类风湿关节炎患者的HLA-DR4表型和TNFα-308、TNFRII+196多态性的作用研究
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摘要
背景:类风湿关节炎(RA)是一种病因不明的自身免疫性疾病,遗传、免疫分子调节在发病机制上起着主要作用。研究认为具有特定的HLA抗原者(如HLA-DR_4),当受到外界刺激或发生自身改变时,HLA的抗原决定簇发生了改变,借助共同表位和基因剂量效应,使具有HLA的有核细胞成为免疫活化的靶子,产生T细胞激活及一系列免疫介质如细胞因子的释放,导致RA发生。本研究试图进一步探索HLA-DR_4表型与细胞因子肿瘤坏死因子(TNF-α)及其受体(TNFRII)的单核甘酸多态性(SNP)的相互作用在RA的发病中的影响。
目的:通过对RA患者HLA-DR_4表型和TNFα-308、TNFRⅡ+196的多态性之间相互作用的研究,探讨基因对RA患病风险、基因对相应的细胞因子浓度和临床病情指标的影响,从而进一步探索3个基因在RA发病中的作用。
方法:确定112例RA患者和129例健康对照者为研究对象,首先抽提外周血白细胞的基因组DNA,然后用PCR-SSP检测HLA-DR_4表型和PCR-RFLP检测TNFα的-308位点和TNFRⅡ的+196位点的多态性,采用ELISA检测外周血清TNF-α、sTNFRⅡ浓度,最后收集临床病情指标资料(包括性别、年龄、病程、休息痛VAS评分、压痛关节数、肿胀关节数、握力、晨僵时间、ESR、CRP、RF、关节功能、x线分期)进行分析。
结果:
(1) HLA-DR_4表型在RA患者组(50%)与健康者组(26.36%)阳性率的差异有明显的统计学意义(P=0.000),HLA-DR_4(+)使得患者发生RA的风险较健康者升高了2.794倍(95%CI:1.630-4.790),性别的分层分析发现HLA-DR_4(+)使得女性患者发生RA的风险升高了3.556倍(95%CI:1.811-6.979)。
(2) RA患者组与健康者组的TNFα-308等位基因型AA/GA/GG(0/8/104 vs 2/23/104,P=0.010)、少见等位基因型(AA+GA)/GG(8/104vs 25/104,P=0.006)和等位基因A/G(8/216 vs 27/231,P=0.004)构成比的差异有明显的统计学意义,TNFα-308少见等位基因型(AA+GA)和等位基因A使得患者发生RA的风险性较健康者升高3.125倍(95%CI:1.347-7.248)和3.156倍(95%CI:1.403-7.097)。性别的分层分析发现RA男患者组与男健康者组的TNFα-308等位基因型AA/GA/GG(0/2/34 vs 1/12/32,P=0.015)、少见等位基因型(AA+GA)/GG(2/34 vs13/32,P=0.007)和等位基因A/G(2/70 vs 14/76,P=0.007)构成比的差异有明显的统计学意义,TNFα-308少见等位基因型(AA+GA)和等位基因A使得男性发生RA的风险升高了6.906倍(95%CI:1.444-33.031)和6.447倍(95%CI:1.415-29.383)。
(3)RA患者组与健康者组的TNFRⅡ+196等位基因型GG/TG/TT(5/62/45 vs 9/56/64)、少见等位基因型(GG+TG)/TT(67/45 vs 65/64)、等位基因G/T(72/152 vs 74/184)构成比的差异没有明显的统计学意义,性别的分层分析发现等位基因型GG/TG/TT在女患者与女健康者之间的差异(3/49/24 vs 8/28/48,P=0.000)具有明显的统计学意义;少见等位基因型(GG+TG)/TT在女性患者与女健康者(52/24 vs 36/48,P=0.001)、男性患者与男健康者(15/21 vs 29/16,P=0.041)之间的差异具有明显的统计学意义,使得女性发生RA的风险升高2.889倍(95%CI:1.510-5.526),男性发生RA的风险降低到0.394倍(95%CI:0.160-0.970);而等位基因G/T的性别分层差异没有统计学意义。
(4)HLA-DR_4、TNFα-308组成的5种组合基因型中,HLADR_4(+)TNFα-308(GG)基因型使得患者发生RA的风险较HLADDR_4(-)TNFα-308(GG)基因型增高2.931倍(95%CI:1.642-5.233)。
(5)HLA-DR_4、TNFRⅡ+196组成的6种组合基因型中,HLA-DR_4(+)TNFRⅡ+196(TT)基因型与HLA-DR_4(+)TNFRⅡ+196(TG)基因型使得患者发生RA的风险较HLA-DR_4(-)TNFRⅡ+196(TT)基因型分别增高2.476倍(95%CI:1.120-5.473)和6.136倍(95%CI:2.548-14.775),HLA-DR_4(+)TNFRRⅡ+196(TG)基因型使得患者发生RA的风险较HLA-DR_4(-)TNFRⅡ+196(TG)基因型增高4.313倍(95%CI:1.851-10.050)。
(6) TNFα-308、TNFRⅡ+196组成的7种组合基因型中,TNFα-308(GA)TNFRⅡ+196(TT)基因型和TNFα-308(GA)TNFRⅡ+196(TG)基因型使得患者发生RA的风险较TNFα-308(GG)TNFRⅡ+196(TG)基因型分别降低到0.212倍(95%CI:0.056-0.804)和0.282倍(95%CI:0.084-0.945)。
(7) HLA-DR_4、TNFα-308、TNFRⅡ+196组成的11种组合基因型中,HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TT)基因型和HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+1 96(TG)基因型较HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TT)基因型使患者发生RA的风险升高2.64倍(95%CI:1.124-6.202)和5.8倍(95%CI:2.297-14.646);HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TG)基因型较HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TG)基因型使得患者发生RA的风险性升高了4倍(95%CI:1.637-9.775)。
