대한류마티스학회지 Vol. 14, No. 2, June, 2007 원저 베체트병환자에서 TNF-α 와 TNF 수용체유전자의다양성 울산대학교의과대학금강아산병원내과학교실, 서울아산병원내과학교실알레르기류마티스내과 *, 소화기내과 **, 성신여자대학교자연과학대학생물학과 *** 서욱장ㆍ김용길 * ㆍ양석균 ** ㆍ박경숙 *** ㆍ이창근 * ㆍ유빈 * ㆍ문희범 * =Abstract= Polymorphisms of TNF-α Gene and TNF Receptor Gene in Behcet's Disease Wook Jang Seo, M.D., Yong Gil Kim, M.D.*, Suk-Kyun Yang, M.D.**, Kyung Sook Park, Ph.D***, Chang-Keun Lee, M.D.*, Bin Yoo, M.D.*, Hee-Bum Mon, M.D.* Department of Internal Medicine, KeumKang Asan Hospital, Divisions of Allergy and Rheumatology* and Gastroenterology**, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Department of Biology, Sungshin Women's University***, Seoul, Korea Objective: TNF-α has a pivotal role in the development of inflammation on mucous lesion in Behcet s disease like Crohn s disease. We examined three single nucleotide polymorphisms (SNPs) of TNF receptor gene of intestinal Behcet s disease and Behcet's disease without gastrointestinal involvement. Methods: DNA of peripheral blood samples was obtained from 43 patients with intestinal Behcet s disease, 59 patients with Behcet s disease without gastrointestinal involvement and 60 healthy controls. After polymerase chain reaction (PCR), we examined SNPs of TNF-α gene ( 308, 238) and TNF receptor gene ( 1493, 196, 1466) by SNaPshot assay. We also analyzed reconstruction of haplotypes of three TNF receptor genes. Results: No significant difference was observed in the distribution of TNF-α gene ( 308, 238) and TNF receptor gene ( 1493, 196, 1466) polymorphisms among the groups. Haplotype reconstruction analysis of three TNF receptor genes showed difference in allele group of (T-T-G) ( 1493/ 196/ 1493) between patients with intestinal Behcet s disease and Behcet s disease without gastrointestinal involvement (p<0.05). However, other allele groups revealed no <접수일 :2007년 2월 5일, 심사통과일 :2007년 3월 28일> 통신저자 : 유빈서울시송파구풍납2동 388-1 울산대학교의과대학서울아산병원알레르기류마티스내과 Tel:02) 3010-3282, Fax:02) 3010-6969, E-mail:byoo@amc.seoul.kr 136
서욱장외 : 베체트병환자의유전자다양성 difference among the groups. Conclusion: The role of TNF-α gene ( 308, 238) polymorphisms and TNF receptor gene ( 1493, 196, 1466) polymorphisms in the pathogenesis of Behcet s disease is not supported by this data. Haplotype reconstruction analysis showed that haplotype of T-T-G (TNFR2, 1493/ 196/ 1466) in Behcet s disease may have protective effect on gastrointestinal involvement of this disease. Key Words: Behcet s disease, Single nucleotide polymorphism, Haplotype 서론베체트병은여러장기를침범하는혈관염으로재발성구강과성기궤양, 안구염증과피부병변이주임상증상이다. 