http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(2): 321–326 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844304

ORIGINAL ARTICLE

Interleukin-1-related genes polymorphisms in Turkish patients with Behçet disease: a meta-analysis

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

Jun Zou and Jian-Long Guan Department of Rheumatology, Huadong Hospital, Fudan University, Shanghai, PR China Abstract

Keywords

Objectives. Polymorphisms in the Interleukin (IL)-1-related genes at the locations 889, 511,  3962 and mspa1l 1100 have been investigated for possible association with Behçet’s disease (BD). Methods. A literature-based search was conducted to identify all relevant studies. Five independent studies from Turkish population met the included criteria. Results. IL-1α -889 CT [odds ratio (OR)  0.72, 95% confidence interval (CI)  0.55–0.95], IL-1α 889 TT (OR  0.61, 95% CI  0.40–0.93), IL-1β  3962 C (OR  1.41, 95% CI  1.07–1.88), IL-1β  3962 T (OR  0.71, 95% CI  0.53–0.94) IL-1β  3962 CC (OR  2.08, 95% CI  1.08–3.99), IL-1β  3962 CT (OR  0.58, 95% CI  0.38–0.88), IL-1 receptor antagonist (IL-1 Ra) mspa1l 1100 CT (OR  0.69, 95% CI  0.49–0.96), IL-1 Ra mspa1l 1100 TT (OR  1.50, 95% CI  1.08–2.08) had a significant association with BD. The pooled estimates for IL-1α -889 C, IL-1α -889 CC, IL-1α -889 T had a non-significant association with BD. Conclusions. IL-1α -889 CT, IL-1α -889 TT, IL-1β  3962 C, IL-1β  3962 T, IL-1β  3962 CC, IL-1β  3962 CT, IL-1 Ra mspa1l 1100 CT, IL-1Ra mspa1l 1100 TT promoter polymorphisms may confer susceptibility to BD in Turkish population.

Behçet’s disease, Interleukin-1, Meta-analysis, Polymorphisms

Introduction Behçet’s disease (BD) is a chronic, relapsing, multi-systemic inflammatory disorder, characterized by orogenital ulcers and microvascular skin and ocular lesions [1]. While the exact pathogenesis of BD remains to be elucidated, immunological mechanisms play a major part in the aetiopathogenesis of BD [2]. Interleukin (IL) 1, especially IL-1β is a uniquely proinflammatory cytokine fundamental to autoinflammatory diseases [3]. BD has many clinical findings overlapping with those of autoinflammatory disorders [4], and circulating monocytes of BD patients produce large amounts of IL-1β [5]. Additionally, treatments with anti-IL 1β antibody [6,7] or IL-1 blockade [8] have resulted in improvement of the disease that is resistant to conventional therapy. Several studies have investigated the potential association between polymorphisms in the IL-1-related genes at the positions 889, 511,  3962 and IL-1 receptor antagonist (IL-1 Ra) mspa1l 1100 and risk of BD. However, the allelic and genotypic associations of these studies have been inconsistent and controversial. Therefore, a meta-analysis was conducted to estimate the putative influence of polymorphisms in the IL-1 gene cluster at positions 889, 511,  3962 and IL-1 Ra mspa1l 1100 on susceptibility to BD.

Materials and methods Electronic searches were conducted using standardized search strategies for meta-analysis and systematic review of observaCorrespondence to: Jian-Long Guan, Department of Rheumatology, Huadong Hospital, Fudan University, West Yan’an Road No. 221, Shanghai 200040, PR China. Tel:  086-21-6248-3180x80213. Fax: 086-21-6248-6420. E-mail: [email protected]