(8) RA患者组与健康者组的TNF-α浓度(pg/ml)的差别(34.56±21.04 vs 20.63±15.46,P=0.000)具有统计学意义。特定组合基因型的RA患者与健康者组的血清TNF-α浓度差异具有统计学意义。析因设计的方差分析发现TNFα-308基因型~*TNFRⅡ+196基因型(P=0.037)、HLA-DR_4表型~*TNFα-308基因型~*TNFRⅡ+196基因型(P=0.009)以及组别(P=0.000)、组别~*HLA-DR_4表型~*TNFα-308基因型(P=0.001)的交互作用对TNF-α浓度的影响具有统计学意义。
(9)RA患者组与健康者组之间的sTNFRⅡ浓度(ng/ml)的差别(8.544±6.29 vs 5.48±4.41,P=0.000)具有统计学意义。特定组合基因型的RA患者与健康者组的血清sTNFRⅡ浓度差异具有统计学意义。析因设计的方差分析发现组别(P=0.000)、组别~*性别~*HLA-DR_4表型(P=0.038)、组别~*TNFa-308基因型(P=0.025)、组别~*TNFα-308基因型~*TNFRⅡ+196基因型(P=0.037)的交互作用对sTNFRⅡ浓度的影响具有统计学意义。
(10)单一基因型对于RA病情的影响:HLA-DR_4(+)与HLA-DR_4(-)患者比较,发病年龄(岁)提早(42.59±14.07 vs 47.36±10.89,P=0.047),RF浓度(IU/mL)较高(471.32±435.22 vs 308.13±331.34,P=0.028)。TNFα-308的2种基因型GA/GG的患者比较没有发现有统计学意义的差异。TNFRⅡ+196的3种基因型GG/TG/TT的RA患者比较,其性别比(男/女)构成的差异(2/3 vs 13/49 vs 21/24,P=0.018)和RF浓度(IU/mL)的差异(917.00±674.77 vs 353.58±362.85 vs 380.93±365.39,P=0.008)有统计学意义。
(11)组合基因型对RA病情的影响:HLA-DR_4与TNFα-308的组合基因型中,HLA-DR_4(+)TNFα-308(GG)基因型与HLA-DR_4(-)TNFα-308(GG)基因型之间相比在发病年龄(岁)的差异(42.35±14.27vs 47.71±10.95,P=0.033)有统计学意义;而TNFRⅡ+196与其它2个基因的两两组合的基因型和3个基因组合的基因型,其间的比较只有性别构成差异的统计学意义最终保留下来。析因设计资的方差分析,发现HLA-DR_4表型(P=0.013)、TNFRⅡ+196基因型(P=0.005)、性别~*TNFRⅡ+196基因型(P=0.043)的交互作用对RF滴度的影响具有统计学意义。
结论:
(1) HLA-DR_4表型(+)提高了RA患者,尤其是RA女性患者的患病风险。
(2) TNF-α基因-308位点的多态性提高了RA患者、尤其是RA男性患者的患病风险。
(3) TNFRⅡ基因+196位点的多态性与RA患者患病风险之间的关系比较复杂。
(4)特定的HLA-DR_4、TNFα-308、TNFRⅡ+196组合基因型改变了RA发生的风险:TNFα-308(GG)轻微升高、TNFRⅡ+196(TT)轻微降低和TNFRⅡ+196(TG)显著升高基于HLADR_4基础上的RA患病风险。
(5)血清TNF-α水平的差异与基因、疾病、疾病和基因二者之间的交互作用有关,而sTNFRⅡ水平的差异与疾病、疾病和性别和基因三者之间的交互作用有关。
(6)单一基因和组合基因型对于RA病情的影响仅体现在某些方面,如发病年龄、性别比构成及RF浓度的高低,而多因素的共同作用对RF滴度的差异有影响。
Backgroud:
Rheumatoid Arthritis(RA) is an autoimmune disease which etiology is unknown. Heredity and immunological regulation have played significant roles in pathogenesis. Special human leucocyte antigen(HLA) which was confronted with external stimuli or altered by itself had been changed by shared epitope and dosage effect of gene. Nucleated cells who carried HLA become the target of immunological activation and T cell was activated, then a series of immunogenic molecules were released such as cytokines which induced the occurrence of RA. So we want to keep up investigating furthurly if the interaction among HLA-DR_4 phenotype and Tumor Necrosis Factor(TNF) and its receptor Tumor Necrosis Factor Recepor(TNFR) by Single Nucleotide Polymorphism (SNP) could influence the occurrence of RA.
Objective:
By investigating the interactions among HLA-DR_4 phenotype and TNF and TNFR by SNP, we want to acquire the information about the effects of three genes on RA risk of onset and concentration of cytokines and clinical manifestation which could help us to apprehend furthurly the pathogenesis of RA.
Methods:
Our study objects were 112 RA patients and 129 Healthy Subjects. Genomic DNA of white blood cell were extracted, then PCR-SSP was used to determine phenotype of HLA-DR_4 and PCR-RFLP were used to genotype for the A/G polymorphism at -308 position of TNF-αgene and the T/G polymorphism at +196 position of TNFRⅡgene. Levels of TNF-α、sTNFRⅡwere measured by using ELISA. Finally clinical features of RA patients including sex、age、disease duration、VAS of rest pain、tender joints of 28、swollen joints of 28、grip、time of morning stiffness、ESR、CRP、RF、function of joints、radiologiucal stages were measured.
Results:
(1) The difference in positive rate of HLA-DR_4 phenotype between RA patients (50%) and healthy subjects (26.36%) had statistical significance (P=0.000). Positive HLA-DR_4 increased risk of onset in RA patients 2.794 times than that in healthy subjects[95%Confidence Index(CI):1.630-4.790]. Stratified analysis for sex showed Positive HLA-DR_4 increased risk of onset in female RA patients 3.556 times than that in female healthy subjects [95%CI: 1.811 -6.979].
(2) The difference of composition in allelotype AA/GA/GG (0/8/104 vs 2/23/104, P=0.010)、rare allelotype (AA+GA)/GG (8/104 vs 25/104, P=0.006) and allele A/G (8/216 vs 27/231, P = 0.004) on TNFα-308 between RA patients and healthy subjects had statistical significance. Rare allelotype (AA+GA) and allele A on TNFα-308 increased risk of onset in RA patients 3.125 times (95%CI: 1.347-7.248) and 3.156 times (95%CI: 1.403-7.097) than that in healthy subjects. Stratified analysis for sex showed the difference of composition in allelotype AA/GA/GG (0/2/34 vs 1/12/32, P=0.015)、rare allelotype (AA+GA)/GG (2/34 vs 13/32, P=0.007) and allele A/G (2/70 vs 14/76, P=0.007) on TNFα-308 between male RA patients and male healthy subjects still existed. Rare allelotype (AA+GA) and allele A/G on TNFα-308 increased risk of onset in male RA patients 6.906 times (95%CI: 1.444-33.031) and 6.447 times (95%CI: 1.415-29.383) than that in male healthy subjects .
(3) The difference of composition in allelotype GG/TG/TT (5/62/45 vs 9/56/64)、rare allelotype (GG+TG)/TT (67/45 vs 65/64) and allele G/T (72/152 vs 74/184) on TNFRⅡ+196 between RA patients and healthy subjects had no statistical significance. Stratified analysis for sex showed the difference in allelotype GG/TG/TT (3/49/24 vs 8/28/48, P=0.000) on TNFRⅡ+196 between female RA patients and female healthy subjects had statistical significance. The difference in rare allelotype (GG+TG) /TT on TNFRⅡ+196 between female RA patients and female healthy subjects (52/24 vs 36/48, P=0.001) and between male RA patients and male healthy subjects (15/21 vs 29/16, P=0.041) had statistical significance,which increased risk of onset in female RA patients 2.889 times(95%CI: 1.510-5.526) than that in female healthy subjects and lowered risk of onset in male RA patients 0.394 times (95%CI: 0.160-0.970) than that in male healthy subjects. However, there was no statistical significancant difference in allele G/T on TNFRⅡ+196 between RA patients and healthy subjects.
(4) Among 5 kinds of allele genotypes combination with HLA-DR_4 and TNFα-308 ,HLA-DR_4(+)TNFα-308(GG) increased risk of onset in RA patients 2.931 times (95%CI:1.642-5.233) than that in HLADR_4(-) TNFα-308(GG) of healthy subjects.
