Abstract
Purpose
Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease that characteristically affects the sacroiliac joints and the spine. The exact pathogenesis of AS remains poorly understood, but genetic factors play a key role in disease development. Several genes have been consistently associated with susceptibility to AS. This study was conducted in Turkish AS patients to determine the frequency of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and interleukin-4 (IL-4) gene 70 bp variable number of tandem repeats (VNTR) variants, as well as their association with clinical characteristics.
Methods
Genomic DNA obtained from 272 persons (122 AS patients and 150 healthy controls) was used in this study. Genomic DNA was isolated and genotyped using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR C677T and IL-4 70 bp VNTR gene variants, which were determined using specific PCR primers.
Results
There was statistically significant difference between the groups with respect to MTHFR genotype distribution (p = 0.02) and allele frequencies (p < 0.001). When we examined MTHFR and IL-4 genotype frequencies according to clinical characteristics, we found an association between the homozygous MTHFR TT genotype and ocular involvement, although this did not reach statistical significance (p = 0.02). However, we did not find any difference between the groups with respect to IL-4 genotype distribution or allele frequencies and clinical characteristics (p > 0.05).
Conclusion
Our findings suggest that there is an association of the MTHFR gene C677T polymorphism with the susceptibility of a person for development of AS. However, the IL-4 gene is not associated with AS within the same population.
Zusammenfassung
Ziel
Die ankylosierende Spondylitis (AS) ist eine chronisch entzündliche rheumatische Erkrankung, die typischerweise die Sakroiliakalgelenke und die Wirbelsäule betrifft. Die Pathogenese der AS ist bis heute nicht genau geklärt, jedoch spielen genetische Faktoren eine wesentliche Rolle bei ihrer Entstehung. Durchgängig wurden mehrere Gene mit der Anfälligkeit für eine AS in Verbindung gebracht. Die vorliegende Studie an türkischen AS-Patienten wurde mit dem Ziel durchgeführt, die Häufigkeit des Methylentetrahydrofolatreduktase(MTHFR)-Gens C677T und von 70-bp-Variable-Number-of-Tandem-Repeats(VNTR)-Varianten des Interleukin-4(IL-4)-Gens sowie ihren Zusammenhang mit klinischen Merkmalen zu ermitteln.
Methoden
In dieser Studie wurde genomische DNA von 272 Personen (122 AS-Patienten und 150 gesunde Kontrollen) eingesetzt. Isoliert und genotypisiert wurde die genomische DNA unter Verwendung eines polymerasekettenreaktions(PCR)-basierten Restriktionsfragmentlängenpolymorphismus(RFLP)-Assays für die Genvarianten MTHFR-C677T und IL-4-70-bp-VNTR, die mittels spezifischer PCR-Primer bestimmt wurden.
Ergebnisse
Es bestanden statistisch signifikante Unterschiede zwischen den Gruppen in Hinblick auf die MTHFR-Genotypverteilung (p = 0,02) und -Allelfrequenz (p < 0,001). Bei der Untersuchung der MTHFR- und IL-4-Genotyphäufigkeit gemäß klinischen Merkmalen stellte sich ein Zusammenhang zwischen homozygotem MTHFR-TT-Genotyp und Augenbeteiligung heraus, allerdings erreichte dieser keine statistische Signifikanz (p = 0,02). Es fand sich jedoch kein Unterschied zwischen den Gruppen in Bezug auf die IL-4-Genotypverteilung und -Allelfrequenz und klinische Merkmale (p > 0,05).
Schlussfolgerung
Den vorliegenden Befunden zufolge gibt es einen Zusammenhang zwischen dem MTHFR-Gen-C677T-Polymorphismus und der Anfälligkeit einer Person für die Entwicklung einer AS. Das IL-4-Gen ist innerhalb derselben Population jedoch nicht mit AS vergesellschaftet.