History Received 21 March 2013 Accepted 8 May 2013 Published online 31 October 2013

tional studies as described earlier [9]. Identification of Eligible Studies and Data Extraction We searched MEDLINE (1950–July 31, 2012), EMBASE (1980–July 31, 2012), Cochrane Central Register of Controlled Trials (1993–July 31, 2012), and China Series full-text database (1982–July 31, 2012) for all relevant studies that examined the association of the IL-1 promoter polymorphisms with BD. Trails from all languages were included on the basis of English abstract and content. The search terms used for MEDLINE were modified according to database requirements. The following Medical Subject Heading or Embase terms and/ or text words were used: Behçet’s syndrome, Behçet’s disease, IL 1, genetic polymorphism, genetic predisposition and allele. No restrictions were placed on language, race, ethnicity or geographic area. The titles and abstracts from the search results were examined closely for potential inclusion in the study. We reviewed the bibliographies of the identified articles to locate further eligible studies. For inclusion, a trail had to meet the following criteria established by the study team: (1) it was published by July 31, 2012, (2) patients were diagnosed according to the diagnostic criteria prepared by the International Study Group for Behçet’s disease (1990) [10], (3) it had original data and (4) the data reported were adequate to perform statistical analysis (odds ratio). Studies were excluded if (1) they contained overlapping data, (2) family members were studied, (3) incomplete data of gene position, and (4) they were review articles and publications in duplicate. Allele and genotype frequencies of the IL-1-related genes polymorphisms at locations 889, 511,  3962 and mspa1l 1100 from each perspective study were determined in patients and controls. All allele and genotype frequencies were estimated the odds ratios (OR) and its 95% confidence interval (CI) in BD patients and controls. Either fixed or random-effects model was

322

J. Zou and J.-L. Guan

Mod Rheumatol, 2014; 24(2): 321–326

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

Figure 1. Flow diagram of studies identified in the systematic review.

employed. An I2 statistic was used to measure the proportion of inconsistency in individual studies that could not be explained by chance [11]. Statistical heterogeneity was assessed through I2 statistic and its values of 25%, 50% and 75% correspond to low, moderate and high. Analysis with Begg’s test and Egger’s test was performed to explore for publication bias. P  0.05 was considered statistically significant. Meta-analysis was performed with the metan command in the Stata statistical software package (version 12.0, StataCorp, College Station, TX).

Results The literature search identified 58 articles with 7 relevant publications (Figure 1). Zhang and Tonghua [12] and Liu et al. [12,13] examined a possible association of polymorphisms of IL-1 Ra

with susceptibility for BD; however, the data of gene position were not available. Thus both studies were excluded. Five studies included in the meta-analysis consisted of original articles with case-control study design, published in full text, and study subjects from Turkish population [14–18], (Table 1). All of five reported on allele and genotype frequencies of IL-1α -889, IL-1β -511, and three studies on IL-1β 3962, three studies on IL-1 Ra mspa1l 1100 positions. Only 3/5 studies examined the association between the polymorphisms of the IL-1 cluster gene at IL-1α -889, IL-1β -511, IL-1β  3962, IL-1 Ra [16–18]. The total number of patients with BD was 438 and the total number of controls was 508. Generally, IL-1α -889 CT (OR  0.72, 95% CI  0.55–0.95), IL-1α -889 TT (OR  0.61, 95% CI  0.40–0.93), IL-1β  3962 C (OR  1.41, 95% CI  1.07–1.88), IL-1β  3962 T (OR  0.71, 95% CI  0.53–0.94) IL-1β  3962 CC (OR  2.08, 95%

Table 1. Characteristics of studies included in this meta-analysis and genotype and allele frequencies of IL-1α -889 CT/TT, IL-1β  3962 C/T, CC/CT and IL-1 Ra mspa1l 1100 C/T, CT/TT in patients with BD.