(5) Among 6 kinds of allele genotypes combination with HLA-DR_4 and TNFRⅡ+196, HLA-DR_4(+)TNFRⅡ+196(TT) and HLA-DR_4(+) TNFRⅡ+196(TG) increased risk of onset in RA patients 2.476 times (95%CI:1.120-5.473) and 6.136 times (95%CI:2.548-14.775) than that in HLA-DR_4(-)TNFRⅡ+196(TT) of healthy subjects,HLA- DR_4(+)TNFRⅡ+196(TG) increased risk of onset in RA patients 4.313 times (95%CI: 1.851-10.050) than that in HLA-DR_4(-)TNFRⅡ+196(TG) of healthy subjects.
(6) Among 7 kinds of allele genotypes combination with TNFα-308 and TNFRⅡ+196, TNFα-308(GA)TNFRⅡ+196(TT) and TNFα-308(GA) TNFRⅡ+196(TG) lowered risk of onset in RA patients 0.212 times (95%CI: 0.056-0.804) and 0.282 times (95%CI:0.084-0.945) than that in TNFα-308(GG) TNFRⅡ+196 (TG) of healthy subjects.
(7) Among 11 kinds of allele genotypes combination with HLA-DR_4、TNFα-308 and TNFRⅡ+196, HLA-DR_4(+)TNFα-308(GG) TNFRⅡ+196(TT) and HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TG) increased risk of onset in RA patients 2.64 times (95%CI:1.124-6.202) and 5.8 times (95%CI:2.297- 14.646) than that in HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TT) of healthy subjects. HLA-DR_4(+)TNFα-308 (GG)TNFRⅡ+196 (TG) increased risk of onset in RA patients 4 times (95%CI: 1.637-9.775) than that in HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TG) of healthy subjects.
(8) The difference of concentration of serum TNF-α(pg/ml) between RA patients and healthy subjects (34.56±21.04 vs 20.63±15.46,P=0.000) had statistical significance. The difference of TNF-αconcentration between certain allele genotype combination of RA patients and healthy subjects had statistical significance. By analysis of variance of factorial design, interactions existing in mfgene~*tnfrgene(P=0.037)、dr_4~*tnfgene ~*tnfrgene(P=0.009) and group(P=0.000)、group~*dr_4~*tnfgene(P=0.001) had statistical significant influence to level of TNF-α.
(9) The difference of concentration of serum sTNFRⅡ(ng/ml) between RA patients and healthy subjects (8.54±6.29 vs 5.48±4.41, P=0.000) had statistical significance. The difference of sTNFRⅡconcentration between certain allele genotype combination of RA patients and healthy subjects had statistical significance. By analysis of variance of factorial design, interactions existing in group(P=0.000)、group~*sex ~*dr4(P=0.038)、group~*tnfgene(P=0.025)、group~*tnfgene~*tnfrgene (P=0.037) had statistical significant influence to level of sTNFRⅡ.
(10) A single allelotype had a certain influence to clinical manifestations of RA. Patients of HLA-DR_4(+) had more earlier onset age (42.59±14.07 vs 47.36±10.89, P=0.047) and higher level (IU/mL)of RF (471.32±435.22 vs 308.13±331.34, P=0.028 ) than those of HLA-DR_4(-).There were no statistical significance between patients of TNFα-308(GG) and TNFα-308(GA). Among patients of three kind of TNFRⅡ+196 allelotype GG/TG/TT, there were statistical significance in sex composition male/female (2/3 vs 13/49 vs 21/24,P=0.018) and level(IU/mL)of RF(917.00±674.77 vs 353.58±362.85 vs 380.93±365.39, P=0.008).
(11) Allele genotypes combination also had a certain influence to clinical manifestations of RA. The difference of onset of disease between HLA-DR_4(+)TNFα-308(GG) and HLA-DR_4(-)TNFα-308(GG) (42.35±14.27 vs 47.71±10.95, P=0.033) had statistical significance. Combinations of TNFRⅡ+196 with one or two of other Allele only had statistical significance in sex composition.By analysis of variance of factorial design, interactions existing in dr4(P=0.013)、tnfrgene (P=0.005)、sex~*tnfrgene(P=0.043) had statistical significant influence to level of RF.
Conclusions:
(1) Positive HLA-DR_4 phenotype increased risk of onset in RA patients especially female RA patients.
(2) Polymorphism of TNF-αat position -308 increased risk of onset in RA patients especially male RA patients.
(3) The relationship between polymorphism of TNFRⅡat position +196 and RA was sophisticated.
(4) Certain allele genotype combination of HLA-DR_4、TNFα-308 and TNFRⅡ+196 altered the risk of onset, TNFα-308(GG) increased slightly、TNFRⅡ+196(TT) decreased slightly and TNFRⅡ+196(TG) increased obviously the risk of onset based on HLADR4 phenotype.
