Polymorphic variants of MIF gene and prognosis in steroid therapy in children with idiopathic nephrotic syndrome
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Nephrotic syndrome (NS) is the most common reason of proteinuria in children and can be caused by the pathology of renal glomeruli. Steroid therapy is typically used in this disorder. It has been shown that MIF is a cytokine which counteracts the immunosuppressive properties of glucocorticoids. The aim of this study was looking for a correlation between MIF polymorphisms and genetic susceptibility to steroid resistance in children with INS (Idiopathic NS). Methods: The study was performed in 71 patients with INS including SRNS (steroid resistance nephrotic syndrome) (41) and SSNS (steroid sensitive nephrotic syndrome) (30) and in 30 control subjects. We employed Sanger sequencing and capillary electrophoresis. Linkage disequilibrium was made using Haploview and PHASE. Results: We didn't observe a statistical significance between SNPs detected in patients with INS and controls. Our studies revealed statistical significance for two polymorphisms: rs2070767C > T and rs2000466T > G between patients with SRNS and SSNS. The results for rs34383331T > A are close to being statistically significant. Statistical significance was revealed for CATT5/CATT6 genotype in SRNS group vs SSNS group (OR=4.604, 95%CI=1.356-15.632, p=0.0168). We found that the frequency of 5/X-CATT genotype compared with X/X-CATT genotype was significantly higher in SRNS patients vs SSNS (OR=3.167, 95%CI=1.046-9.585, p=0.0426). In linkage disequilibrium analysis we didn't show involvement in susceptibility to INS and steroid sensitive phenotype. Conclusions: Our results suggest that the role of MIF polymorphisms in the susceptibility to positive response to steroid therapy is still unresolved. It indicates that MIF may be involved in indirect and complex molecular mechanisms of steroid activity in hormone-dependent metabolic pathways in children with INS. Because of ambiguous findings, pleiotropic features of this cytokine require that more research should be undertaken.
- Abid A, Khaliq S, Shahid S, Lanewala A, Mubarak M, Hashmi S, Kazi J, Masood T, Hafeez F, