The Association Study Of Polymorphism In The Promoter Region-308 Tumor Necrosis Factor-α Gene With Etanercept Treatment In Ankylosing Spondylitis

PartⅠThe association of the-308 tumor necrosis factor-a gene polymorphism of ankylosing spondylitis(AS) with clinical disease progression and disease susceptibilityOBJECTIVETo explore the association of the polymophisms of TNF-a promoter gene at positions TNF-a-308 with susceptibility and clinical pathological changes in AS.METHODSPolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)was applied to genotype TNF-a-308 in 150 patients of AS and 100 healthy controls.The basis sequences of mutation were analyzed by DNA sequence analysis.The frequency of the alleles and genotypes of TNF-a- -308 were directly counted.The serum TNF-alpha levels were detected by the Enzyme-linked immunosorbent assay.The clinical data of ESR,CRP,spinal inflammation score and radiographic degree of sacroiliac joint damage were separately assessed in according to three groups of TNF-a-308 G/G,G/A and A/A. RESULTS:The frequency of TNF-a-308 G/G,G/A and A/A alleles was respectively 82%(123 cases)and 14%(21 cases)and 4%(6 cases)in AS group,which was not significantly different compared respectively with 87%(87 cases)and 13%(13 cases)and 0 %(0 cases)in the control group.There is no one case of TNF-a-308 A/A alleles in the control group.The median of serum TNF-a levels(9.44±1.29 pg/ml)of the G/G group were significantly lower than those of the G/A group(13.49±1.27 pg/ml)and A/A group(15.13±2.97 pg/ml).(P＜0.05).There were no statistically difference of the median of serum TNF-a levels Between the G/A group(13.49±1.27 pg/ml)and the A/A group(15.13±2.97 pg/ml) in AS patients.The median of serum TNF-a levels of the AS group were higher than those(5.64±1.18 pg/ml)of the healthy control group.(P＜0.05).The spinal inflammation score and percentage of more thanⅢdegree of radiographic damage of Sacroiliac joint in AS patients with TNF-a-308 G/G phenotype were significantly higher than those of AS patients with G/A and A/A phenotype group.(P＞0.05).The median of ESR and CRP of the G/G group were lower than those of the G/A group.They were 38.8±23.5 mm/h vs 72.8±32.3 mm/h,49.8±32.70 mg/l vs 39.2±29.05 mg/l respectively,and statistically different(p＜0.05).There were no statistically difference of the median of ESR and CRP Between the G/A group and the A/A group.(p＞0.05)CONCLUSION:Our data suggest that the polymorphisms of TNF-a promoter gene at positions of-308 allele has no association with AS susceptibility.But the polymorphisms of TNF-a promoter gene at the position of-308 might exert great influence on AS according to the radio-graphic degree of Sacroiliac joint damage and spinal inflammation score,ESR,CRP and the serum TNF-alpha levels and diseased region.PartⅡAssociation of -308 tumor necrosis factor-agene polymorphism with the therapeutic response to TNF-ablocker(Etanercept)in AS patientsOBJECTIVETo examine whether the TNF-a-308 polymorphism influences the therapeutic response to Etanercept in patients with AS.METHODSA total of 100 activity AS patients were genotyped by polymerase chain reaction for the-308 TNF-apromoter polymorphism at our part one study were recruited,They were treated with etanercept(25mg, Subcutaneous injection,once a week by 12 weeks),Combined MTX/ SSZ and(or)one of NSAIDs drugs,Record the change of clinical observation index at 0,4,8,12 weeks.Clinical response was assessed after 12 weeks by the Bath Ankylosing Spondylitis Activity Index (BASDAI)for AS patients.Take 4,8,12 weeks ASAS20/50/70 ratio of improvement,ESR and CRP changes as in the assessment the effectiveness of targeted therapy.RESULTSAfter 12 weeks,Moderate response(n=27)was no difference within three genotype groups(G/G 24/86,A/G 2/10,A/A 1/4,p＞0.05).There were 8 patients with the G/G genotype and 6 patients with the A/G genotype and 2 patients with the A/A genotype who failed to respond to Etanercept treatment(p＜0.01),furthermore good response(n=57)was predominantly seen in patients with the G/G genotype(G/G 54/86,A/G 2/10,A/A 1/4 P=0.004＜0.05).The average score of BASDAI improvement value in G/G phenotype(42.75±11.4)was significantly higher than G/A(35.8±13.78)and A/A phenotype(36.6±12.64).(P＜0.05).The Percentage of AS patients who obtained ASAS20 improvement with G/G,G/A phenotype was 94.2%,70%respectively at 12 weeks (p=0.044＜0.05),.and 75%in the G/A phenotype,which was not significantly different compared with G/G phenotype (94.2%vs75%,p＞0.05).The Percentage of AS patients who obtained ASAS50 improvement with G/G,G/A and A/A genotype was 52.3%, 40%and 25%respectively(p＞0.05)at 12 weeks.The Percentage of AS patients who obtained ASAS70 improvement with G/G or G/A or A/A genotype was 24.4%,30%and 0%respectively(p＞0.05)at 12 weeks.CONCLUSION:The data suggest that humans with a TNF-a-308 G/G genotype are better responders to Etanercept treatment than those with A/A or A/G phenotypes and polymorphism have no significant relation to efficacy which was assessed by the ASAS evaluation criterions,...