(5) The difference in level of TNF-αwas related to allele gene、disease、interactions between disease and allele gene. However, the difference in level of sTNFRⅡwas related to disease、interactions among disease、sex and allele.
(6) The influence of Single allelotype and Allele genotypes combination mainly embodyied in some aspcets such as onset age、sex composition and level of RF. Interaction of multi-factor leaded to difference in level of RF.
目的:通过对RA患者HLA-DR_4表型和TNFα-308、TNFRⅡ+196的多态性之间相互作用的研究,探讨基因对RA患病风险、基因对相应的细胞因子浓度和临床病情指标的影响,从而进一步探索3个基因在RA发病中的作用。
方法:确定112例RA患者和129例健康对照者为研究对象,首先抽提外周血白细胞的基因组DNA,然后用PCR-SSP检测HLA-DR_4表型和PCR-RFLP检测TNFα的-308位点和TNFRⅡ的+196位点的多态性,采用ELISA检测外周血清TNF-α、sTNFRⅡ浓度,最后收集临床病情指标资料(包括性别、年龄、病程、休息痛VAS评分、压痛关节数、肿胀关节数、握力、晨僵时间、ESR、CRP、RF、关节功能、x线分期)进行分析。
结果:
(1) HLA-DR_4表型在RA患者组(50%)与健康者组(26.36%)阳性率的差异有明显的统计学意义(P=0.000),HLA-DR_4(+)使得患者发生RA的风险较健康者升高了2.794倍(95%CI:1.630-4.790),性别的分层分析发现HLA-DR_4(+)使得女性患者发生RA的风险升高了3.556倍(95%CI:1.811-6.979)。
(2) RA患者组与健康者组的TNFα-308等位基因型AA/GA/GG(0/8/104 vs 2/23/104,P=0.010)、少见等位基因型(AA+GA)/GG(8/104vs 25/104,P=0.006)和等位基因A/G(8/216 vs 27/231,P=0.004)构成比的差异有明显的统计学意义,TNFα-308少见等位基因型(AA+GA)和等位基因A使得患者发生RA的风险性较健康者升高3.125倍(95%CI:1.347-7.248)和3.156倍(95%CI:1.403-7.097)。性别的分层分析发现RA男患者组与男健康者组的TNFα-308等位基因型AA/GA/GG(0/2/34 vs 1/12/32,P=0.015)、少见等位基因型(AA+GA)/GG(2/34 vs13/32,P=0.007)和等位基因A/G(2/70 vs 14/76,P=0.007)构成比的差异有明显的统计学意义,TNFα-308少见等位基因型(AA+GA)和等位基因A使得男性发生RA的风险升高了6.906倍(95%CI:1.444-33.031)和6.447倍(95%CI:1.415-29.383)。
(3)RA患者组与健康者组的TNFRⅡ+196等位基因型GG/TG/TT(5/62/45 vs 9/56/64)、少见等位基因型(GG+TG)/TT(67/45 vs 65/64)、等位基因G/T(72/152 vs 74/184)构成比的差异没有明显的统计学意义,性别的分层分析发现等位基因型GG/TG/TT在女患者与女健康者之间的差异(3/49/24 vs 8/28/48,P=0.000)具有明显的统计学意义;少见等位基因型(GG+TG)/TT在女性患者与女健康者(52/24 vs 36/48,P=0.001)、男性患者与男健康者(15/21 vs 29/16,P=0.041)之间的差异具有明显的统计学意义,使得女性发生RA的风险升高2.889倍(95%CI:1.510-5.526),男性发生RA的风险降低到0.394倍(95%CI:0.160-0.970);而等位基因G/T的性别分层差异没有统计学意义。
(4)HLA-DR_4、TNFα-308组成的5种组合基因型中,HLADR_4(+)TNFα-308(GG)基因型使得患者发生RA的风险较HLADDR_4(-)TNFα-308(GG)基因型增高2.931倍(95%CI:1.642-5.233)。
(5)HLA-DR_4、TNFRⅡ+196组成的6种组合基因型中,HLA-DR_4(+)TNFRⅡ+196(TT)基因型与HLA-DR_4(+)TNFRⅡ+196(TG)基因型使得患者发生RA的风险较HLA-DR_4(-)TNFRⅡ+196(TT)基因型分别增高2.476倍(95%CI:1.120-5.473)和6.136倍(95%CI:2.548-14.775),HLA-DR_4(+)TNFRRⅡ+196(TG)基因型使得患者发生RA的风险较HLA-DR_4(-)TNFRⅡ+196(TG)基因型增高4.313倍(95%CI:1.851-10.050)。
(6) TNFα-308、TNFRⅡ+196组成的7种组合基因型中,TNFα-308(GA)TNFRⅡ+196(TT)基因型和TNFα-308(GA)TNFRⅡ+196(TG)基因型使得患者发生RA的风险较TNFα-308(GG)TNFRⅡ+196(TG)基因型分别降低到0.212倍(95%CI:0.056-0.804)和0.282倍(95%CI:0.084-0.945)。