Study ID Ozcimen et al. (2011) Akman et al. (2008) Alayli et al. (2007) Coskun et al. (2005) Karasneh et al. (2003)

IL-1α-889 Number of patients Number of control Patients’ mean age Duration of disease CT (male/female) (male/female) (years) (years) Cases Controls 82/50 61/44 NOT AVAILABLE NOT AVAILABLE 39/97 32/75 29/43 99/64 17/53 22/48 33.6  10.2 7.0  5.6 40/40 58/47 18/80 40/105 35.4  10 8.4  6.5 29/28 22/35 33/72 69/163 34.9  9.9 6.6  6.3 48/49 37/40 44/128 49/105 38.8  10.4 14.2  6.5

TT Cases 6/97 4/53 13/80 9/72 8/128

Controls 6/75 7/48 35/105 16/163 11/105

Study ID Ozcimen et al. (2011) Akman et al. (2008) Alayli et al. (2007) Coskun et al. (2005) Karasneh et al. (2003)

IL-1β  3962 C Cases 150/192 89/110 94/160 – –

Controls 109/148 79/112 107/210 – –

T Cases 42/192 21/110 66/160 – –

Controls 39/148 33/112 103/210 – –

CC Cases 59/96 35/55 16/80 – –

Controls 39/74 28/56 5/105 – –

CT Cases 32/96 19/55 62/80 – –

Controls 31/74 23/56 97/105 – –

Study ID Ozcimen et al. (2011) Akman et al. (2008) Alayli et al. (2007) Coskun et al. (2005) Karasneh et al. (2003)

IL-1Ra C Cases 44/194 – 55/160 – 71/260

Controls 48/154 – 90/210 – 58/210

T Cases 150/194 – 105/160 – 189/260

Controls 106/154 – 120/210 – 152/210

CT Cases 32/97 – 39/80 – 47/130

Controls 36/77 – 58/105 – 46/105

TT Cases 59/97 – 33/80 – 71/130

Controls 35/77 – 31/105 – 53/105

Interleukin-1-related genes polymorphisms 323

DOI 10.3109/14397595.2013.844304

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

Figure 2. Forest plot of meta-analysis of IL-1α -889 CT associated with BD versus control. Squares represent study-specific ORs estimates (size of the square reflects the studyspecific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary OR estimates with corresponding 95% CIs.

CI  1.08–3.99), IL-1β  3962 CT (OR  0.58, 95% CI  0.38– 0.88), IL-1 Ra mspa1l 1100 CT (OR  0.69, 95% CI  0.49–0.96), IL-1 Ra mspa1l 1100 TT (OR  1.50, 95% CI  1.08–2.08) had a statistically significant association with BD. IL-1β  3962 C and IL-1β  3962 CC, IL-1 Ra mspa1l 1100 TT increased the risk of BD by 1.41 (I2  0%) 2.08 (I2  51.5%) and 1.50 (I2  0%), respectively, whereas IL-1α -889 CT, IL-1α -889 TT, IL-1β  3962 T, IL-1β  3962 CT, IL-1 Ra mspa1l 1100 CT were associated with decreased risks of BD. There was no heterogeneity for IL-1β  3962 T, IL-1 Ra mspa1l 1100 CT/TT and mild or moderate statistical heterogeneity for L-1α -889 CT, IL-1α -889 TT, IL-1β  3962 CT. The results of the meta-analysis are summarized in Figures 2–5. Additionally, IL-1α -889 C (OR  1.54, 95% CI  0.98–2.41) with I2  78.8%, IL-1α -889 CC (OR  1.73, 95% CI  0.99–3.02)

Figure 3. Forest plot of meta-analysis of IL-1α -889 TT associated with BD versus control. Squares represent study-specific odds ratios estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary odds ratio estimates with corresponding 95% CIs.

with I2  76.2%, IL-1α -889 T (OR  0.65, 95% CI  0.42–1.02) with I2  78.8%, IL-1 Ra mspa1l 1100 C (OR  0.78, 95% CI  0.61–1.00, P  0.05) with I2  4.4%, IL-1 Ra mspa1l 1100 T (OR  1.28, 95% CI  1.00–1.65, P  0.05) with I2  4.4% had a non-significant association with BD. Besides IL-1β -511 was not associated to BD (data not shown). In order to exclude publication bias, we performed Begg’s test (Figure 6) and Egger’s test and the results showed that there was no evidence of publication bias from P  0.05.

