS （11.5% vs 6.9%） （OR： 1.753, 95%CI： 1.078-2.852, P=0.022）. （2） Analysis of variance found that the duration of morning stiffness （F=3.168, P=0.044） and peripheral joint tenderness counts （F=4.598, P=0.011 ） among the three genotype groups of TNFRSF1B （rs1061622） in patient with AS were evidently differed with each other. Bath AS functional index （BASFI） among different genotype groups of TNFRSF1A （rs2234649） in AS had remarkable diversity （F=5.783, P=0.004）. None of above indicators among groups of different genotypes of TNFRSF1A （rs767455） in AS were uniform （P〉0.05）. （3） Forty-four patients were treated with TNF-c~ antagonist （entanercept）, 25 mg, subcutaneous injection, twice weekly for 3 months, then followed with Sulfaslazine （SASP） 2.0 g/d and Celecoxib 0.4 g/d for another 9 months. ASAS20 was the primary endpoint for the evaluation of therapeutic effect at the visit of 3 month and 12 month. No associations were found between SNP and short or long term outcome of treatment with TNF-o~ antagonist in AS （P〉0.05）. Conclusion TNFRSF1A （rs767455） SNP correlates with susceptibility to AS in Anhui Han local patients. Carriers of TNF- c~ receptor gene haplotype （rs1061622T-rs2234649A-rs767455G） may increase the susceptibility to AS. SNP of TNFRSF1B （rs1061622） is associated with disease activity in AS, while SNP of TNFRSF1A（rs2234649） relates to functional index of the disease. There is no association between SNP of TNFRSF1A / TNFRSF1B and short or long term outcome of treatment with TNF-α antagonist in AS.