발병원인에대해서는아직까지잘알려져있지않지만활동적인베체트병환자에서 TNF-α와 TNF 수용체농도가증가되어있음이알려져있다 (1-3). 또한 TNF-α 유전자촉진자부위 (promoter region) 의다형성 (polymorphism) 이 TNF 분비와연관되어있음이보고되었으며, 이것이베체트병의염증성반응에중요한역할을할것으로생각되었다. 베체트병중불응성포도막염, 베체트장염과구강성기궤양을 TNF-α 길항제로치료하면호전된다는보고가있어서이러한생각들을뒷받침해주었다 (4-6). 지금까지잘알려진 TNF-α 유전자의단일염기다형성부위 (single nucleotide polymorphic sites) 는 238, 308, 376, 857, 863, 1031이고, TNF 수용체의단일염기다형성부위는 196, 1466, 1493, 1663, 1690이다 (7,8). 이러한연구결과를바탕으로 TNF-α와 TNF 수용체의단일염기다형성과베체트병과의연관성을밝히려는연구가시도되었으나대부분연관성을발견하지못했다 (9,10). 다만베체트병의안구병변을가진환자를대상으로한연구에서 TNF-β +252의 SNP가안구병변과관련이있다고보고된바있다 (11,12). 베체트장염은임상양상이크론병과비슷한데, 크론병에서점막병변의발생에 TNF-α가중요한역할을하며 TNF-α 유전자부위의단일염기다형성이병의중증도와관련이있는것으로알려져있다 (13). 또한단일염기다형성부위의유전자형보다일배체형의배치또는조합 (haplotype configuration or combiantion) 이표현형 (phenotype) 의결과들을결정하는데더중요한역할을한다고알려져있다 (14,15). 최근에 TNF-α 유전자 1031 T/C 다형성이베체트병과연관되어있다는연구결과가발표되었으며 (16) 국내에서도이와관련된연구가있었다 (17). 하지만베체트장염환자를중점대상으로한연구는없었으며베체트장염환자군을대상으로한 TNF 수용체유전자의일배체형조합분석연구또한없었다. 본연구는베체트장염환자군을대상으로 TNFα의생성과주로관련된 TNF-α ( 238 G/A, 308 G/ A) 부위와 TNF 수용체 ( 1493, 196, 1466) 부위유전자의 SNP를장염이없는베체트병환자군과정상인군과비교하여그차이를알아보았다 (18-20). 또한 TNF-α와 TNF 수용체유전자부위를각각한군으로하여일배체형분석을통해베체트장염환자군, 장염이없는베체트병환자군과정상인군과의차이를알아보고자한다. 대상및방법 1. 대상국내소재 1개 3차진료기관에서내시경소견과병리소견을통해베체트장염으로의심되는환자를대상으로일본베체트연구학회의기준 (1987) 으로진단하였으며 (n=43), 대조군은동일병원에서같은진단기준을사용하여베체트병으로진단받은환자중장염이없는환자 (n=59) 와건강검진에서이상소견을보이지않은사람중에서성별과연령을고려하여 (n=60) 선정하였다. 베체트장염환자와장염이없는베체트병환자는설문조사와의무기록분석을통하여다시분류하였다. 모든환자들은연구동의서에서면동의를하였고연구동의서사본을제공 137
대한류마티스학회지제 14 권제 2 호 2007 받았으며, 연구는지역임상연구윤리위원회의인준하에시행되었다. 2. 연구방법 1) DNA의추출 : 대상환자와대조군의정맥에서 10 cc의혈액을채취한후, 혈액의백혈구에서 QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) 을이용하여 DNA를추출하였다. 추출한 DNA는 80 o C에서냉동보관하였다. 2) TNF-α와 TNF 수용체유전자형분석 (1) 중합효소연쇄반응생성물의정제과정 : 추출한 DNA를시발체 1.25 pmol, 250μM 의 dntp, 2.5 mm의 MgCl 2, X10 완충액 (Applied Biosystems, CA, USA) 과 Taq polymerase (Applied Biosystems) 0.15 unit가포함된 50μL 의 buffer에서 PCR thermal cycler (Perkin- Elmer Cetus, Norwalk, CT, USA) 을이용하여증폭시켰다. 중합효소연쇄반응의조건은 94 o C에서 30초, 65 o C에서 30초, 72 o C에서 30초를 5회반복한후다 시 94 o C에서 30초, 55 o C에서 30초, 72 o C에서 30초를 15회반복하는것이었으며이때사용된시발체의염기서열은표 1과같다. 이후중합효소연쇄반응생성물을 1 unit의 Shrimp Alkaline Phosphatase (Amersham Bioscience, Uppsala, Sweden) 와 2 unit의 Exokinase I (Amersham Bioscience) 을혼합하여 37 o C에서 1시간동안반응시켜중합효소연쇄반응후남아있는 dntp와시발체를제거하였다. 다시 72 o C에서 15 분간반응시켜 Shrimp Alkaline Phosphatase와 Exokinase I을불활성화시킨후정제된중합효소생성물을얻었다. (2) 단일염기연장반응 (single base extension reaction): 단일염기연장반응은단일염기다형성이있는부위의바로전까지결합되도록설계된내부연장시발체를사용하였으며내부연장시발체의염기서열은표 2와같다. 시발체연장반응은 SNaPshot ddntp Primer Extension Kit (Applied Biosystems) 을이용하였다. 