Discussion BD is a multifactorial genetic background disease which, in combination with environmental risk factors such as infectious agents, is probably of importance in determining the susceptibility. Association with MHC genes, including HLA-B*51, MHC

324

J. Zou and J.-L. Guan

Mod Rheumatol, 2014; 24(2): 321–326

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

Figure 4. Forest plot of meta-analysis of IL-1β  3962 CC associated with BD versus control. Squares represent study-specific ORs estimates (size of the square reflects the studyspecific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary OR estimates with corresponding 95% CIs.

class I chain-related genes, tumor necrosis factor (TNF) α and TNF β polymorphisms have been widely reported. IL-1 gene cluster polymorphisms have been studied in this context. Furthermore, polymorphisms in this gene cluster may affect function and cause increased expression of IL1 in BD patients. To the best of our knowledge, this is the first study to evaluate the relationship between the IL-1 gene cluster polymorphisms and BD using a meta-analysis. Our meta-analysis confirmed the association between three IL-1 gene cluster polymorphisms and susceptibility of BD. The carriage of IL-1α -889 allele T is associated with elevated IL-1α in gingival crevicular fluid either patients with severe periodontal disease [19] and increased IL-1β plasma levels in healthy individuals [20]. Our study demonstrates carriage of the IL-1α 889 genotype CT/TT had 28% and 39% lower risk to develop BD, respectively. However IL-1α -889 genotype CC and IL-1α 889 allele C might increase the risk of BD. IL-1α 889 polymorphisms lie upstream in the 5’ regulatory region

in a sequence involved in transcriptional silencing of the IL-1α gene [21]. The IL-1α 889 polymorphisms have been reported to be associated with various inflammatory diseases including systemic sclerosis [22] and juvenile rheumatoid arthritis [21]. Conflicting results have been reported regarding the influence of IL-1β -511 polymorphisms on protein synthesis; several studies have shown that the possession of the TT genotype is associated with an increased production of IL-1 [23–25], while an opposite effect was observed in another study [26]. Five studies included in the current meta-analysis also demonstrated conflicting results. Alayli et al. [16] reported carrying IL-1β -511 genotype CC was more common in BD. Ozcimen et al. [18] found IL-1β -511 genotype TT was more frequent in BD patients. The other three studies [14,15,17] reported no significant difference in genotype and allele frequencies of IL-1β -511 between the patients and controls. Our analysis failed to detect IL-1β -511 gene polymorphisms significantly correlated with BD.

Figure 5. Forest plot of metaanalysis of IL-1 Ra mspa1l 1100 TT associated with BD versus control. Squares represent study-specific ORs estimates (size of the square reflects the study-specific statistical weight, that is, the inverse of the variance); horizontal lines represent 95% CIs; diamonds represent summary odds ratio estimates with corresponding 95% CIs.

Interleukin-1-related genes polymorphisms 325

DOI 10.3109/14397595.2013.844304

larger studies on different ethnic groups are required to reduce the ethnic variation-produced bias.

Conflict of interest None.

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

References

Figure 6. Publication bias in the studies. Begg’s funnel plot indicating no publication bias in the studies included in this meta-analysis. No indication of publication bias was noted from both visualization of funnel plot and Egger’s test.

