류마티스 관절염 환자에서 HLA-DRB1의 유전적 변이와 Etanercept 치료 반응과의 연관성: 예비 연구 = Genetic Variation in the HLA-DRB1 and the Response to Treatment of Rheumatoid Arthritis with Etanercept: Preliminary Study

다국어 초록 (Multilingual Abstract)

Objective: To investigate the roles of genetic variation in the HLA-DRB1 as predictors of response to etanercept treatment in rheumatoid arthritis (RA) patients. Methods: Clinical responses of 66 patients treated with etanercept were determined according to the ACR criteria (ACR20 and 70). HLA-DRB1 typing and further subtyping of all alleles were performed by polymerase chain reaction, sequence-specific oligonucleotide probe hybridization, and direct DNA sequencing analysis. We tested whether genetic variation in the HLA-DRB1 influenced on the responses to 12 weeks of etanercept therapy. Univariate and multivariate analyses were performed to compare allele and genotype distribution between responders and nonresponders. Results: When allelic association with etanercept response was analyzed with ACR20 and ACR 70 criteria for shared epitope alleles (HLA-DRB1 *0101, *0401, *0404, *0405, *0410, *1001, and *1406 alleles) and protective alleles (HLA-DRB1*0701, *0802, *1301, *1302, *1403, and *1405 alleles), there was no association with etanercept efficacy. When ACR20 nonresponders were compared with ACR70 responders, there was no significant association. Next, we tested genotypic association for shared epitope carriage status. The presence of HLA-DRB1 alleles encoding the shared epitope (1 and 2 copies) was marginally associated with nonresponse effect for ACR 70 response (OR=0.27, 95% CI=0.08∼0.93, P=0.045). Conclusion: There was no influence of genetic variation in the HLA-DRB1 on the response to treatment of RA with etanercept.

참고문헌 (Reference)

1 "한국인 류마티스 관절염 환자에서 질병 중증도 표지자로서의 HLA-DR4 유용성" 8 : 8-13, 2001

2 "류마티스 관절염 환자에서 Shared Epitope의 임상적 의의" 8 : 34-40, 2001

3 "Variation of genetic markers in patients treated with classic DMARDs or etanercept" 46 : 2002

4 "Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor(p75)-Fc fusionprotein" 337 : 141-147, 1997

5 "The shared epitope hypothesis:an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis" 30 : 1205-13, 1987

6 "The shared epitope and severity of rheumatoid arthritis" 28 : 59-78, 2002

7 "The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept" 50 : 2750-2756, 2004

8 "The influence of a polymorphism at position -857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis" 44 : 547-552, 2005

9 "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis" 31 : 315-24, 1988

10 "Role of cytokines in rheumatoid arthritis" 14 : 397-440, 1996

11 "Psychometric evaluation of a Korean Health Assessment Questionnaire for clinical research" 25 : 1975-1979, 1998

12 "Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis" 48 : 1849-1859, 2003

13 "Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis" 34 : 1125-32, 1991

14 "Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice" 151 : 6602-7, 1993

15 "Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial" 354 : 1943-1949, 1999

16 "Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901" 50 : 3468-3475, 2004

17 "Disease severity in rheumatoid arthritis relationships of plasma tumor necrosis factor-alpha and fibrin D-dimer to traditional severity and functional measures" 353-61, jclinimmunol1992

18 "Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum" 31 : 1041-5, 1988

19 "Clinical responses to tumor necrosis factor alpha antagonists do not show a bimodal distribution:data from the Stockholm tumor necrosis factor alpha followup registry" 48 : 1500-1503, 2003

20 "Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients" 50 : 1077-1082, 2004

21 "American College of rheumatology.Preliminary definition of improvement in rheumatoid arthritis" 38 : 727-735, 1995

22 "A simple salting out procedure for extrating DNA from human nucleated cells" 16 : 1215-, 1988

23 "A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis" 343 : 1586-1593, 2000