시발체연장반응후 1 unit의 Shrimp Al- Table 1. The sequences of sense and anti-sense primers Name Primer Sequence TNF-α 238G/A Sense 5'-AGAAGGAAACAGACCACAGAC-3' 5'-GGGAAAGAATCATTCACCCA-3' TNF-α 308G/A Sense 5'-AGAAGGAAACAGACCACAGAC-3' 5'-GGGAAAGAATCATTCAACCA-3' TNFR2 1466G/A Sense 5'-CTTCTCCAAGGAGGAATGT-3' 5'-TCACAGAGAGTCAGGGACTT-3' TNFR2 196G/T Sense 5'-TCCTCCTCCTCCAGCTGT-3' 5'-TAAGTGTACTGCCCCTGGG-3' TNFR2 1493C/T Sense 5'-CCAAGAGCAGAGGCAGCG-3' 5'-ATGCCCCGAACGTCCATG-3' TNF: tumor necrosis factor, TNFR: TNF-receptor Table 2. The sequences of internal extension primers Site TNF-α 238G/A TNF-α 308G/A TNFR2 1466G/A TNFR2 196G/T TNFR2 1493C/T Extension primer sequence 5'-GCCCAGAAGACCCCCCTCGGAATC-3' 5'-TAGGTTTTGAGGGGCATG-3' 5'-CTGCAGGCCAAGAGCAGAGGCAGCG-3' 5'-GGACGTCCACGTGCAGACTGCATCC-3' 5'-CCAGCCAGCCTTCCGAGAGGGACAC-3' TNF: tumor necrosis factor, TNFR: TNF-receptor 138
서욱장외 : 베체트병환자의유전자다양성 kaline Phosphatase를반응액에넣은후 37 o C에서 1시간동안반응시키고다시 72 o C에서 15분간반응시켜정제된연장시발체를얻었다. (3) 유전자분석 : 연장시발체를 ABI 3700 DNA analyzer (Applied Biosystems) 을이용하여전기영동을시행하였다. 결과분석은 GeneScan과 Genotyper (Applied Biosystems) 을이용하였다. 3. 통계학적분석베체트장염환자와장염이없는베체트병환자, 정상인군에서 TNF-α와 TNF 수용체유전자각위치의유전자형과대립유전자 (allele) 빈도를구하였고, chi-square test와 Fisher's exact test를이용하여비교분석하였다. 이들의분석에는 SPSS (Version 10.0, SPSS Inc, Chicago, IL) 을이용하였다. TNF-α 유전자 2 부위와 TNF 수용체유전자 3 부위를한군으로묶은후 SAS genetics (Version 10.0, SAS Institute Inc, Cary, NC) 을이용하여일배체형분석을시행하였다. 결과는 95% 신뢰구간으로하였고양측검정의 p값이 0.05 이하인경우를통계적으로의미있는것으로하였다. Table 3. Characteristics of GBD patients and BD patients GBD (n=43) BD (n=59) p-value Sex Male 24 (55.8) 29 (49.2) Female 19 (44.2) 30 (50.8) Age (year, range) 40.5 (19 63) 42.3 (19 64) Oral ulcer 43 (100) 59 (100) Genital ulcer 30 (69.8) 49 (83.1) Eye lesion* 2 (4.7) 8 (13.6) Uveitis 1 (2.3) 8 (13.6) Skin lesion 25 (58.1) 54 (91.5) EN 12 (27.9) 45 (76.3) Arthritis 8 (18.6) 31 (52.5) 0.01 DVT 1 (2.3) 8 (13.6) GI involvement TI 25 (58.1) IC valve 21 (48.8) Data are shown as the number of patients (%). *Eye lesion including uveitis, retinal vasculitis, and hypopyon. BD: Behcet's disease without intestinal involvement, DVT: deep vein thrombosis, EN: Erythema nodosum, GBD: gastrointestinal Behcet's disease, IC valve: ileocecal valve, GI: gastrointestinal, : not significant, TI: terminal ileum 결과 1. 베체트장염환자와장염이없는베체트병환자의특징및비교베체트장염환자와장염이없는베체트병환자비교시남녀비율 (1:0.77 vs. 1:1.03), 평균연령 (40.5±9.2 vs. 42.31±8.4) 에서는차이를보이지않았다. 구강궤양 (100% vs. 100%), 성기궤양 (69.8% vs. 83.1%), 안구병변 (4.7% vs. 13.6%), 포도막염 (2.3% vs. 13.6%) 은두군간에서큰차이를보이지않았으며, 안구병변이나포도막염을제외하고는병변의침범비율이기존의보고와차이를보이지않았다 (13). 