(7) HLA-DR_4、TNFα-308、TNFRⅡ+196组成的11种组合基因型中,HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TT)基因型和HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+1 96(TG)基因型较HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TT)基因型使患者发生RA的风险升高2.64倍(95%CI:1.124-6.202)和5.8倍(95%CI:2.297-14.646);HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TG)基因型较HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TG)基因型使得患者发生RA的风险性升高了4倍(95%CI:1.637-9.775)。
(8) RA患者组与健康者组的TNF-α浓度(pg/ml)的差别(34.56±21.04 vs 20.63±15.46,P=0.000)具有统计学意义。特定组合基因型的RA患者与健康者组的血清TNF-α浓度差异具有统计学意义。析因设计的方差分析发现TNFα-308基因型~*TNFRⅡ+196基因型(P=0.037)、HLA-DR_4表型~*TNFα-308基因型~*TNFRⅡ+196基因型(P=0.009)以及组别(P=0.000)、组别~*HLA-DR_4表型~*TNFα-308基因型(P=0.001)的交互作用对TNF-α浓度的影响具有统计学意义。
(9)RA患者组与健康者组之间的sTNFRⅡ浓度(ng/ml)的差别(8.544±6.29 vs 5.48±4.41,P=0.000)具有统计学意义。特定组合基因型的RA患者与健康者组的血清sTNFRⅡ浓度差异具有统计学意义。析因设计的方差分析发现组别(P=0.000)、组别~*性别~*HLA-DR_4表型(P=0.038)、组别~*TNFa-308基因型(P=0.025)、组别~*TNFα-308基因型~*TNFRⅡ+196基因型(P=0.037)的交互作用对sTNFRⅡ浓度的影响具有统计学意义。
(10)单一基因型对于RA病情的影响:HLA-DR_4(+)与HLA-DR_4(-)患者比较,发病年龄(岁)提早(42.59±14.07 vs 47.36±10.89,P=0.047),RF浓度(IU/mL)较高(471.32±435.22 vs 308.13±331.34,P=0.028)。TNFα-308的2种基因型GA/GG的患者比较没有发现有统计学意义的差异。TNFRⅡ+196的3种基因型GG/TG/TT的RA患者比较,其性别比(男/女)构成的差异(2/3 vs 13/49 vs 21/24,P=0.018)和RF浓度(IU/mL)的差异(917.00±674.77 vs 353.58±362.85 vs 380.93±365.39,P=0.008)有统计学意义。
(11)组合基因型对RA病情的影响:HLA-DR_4与TNFα-308的组合基因型中,HLA-DR_4(+)TNFα-308(GG)基因型与HLA-DR_4(-)TNFα-308(GG)基因型之间相比在发病年龄(岁)的差异(42.35±14.27vs 47.71±10.95,P=0.033)有统计学意义;而TNFRⅡ+196与其它2个基因的两两组合的基因型和3个基因组合的基因型,其间的比较只有性别构成差异的统计学意义最终保留下来。析因设计资的方差分析,发现HLA-DR_4表型(P=0.013)、TNFRⅡ+196基因型(P=0.005)、性别~*TNFRⅡ+196基因型(P=0.043)的交互作用对RF滴度的影响具有统计学意义。
结论:
(1) HLA-DR_4表型(+)提高了RA患者,尤其是RA女性患者的患病风险。
(2) TNF-α基因-308位点的多态性提高了RA患者、尤其是RA男性患者的患病风险。
(3) TNFRⅡ基因+196位点的多态性与RA患者患病风险之间的关系比较复杂。
(4)特定的HLA-DR_4、TNFα-308、TNFRⅡ+196组合基因型改变了RA发生的风险:TNFα-308(GG)轻微升高、TNFRⅡ+196(TT)轻微降低和TNFRⅡ+196(TG)显著升高基于HLADR_4基础上的RA患病风险。
(5)血清TNF-α水平的差异与基因、疾病、疾病和基因二者之间的交互作用有关,而sTNFRⅡ水平的差异与疾病、疾病和性别和基因三者之间的交互作用有关。
(6)单一基因和组合基因型对于RA病情的影响仅体现在某些方面,如发病年龄、性别比构成及RF浓度的高低,而多因素的共同作用对RF滴度的差异有影响。
Backgroud:
Rheumatoid Arthritis(RA) is an autoimmune disease which etiology is unknown. Heredity and immunological regulation have played significant roles in pathogenesis. Special human leucocyte antigen(HLA) which was confronted with external stimuli or altered by itself had been changed by shared epitope and dosage effect of gene. Nucleated cells who carried HLA become the target of immunological activation and T cell was activated, then a series of immunogenic molecules were released such as cytokines which induced the occurrence of RA. So we want to keep up investigating furthurly if the interaction among HLA-DR_4 phenotype and Tumor Necrosis Factor(TNF) and its receptor Tumor Necrosis Factor Recepor(TNFR) by Single Nucleotide Polymorphism (SNP) could influence the occurrence of RA.