The current study demonstrated individual bearing IL-1β  3962 CC and IL-1β  3962 C increase the susceptibility of BD by 2 and 1.4-fold, while IL-1β  3962 CT and IL-1β  3962 T reduce the risk to 0.58 and 0.71-fold, respectively. Ozcimen found that IL-1β 3962 gene polymorphism seems to be associated with the presence of Erythema nodosum in BD [18]. Besides IL-1β  3962 polymorphisms have been reported to confer a risk to develop an increasing number of systemic autoinflammatory diseases as well. Sarial et al. [27] reported decrease in frequency of IL-1 TC  3962 genotype in the multiple sclerosis patients versus normal subjects in Iranian population. There was an increased frequency of IL-1β  3962 TT in Romanian multiple myeloma patients [28]. IL-1 Ra is a protein that binds to IL-1 R, which inhibits the binding of IL-1α and IL-1β to the IL-1 R. Polymorphism of IL-1 Ra (allele 2) has been shown to be associated with increased production of IL-1 Ra [29]. Our result revealed that bearing IL-1 Ra mspa1l 1100 TT has a 1.5-fold risk of BD, while IL-1 Ra mspa1l 1100 CT might decrease the risk to 0.31-fold. Moreover, IL-1 Ra polymorphisms have been reported in association with other autoimmunal diseases, such as ulcerative colitis [30], systemic lupus erythematosus [31], alopecia areata [32] and lichen sclerosus [33]. This meta-analysis had several limitations. Firstly, heterogeneity is a potential problem when interpreting any results obtained by meta-analyses. We minimized this likelihood by performing a careful search for published studies, using explicit criteria for study inclusion, precise data extraction and strict data analysis as best as we can. However, some pooled ORs were obtained from heterogeneous studies. Secondly, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings may be unpublished. Additionally, in view of recent interest in possibility of linkage disequilibrium between the two polymorphic sites, it would have been interesting to include an examination of haplotype in our meta-analysis. However, only Karasneh et al. reported the risk of carrying IL-1α  889CC/IL-1β  5889TT haplotype was higher than the individual risks of having one copy of IL-1α 889CC and IL-1β  5889TT genotypes, so we were unable to comment on this aspect. Notably, in this analysis, the sample sizes of several included studies were rather small. Only one study included 128 cases of BD, and most of the studies included less than 100 cases. Additionally, as all the included studies were conducted on Turkish population, the results should be interpreted with great caution. In conclusion, gene polymorphism of IL-1 gene cluster, which in turn leads to the increased expression of IL-1 in BD patient, is involved in the pathogenesis of BD. Further

1. Sakane T, Takeno M, Suzuki N, Inaba G. Behcet’s disease. N Engl J Med. 1999;341(16):1284–91. 2. Zouboulis CC, May T. Pathogenesis of adamantiades-behcet’s disease. Med Microbiol Immunol. 2003;192(3):149–55. 3. Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med. 2009;360(23): 2467–70. 4. Gul A. Behcet’s disease as an autoinflammatory disorder. Curr Drug Targets Inflamm Allergy. 2005;4(1):81–3. 5. Mege JL, Dilsen N, Sanguedolce V, Gul A, Bongrand P, Roux H, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behcet’s disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol. 1993;20(9):1544–49. 6. Gul A, Tugal-Tutkun I, Dinarello CA, Reznikov L, Esen BA, Mirza A, et al. Interleukin-1beta-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet’s disease: an open-label pilot study. Ann Rheum Dis. 2012;71(4):563–6. 7. Deal watch: XOMA and Servier to develop anti-IL-1beta antibody for inflammatory diseases. Nat Rev Drug Discov. 2011;10(3):166. 8. Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA. Resistant Behcet disease responsive to anakinra. Ann Intern Med. 2008; 149(4):284–6. 9. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12. 10. Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet. 1990;335(8697):1078–80. 11. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. 12. Zhang Junming LZ, Tonghua X. Interleukin 1 receptor antagonist gene polymorphism and Behcet’s syndrome. Chinese J Dermatovenereol. 1997;11(4):197–8. 13. Liu Xiang-dong SS-h, Dong-jie X, Guo-ying M, Yun-shan W. Association of il-1 receptor antagonist gene 2/2 genotype with increased susceptibility for Bechcet’s disease with uveitis. J Shandong University (Health Sciences). 2007;45(5):467–9. 14. Karasneh J, Hajeer AH, Barrett J, Ollier WE, Thornhill M, Gul A. Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behcet’s disease. Rheumatology (Oxford). 2003;42(7):8604. 15. Coskun M, Bacanli A, Sallakci N, Alpsoy E, Yavuzer U, Yegin O. Specific interleukin-1 gene polymorphisms in Turkish patients with Behcet’s disease. Exp Dermatol. 2005;14(2):124–9. 16. Alayli G, Aydin F, Coban AY, Sullu Y, Canturk F, Bek Y, et al. T helper 1 type cytokines polymorphisms: association with susceptibility to Behcet’s disease. Clin Rheumatol. 2007;26(8):1299–305. 17. Akman A, Ekinci NC, Kacaroglu H, Yavuzer U, Alpsoy E, Yegin O. Relationship between periodontal findings and specific polymorphisms of interleukin-1alpha and -1beta in Turkish patients with Behcet’s disease. Arch Dermatol Res. 2008;300(1):19–26. 18. Ozcimen AA, Dilek K, Bingol U, Saricaoglu H, Sarandol A, Taskapilioglu O, et al. Oral, IL-1 cluster gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet. 2011;38(4):295–301. 19. Shirodaria S, Smith J, McKay IJ, Kennett CN, Hughes FJ. Polymorphisms in the IL-1A gene are correlated with levels of interleukin-1alpha protein in gingival crevicular fluid of teeth with severe periodontal disease. J Dent Res. 2000;79(11):1864–9. 20. Hulkkonen J. A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals. Eur Cytokine Netw. 2000;11(2):251–5. 21. McDowell TL, Symons JA, Ploski R, Forre O, Duff GW. A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis Rheum. 1995;38(2): 221–8.