피부병변 (58.1% vs. 91.5%) 과홍반성결절 (27.9% vs. 76.3%) 에서는베체트장염군에서낮게관찰되었으나통계적의미는없었다. 하지만관절염의빈도 (18.6% vs. 52.5%) 는베체트장염환자에서의미있게낮았다 (p<0.05). 베체트장염의경우는기존의연구결과보다피부병변, 홍반성결절과관절염의빈도수가적은반면, 장염이없는베체트병의경우에는피부 병변과홍반성결절의빈도수가기존의보고와유사하거나상회하는결과를보였다. 베체트장염병변의위치는말단회장 (58.1%), 회맹판 (48%) 으로기존의보고와차이를보이지않았다 (14) ( 표 3). 2. TNF-α 유전자와 TNF 수용체유전자다형성의비교본연구에서정상대조군및환자군모두에서 Hardy-Weinberg equilibrium을만족하였다. TNF-α 유전자 238, 308 부위와 TNF 수용체유전자 196, 1466, 1493 부위의유전자형의빈도는베체트장염환자군과장염이없는베체트병환자군에서차이를보이지않았다. 또한각각의베체트병환자군과정상인군사이에도의미있는차이를보이지않았다 ( 표 4). 3. TNF-α와 TNF 수용체유전자일배체형의비교 TNF 수용체유전자 3 부위를한군으로하여일배체형분석을시행한결과 T-T-G ( 1493/ 196/ 1466) 139
대한류마티스학회지제 14 권제 2 호 2007 Table 4. Genotype frequencies of TNF-α and TNF receptor gene polymorphisms in GBD patients, BD patients and normal controls Genotype frequency GBD (n=43) BD (n=59) NL (n=60) p-value TNF-α 238 GG 38 (88.4) 53 (88.9) 53 (88.3) GA 5 (11.6) 6 (10.2) 6 (10.0) AA 0 (0.0) 0 (0.0) 1 (1.7) TNF-α 308 GG 39 (90.7) 55 (93.2) 54 (90.0) GA 4 (6.8) 4 (9.3) 6 (10.0) TNFR2 1466 GG 13 (30.2) 23 (39.0) 16 (26.7) GA 18 (41.9) 22 (37.3) 32 (53.3) AA 12 (27.9) 14 (23.7) 12 (20.0) TNFR2 196 GG 2 (4.7) 2 (3.4) 2 (3.3) GT 14 (32.6) 15 (25.4) 13 (21.7) TT 27 (62.8) 42 (71.2) 45 (75.0) TNFR2 1493 CC 16 (37.2) 25 (42.4) 26 (43.3) CT 23 (53.5) 27 (45.8) 29 (48.3) TT 7 (11.9) 4 (9.3) 5 (8.3) Data are shown as the number of patients (%). BD: Behcet's disease without gastrointestinal involvement, GBD: intestinal Behcet's disease, NL: normal controls, : not significant, TNFR2: tumor necrosis factor receptor 2 Table 5. TNF receptor haplotype block analysis in GBD and BD Haplotype GBD (n=43) BD (n=59) d ( 1493/ 196/ 1466) frequency (%) frequency (%) p-value C-G-A 2.9 3.3 C-G-G 1.4 3.2 C-T-A 31.4 32.6 C-T-G 28.1 26.1 T-G-A 6.2 2.7 T-G-G 10.2 6.8 T-T-A 8.2 3.7 T-T-G 11.3 21.4 0.03 BD: Behcet's disease without gastrointestinal involvement, GBD: intestinal Behcet's disease, : not significant 군에서베체트장염환자와장염이없는베체트병환자에서통계적으로유의한차이를보였다 (p<0.05) ( 표 5). 하지만같은유전자군에서베체트장염환자와정상인군과의비교, 장염이없는베체트병환자군과정상인군과의비교및모든베체트병환자군 ( 베체트장염환자군 + 장염이없는베체트병환자군 ) 과정상인군과의비교시통계적으로유의한차이를 보이지않았다. 고찰베체트병은발병원인은잘알려져있지않지만여러가지요인이관여하리라고생각되어지고있으며, 이전의연구를통해유전적소인도중요한요인 140
서욱장외 : 베체트병환자의유전자다양성 의하나로받아들여지고있다. 유전적소인에관여하는중요한유전자에대해서는아직명확히밝혀진바는없지만 HLA-BW51와베체트병의연관성에관한보고는있다 (21). 최근에는여러사이토카인유전자의연관성에관한연구가진행되고있다. 특히 TNF-α는베체트병의병태생리에중요한역할을하는것으로알려져있으며, 크론병의병태생리에도중요한역할을하는것으로알려져있다. 크론병은그임상양상이베체트장염과유사하며 TNF-α와 TNF 수용체유전자의다형성이병인에영향을준다는보고가있었다 (22,23). 특히 TNF-α 유전자중 308, 238이크론병의감수성과관련이있으며, TNF 수용체유전자중이미알려진 196 외에 1466, 1493의단일염기다형성부위혹은일배체형이크론병환자에서특이적으로나타났다 (8,10,13). 