Objective:
By investigating the interactions among HLA-DR_4 phenotype and TNF and TNFR by SNP, we want to acquire the information about the effects of three genes on RA risk of onset and concentration of cytokines and clinical manifestation which could help us to apprehend furthurly the pathogenesis of RA.
Methods:
Our study objects were 112 RA patients and 129 Healthy Subjects. Genomic DNA of white blood cell were extracted, then PCR-SSP was used to determine phenotype of HLA-DR_4 and PCR-RFLP were used to genotype for the A/G polymorphism at -308 position of TNF-αgene and the T/G polymorphism at +196 position of TNFRⅡgene. Levels of TNF-α、sTNFRⅡwere measured by using ELISA. Finally clinical features of RA patients including sex、age、disease duration、VAS of rest pain、tender joints of 28、swollen joints of 28、grip、time of morning stiffness、ESR、CRP、RF、function of joints、radiologiucal stages were measured.
Results:
(1) The difference in positive rate of HLA-DR_4 phenotype between RA patients (50%) and healthy subjects (26.36%) had statistical significance (P=0.000). Positive HLA-DR_4 increased risk of onset in RA patients 2.794 times than that in healthy subjects[95%Confidence Index(CI):1.630-4.790]. Stratified analysis for sex showed Positive HLA-DR_4 increased risk of onset in female RA patients 3.556 times than that in female healthy subjects [95%CI: 1.811 -6.979].
(2) The difference of composition in allelotype AA/GA/GG (0/8/104 vs 2/23/104, P=0.010)、rare allelotype (AA+GA)/GG (8/104 vs 25/104, P=0.006) and allele A/G (8/216 vs 27/231, P = 0.004) on TNFα-308 between RA patients and healthy subjects had statistical significance. Rare allelotype (AA+GA) and allele A on TNFα-308 increased risk of onset in RA patients 3.125 times (95%CI: 1.347-7.248) and 3.156 times (95%CI: 1.403-7.097) than that in healthy subjects. Stratified analysis for sex showed the difference of composition in allelotype AA/GA/GG (0/2/34 vs 1/12/32, P=0.015)、rare allelotype (AA+GA)/GG (2/34 vs 13/32, P=0.007) and allele A/G (2/70 vs 14/76, P=0.007) on TNFα-308 between male RA patients and male healthy subjects still existed. Rare allelotype (AA+GA) and allele A/G on TNFα-308 increased risk of onset in male RA patients 6.906 times (95%CI: 1.444-33.031) and 6.447 times (95%CI: 1.415-29.383) than that in male healthy subjects .
(3) The difference of composition in allelotype GG/TG/TT (5/62/45 vs 9/56/64)、rare allelotype (GG+TG)/TT (67/45 vs 65/64) and allele G/T (72/152 vs 74/184) on TNFRⅡ+196 between RA patients and healthy subjects had no statistical significance. Stratified analysis for sex showed the difference in allelotype GG/TG/TT (3/49/24 vs 8/28/48, P=0.000) on TNFRⅡ+196 between female RA patients and female healthy subjects had statistical significance. The difference in rare allelotype (GG+TG) /TT on TNFRⅡ+196 between female RA patients and female healthy subjects (52/24 vs 36/48, P=0.001) and between male RA patients and male healthy subjects (15/21 vs 29/16, P=0.041) had statistical significance,which increased risk of onset in female RA patients 2.889 times(95%CI: 1.510-5.526) than that in female healthy subjects and lowered risk of onset in male RA patients 0.394 times (95%CI: 0.160-0.970) than that in male healthy subjects. However, there was no statistical significancant difference in allele G/T on TNFRⅡ+196 between RA patients and healthy subjects.
(4) Among 5 kinds of allele genotypes combination with HLA-DR_4 and TNFα-308 ,HLA-DR_4(+)TNFα-308(GG) increased risk of onset in RA patients 2.931 times (95%CI:1.642-5.233) than that in HLADR_4(-) TNFα-308(GG) of healthy subjects.
(5) Among 6 kinds of allele genotypes combination with HLA-DR_4 and TNFRⅡ+196, HLA-DR_4(+)TNFRⅡ+196(TT) and HLA-DR_4(+) TNFRⅡ+196(TG) increased risk of onset in RA patients 2.476 times (95%CI:1.120-5.473) and 6.136 times (95%CI:2.548-14.775) than that in HLA-DR_4(-)TNFRⅡ+196(TT) of healthy subjects,HLA- DR_4(+)TNFRⅡ+196(TG) increased risk of onset in RA patients 4.313 times (95%CI: 1.851-10.050) than that in HLA-DR_4(-)TNFRⅡ+196(TG) of healthy subjects.