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References
Agache M, Mıtulescu CT, Dimancescu M et al (2008) Significance of uveitis in patients with ankylosing spondylitis report from the Romanian Centre of Rheumatic Diseases. J Clin Med 3:168–173
Max R, Lorenz HM, Mackensen F (2010) Ocular involvment in spondyloarthropathies HLA B27 associated uveitis. Z Rheumatol 69(5):397–402
Thomas GP, Brown MA (2010) Genetics and genomics of Akylosing spondylitis. Immunol Rev 233:162–180
Bodur H, Ataman S, Buğdaycı DS et al (2012) Description of the registry of patients with anklosing spondylitis in Turkey: TRASD-IP. Rheumatol Int 32:169–176
Brown AM (2011) Progress in the genetics of ankylosing spondylitis. Brief Funct Genomics. doi:10.1093/bfgp/elr023
Toffoli G, Russo A, Innocenti F et al (2003) Effect of methylenetetrahydrofolate reductase 677CRT polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer 103:294–299
Kang SS, Zhou J, Wong PW et al (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43:414–421
Rosendaal FR (1997) Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol 34:171–177
Seshadri N, Robinson K (2000) Homocysteine, B vitamins and coronary artery disease. Med Clin North Am 84:215–217
Negoro K, Kinouchi Y, Hiwatashi N et al (1999) Crohn’s disease is flanking region of the associated with novel polymorphisms in the tumor necrosis factor gene. Gastroenterology 117:1062–1068
Elkarim RA, Mustafa M, Kivisakk P et al (1998) Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. Eur J Clin Invest 28:295–299
Sobti RC, Maithil N, Thakur H et al (2010) VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population. Mol Cell Biochem 341:139–148
Sezer U, Erciyas K, Pehlivan Y et al (2012) Serum cytokine levels and periodontal parameters in ankylosing spondylitis. J Periodontal Res 47:396–401
Tutuncu ZN, Bilgie A, Kennedy LG, Calin A (1994) Interleukin-6, acute phase reactants and clinical status in ankylosing spondylitis. Ann Rheum Dis 53:425–426
Gratacos J, Collado A, Filella X et al (1994) Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol 33:927–931
Falkenbach A, Herold M (1998) In ankylosing spondylitis serum interleukin-6 correlates with the degree of mobility restriction, but not with short-term changes in the variables for mobility. Rheumatol Int 18:103–106
Gratacos J, Collado A, Pons F et al (1999) Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum 42:2319–2324
Bal A, Unlu E, Bahar G et al (2007) Comparison of serum IL-1 beta, sIL-2R, IL-6, and TNF-alpha levels with disease activity parameters in ankylosing spondylitis. Clin Rheumatol 26:211–215
Lange U, Teichmann J, Stracke H (2000) Correlation between plasma TNF-alpha, IGF-1, biochemical markers of bone metabolism, markers of inflammation disease activity, and clinical manifestations in ankylosing spondylitis. Eur J Med Res 5:507–511
Van der Linden S, Vonder Heide D, Braun J (2006) Ankylosing spondylitis. In: Harris ED (Hrsg) Kelley’s textbook of rheumatology, 7th edn. pp 1125–1138
Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
Baskan BM, Sivas F, Akbulut Aktekin L et al (2009) Serum homocysteine level in patients with ankylosing spondylitis. Rheumatol Int 29:1435–1439
Zalavras CG, Vartholomatos G, Dokou E, Malizos KN (2004) Genetic background of osteonecrosis: associated with thrombophilic mutations? Clin Orthop Relat Res 422:251–255
Ozkul Y, Evereklioglu C, Borlu M et al (2005) 5,10 Methylenetetrahydrofolate reductase C677T gene polymorphism in Behcet’s patients with or without ocular involvement. Br J Ophthalmol 89:1634–1637
Vayá A, Miguel De la Fuente J, Suescun M et al (2012) Posterior ocular involvement in Beçet’s disease and thrombophilic mutations. Clin Hemorheol Microcirc 51:225–228
Karakus N, Yigit S, Kalkan G et al (2012) Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet’s disease. Mol Vis 18:1696–1700
Shang X, Su H, Chang W et al (2012) Association between MTHFR C677T polymorphism and osteonecrosis of the femoral head: a meta-analysis. Mol Biol Rep 39:7089–7094
Reveille JD (2011) The genetic basis of spondyloarthritis. Ann Rheum Dis 70(Suppl 1):i44–i50
Brown MA (2009) Progress in studies of the genetics of ankylosing spondylitis. Arthritis Res Ther 11:254. doi:10.1186/ar2692
Chen C, Zhang X, Li J, Wang Y (2012) Associations of IL-23R polymorphisms with ankylosing spondylitis in East Asian population: a new case–control study and a meta-analysis. Int J Immunogenet 39:126–130
Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143
Inanir A, Yigit S, Tekcan A et al (2013) IL-4 and MTHFR gene polymorphism in rheumatoid arthritis and their effects. Immunol Lett 152:104–108
Yigit S, Inanir A, Tekcan A et al (2013) Association between fibromyalgia syndrome and polymorphism of the IL-4 gene in a Turkish population. Gene 527:62–64
Djouadi K, Nedelec B, Tamouza R et al (2001) Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies. Cytokine 13:98–103
Maksymowych WP, Rahman P, Reeve JP et al (2006) Association of the IL-1 gene cluster with susceptibility to ankylosing spondylitis: an analysis of three Canadian populations. Arthritis Rheum 54:974–985
Timms AE, Crane AM, Sims AM et al (2004) The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet 75:587–595
Paardt M, Crusius JB, García-González MA et al (2002) Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology (Oxford) 41:1419–1423
Wong RH, Wei JC, Huang CH et al (2012) Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol 39:135–140
Reveille JD (2012) Genetics of spondyloarthritis-beyond the MHC. Nat Rev Rheumatol 8:296–304
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Conflict of interest. S. Yigit, A. Inanir, S. Tural, B. Filiz and A. Tekcan state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.
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Yigit, S., Inanir, A., Tural, S. et al. The effect of IL-4 and MTHFR gene variants in ankylosing spondylitis. Z. Rheumatol. 74, 60–66 (2015). https://doi.org/10.1007/s00393-014-1403-2
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DOI: https://doi.org/10.1007/s00393-014-1403-2