이러한보고를토대로저자들은병인과관련이높을것으로추론되는 TNF-α와 TNF 수용체유전자부위 (TNF-α 238 G/A, 308 G/A; TNF 수용체 1493 C/T, 196 G/T, 1466 G/A) 을대상으로베체트장염과장염이없는베체트병과의연관성에대해연구하였다. TNF-α 유전자 308, 238 부위와 TNF 수용체유전자 1493, 196, 1466 부위의유전자형의빈도는베체트장염환자군과장염이없는베체트병환자군과의비교, 베체트장염환자군과정상인군과의비교, 장염이없는베체트병환자군과정상인군과의비교에서차이를보이지않았다. 따라서본연구에서사용한유전자부위의다형성은베체트병의발생과관련이없다는이전의보고와일치하였으며베체트장염의발생과도관련이없는것으로나타났다 (10,11). 동시에시행한일배체형유전자분석에서 TNF-α의유전자 2 부위를한군으로하여분석하였을때각각의환자군과대조군과의차이를보이지않았으나, TNF 수용체유전자 3 부위를한군으로하여일배체형분석을시행한결과 T-T-G ( 1493/ 196/ 1466) 군에서베체트장염환자군과장염이없는베체트병환자군사이에서통계적으로유의한차이를보였다. 하지만같은 T-T-G군에서베체트장염환자군과정상인군, 장염이없는베체트병환자군과정상인군에서는차이를보이지않았다. 이러한결과는 T-T-G ( 1493/ 196/ 1466) 의일배체형을가지는 베체트병환자가베체트장염의발생가능성이낮다고추론할수있다. 하지만일배체형분석을위한연구로는그대상군의숫자가적기때문에추후대규모의연구가필요하다고하겠다. 본연구에참여한베체트장염환자에서안구병변, 피부병변및관절염이 4.7%, 58.1%, 18.6% 로기존의베체트병환자보다적게나타났다. 이것은베체트장염의진단시장염에대한내시경적소견과병리학적소견을중요시하여베체트병의진단기준인 International Study Group for Behcet's Disease (1990) 의기준에맞지않은경우가전체베체트장염환자의 46.5% (20/43) 나차지하고있었기때문으로생각될수있다. 일본베체트연구학회의기준 (1987) 으로보면 complete type 1명 (2.3%), incomplete type 22명 (51.2%), suspicious type 20명 (46.5%) 이었다. Suspicious type의안구병변과피부병변은 0.0% 과 5% 로 suspicious type이전체베체트장염환자의많은부분을차지함으로써안구병변과피부병변이기존의베체트병환자보다적게나타나는것으로설명될수있다. 하지만베체트장염에관한기존의두가지연구결과를보면 complete type이 3%, incomplete type 25%, suspicious type 15% 로안구병변이나피부병변의경우장침범이없는베체트병환자보다적게나타날수있음을알수있다 (24-26). 본연구의제한점은첫째, 본연구는단일기관에서시행된예비실험으로질병의희귀성으로인한연구대상군의숫자가적었다. 이러한조건으로인해환자군선정시합당한통계적방법이시행되지못하였으며또한일배체형의차이를다중분석시의미있는결론을이끌어낼수없었다는점이다. 둘째, 건강검진에서이상이없는사람을정상인군으로선정할때병력에서재발성구내염이있는사람들을제외하지않아이것이교란요인 (confounding factor) 으로작용할수있다는점이있다. 베체트장염은베체트병환자에서드물게발생하지만합병증의발생빈도가높아서베체트병의사망률에크게영향을미치지만, 재발이잦고치료가어렵다고알려져있다 (24). 그럼에도불구하고환자군의희소성으로현재까지베체트장염에대한대규모연구가국내에서는이루어지지않은상태이다. 본연구는한국인베체트장염환자를대상으로하여 141
대한류마티스학회지제 14 권제 2 호 2007 TNF-α와 TNF 수용체유전자의다형성과일배체형분석을처음시행한예비실험으로베체트병에서 TNF 수용체의특정일배체형이베체트장염으로의이행을억제할수있다는결과를보였다는데그의의가있다. 결 크론병의발병과활동성에관련이있는것으로알려진 TNF 수용체유전자 1493, 196, 1493 부위의다형성은베체트장염발생과관련이없는것으로밝혀졌다. TNF-α 유전자 308, 238 부위도베체트장염발생과는관련이없는것으로밝혀졌다. 비록대상군의숫자가적지만 TNF 수용체유전자일배체형군중 T-T-G ( 1493/ 196/ 1466)) 군을가진배체트병환자는베체트장염발생가능성이떨어진다고추론할수있다. 본연구는예비실험으로향후다기관대규모연구를통한확인이필요하다. 론 REFERENCES 1) Sayinalp N, Oezcebe OI, Oezdemir O, Haznedaroglu CH, Dundar S, Kirazli S. Cytokines in Behcet's disease. J Rheumatol 1996;23:321-2. 2) Yamashita N, Kaneoka H, Kaneko S, Takeno M, Oneda K, Koizumi H, et al. Role of gammadelta T lymphocytes in the developement of Behcet's disease. Clin Exp Immunol 1997;107:241-7. 3) Turan B, Gallati H, Eradi H, Gurler A, Michel BA, Villiger PM. Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Behcet's disease: soluble TNFR-75 as a biological marker of disease activity. J Rheumatol 1997;24:128-32. 4) Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN. Effect of infliximab on sight-threatening panuveitis in Behcet's disease. Lancet 2001;358:295-6. 5) Hassard PV, Binder SW, Nelson V, Vasiiauskas EA. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behcet's disease: a case report. Gastroenterol 2001;120:995-9. 6) Robertson LP, Hickling P. Treatment of recalcitrant orogenital ulceration of Behcet's syndrome with inflximab. Rheumatol 2001;40:473-4. 7) Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato H, et al. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-α gene in Japanese. Tissue Antigens 1998;51:605-12. 8) Sashio H, Tamura K, Ito R, Yamamoto Y, Bamba H, Kosaka T, et al. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's diseas, respectively. Immunogenetics 2002;53:1020-7. 9) Tozkir JD, Gul A, Uyar FA, Ozbek U, Direkeneli GS. Tumor necrosis factor-alpha gene promoter region 308 and 376 G A polymorphism in Behcet's disease. Clin Exp Rheumatol 2003;21(Suppl):S15-8. 10) Lee EB, Kim JY, Lee YJ, Park MH, Song YW. TNF and TNF receptor polymorphisms in Korean Behcet's disease patients. Hum Immunol 2003;64:614-20. 11) Verity DH, Wallace GR, Vaughan RW. HLA and tumor necrosis factor (TNF) polymorpsms in ocular Behcet's disease. Tissue Antigens 1999;54:264-72. 12) Mizuki N, Inoko H, Sugimura K, Nishimura K, Nakamura S, Tanaka H, et al. RFLP analysis in the TNF-beta gene and the susceptibility to alloreactive NK cells in Behcet's disease. Invest Ophthalmol Vis Sci 1992;33:3084-90. 13) Louis E, Peeters M, Franchimont D, Seidel L, Fontaine F, Demolin G, et al. Tumor necrosis factor (TNF) gene polymorphism in Crohn's disease (CD): influence on diseae behaviour? Clin Exp Immunol 2000;119:64-8. 14) Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000;26:163-75. 15) Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z, et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohb disease. Nat Genet 2001;29:223-8. 16) Akman A, Sallakci N, Coskun M, Bacanli A, Yavuzer U, Alpsoy E, et al. TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behcet's disease. Br J Dermatol 2006;155:350-6. 17) Park K, Kim N, Nam J, Bang D, Lee ES. Association of TNFA promoter region haplotype in Behcet's Disease. J Korean Med Sci 2006;21:596-601. 18) Stueber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necorsis factor-α concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24:381-4. 142
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