(6) Among 7 kinds of allele genotypes combination with TNFα-308 and TNFRⅡ+196, TNFα-308(GA)TNFRⅡ+196(TT) and TNFα-308(GA) TNFRⅡ+196(TG) lowered risk of onset in RA patients 0.212 times (95%CI: 0.056-0.804) and 0.282 times (95%CI:0.084-0.945) than that in TNFα-308(GG) TNFRⅡ+196 (TG) of healthy subjects.
(7) Among 11 kinds of allele genotypes combination with HLA-DR_4、TNFα-308 and TNFRⅡ+196, HLA-DR_4(+)TNFα-308(GG) TNFRⅡ+196(TT) and HLA-DR_4(+)TNFα-308(GG)TNFRⅡ+196(TG) increased risk of onset in RA patients 2.64 times (95%CI:1.124-6.202) and 5.8 times (95%CI:2.297- 14.646) than that in HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TT) of healthy subjects. HLA-DR_4(+)TNFα-308 (GG)TNFRⅡ+196 (TG) increased risk of onset in RA patients 4 times (95%CI: 1.637-9.775) than that in HLA-DR_4(-)TNFα-308(GG)TNFRⅡ+196(TG) of healthy subjects.
(8) The difference of concentration of serum TNF-α(pg/ml) between RA patients and healthy subjects (34.56±21.04 vs 20.63±15.46,P=0.000) had statistical significance. The difference of TNF-αconcentration between certain allele genotype combination of RA patients and healthy subjects had statistical significance. By analysis of variance of factorial design, interactions existing in mfgene~*tnfrgene(P=0.037)、dr_4~*tnfgene ~*tnfrgene(P=0.009) and group(P=0.000)、group~*dr_4~*tnfgene(P=0.001) had statistical significant influence to level of TNF-α.
(9) The difference of concentration of serum sTNFRⅡ(ng/ml) between RA patients and healthy subjects (8.54±6.29 vs 5.48±4.41, P=0.000) had statistical significance. The difference of sTNFRⅡconcentration between certain allele genotype combination of RA patients and healthy subjects had statistical significance. By analysis of variance of factorial design, interactions existing in group(P=0.000)、group~*sex ~*dr4(P=0.038)、group~*tnfgene(P=0.025)、group~*tnfgene~*tnfrgene (P=0.037) had statistical significant influence to level of sTNFRⅡ.
(10) A single allelotype had a certain influence to clinical manifestations of RA. Patients of HLA-DR_4(+) had more earlier onset age (42.59±14.07 vs 47.36±10.89, P=0.047) and higher level (IU/mL)of RF (471.32±435.22 vs 308.13±331.34, P=0.028 ) than those of HLA-DR_4(-).There were no statistical significance between patients of TNFα-308(GG) and TNFα-308(GA). Among patients of three kind of TNFRⅡ+196 allelotype GG/TG/TT, there were statistical significance in sex composition male/female (2/3 vs 13/49 vs 21/24,P=0.018) and level(IU/mL)of RF(917.00±674.77 vs 353.58±362.85 vs 380.93±365.39, P=0.008).
(11) Allele genotypes combination also had a certain influence to clinical manifestations of RA. The difference of onset of disease between HLA-DR_4(+)TNFα-308(GG) and HLA-DR_4(-)TNFα-308(GG) (42.35±14.27 vs 47.71±10.95, P=0.033) had statistical significance. Combinations of TNFRⅡ+196 with one or two of other Allele only had statistical significance in sex composition.By analysis of variance of factorial design, interactions existing in dr4(P=0.013)、tnfrgene (P=0.005)、sex~*tnfrgene(P=0.043) had statistical significant influence to level of RF.
Conclusions:
(1) Positive HLA-DR_4 phenotype increased risk of onset in RA patients especially female RA patients.
(2) Polymorphism of TNF-αat position -308 increased risk of onset in RA patients especially male RA patients.
(3) The relationship between polymorphism of TNFRⅡat position +196 and RA was sophisticated.
(4) Certain allele genotype combination of HLA-DR_4、TNFα-308 and TNFRⅡ+196 altered the risk of onset, TNFα-308(GG) increased slightly、TNFRⅡ+196(TT) decreased slightly and TNFRⅡ+196(TG) increased obviously the risk of onset based on HLADR4 phenotype.
(5) The difference in level of TNF-αwas related to allele gene、disease、interactions between disease and allele gene. However, the difference in level of sTNFRⅡwas related to disease、interactions among disease、sex and allele.
(6) The influence of Single allelotype and Allele genotypes combination mainly embodyied in some aspcets such as onset age、sex composition and level of RF. Interaction of multi-factor leaded to difference in level of RF.
引文
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