Mod Rheumatol Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 12/15/14 For personal use only.

326

J. Zou and J.-L. Guan

22. Hutyrova B, Lukac J, Bosak V, Buc M, du Bois R, Petrek M. Interleukin 1alpha single-nucleotide polymorphism associated with systemic sclerosis. J Rheumatol. 2004;31(1):81–4. 23. Nemetz A, Nosti-Escanilla MP, Molnar T, Kope A, Kovacs A, Feher J, et al. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999;49(6):527–31. 24. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992;22(6): 396–402. 25. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998;47(3):195–8. 26. Iacoviello L, Di Castelnuovo A, Gattone M, Pezzini A, Assanelli D, Lorenzet R, et al. Polymorphisms of the interleukin-1beta gene affect the risk of myocardial infarction and ischemic stroke at young age and the response of mononuclear cells to stimulation in vitro. Arterioscler Thromb Vasc Biol. 2005;25(1):222–7. 27. Sarial S,Shokrgozar MA, Amirzargar A, Shokri F, Radfar J, Zohrevand P, et al. IL-1, IL-1R and TNFalpha gene polymorphisms in Iranian patients with multiple sclerosis. Iran J Allergy Asthma Immunol. 2008;7(1):37–40.

Mod Rheumatol, 2014; 24(2): 321–326

28. Banu C, Moise A, Arion C, Coriu D, Tanase A. Constantinescu I, Cytokine gene polymorphisms support diagnostic monitoring of Romanian multiple myeloma patients. J Med Life. 2011;4(3): 264–8. 29. Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995;99(2):303–10. 30. Mansfield JC, Holden H, Tarlow JK, Di Giovine FS, McDowell TL,Wilson AG, et al. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology. 1994;106(3):637–42. 31. Blakemore AI, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW. Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum. 1994;37(9):1380–5. 32. Tarlow JK, Clay FE, Cork MJ,Blakemore AI, McDonagh AJ, Messenger AG, et al. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol. 1994;103(3):387–90. 33. Clay FE, Cork MJ, Tarlow JK, Blakemore AI, Harrington CI, Lewis F, et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet. 1994;94(4):407–10.

Interleukin-1-related genes polymorphisms in Turkish patients with Behçet disease: a meta-analysis.

Polymorphisms in the Interleukin (IL)-1-related genes at the locations -889, -511, + 3962 and mspa1l 1100 have been investigated for possible associat...
595KB Sizes 0 Downloads 0 Views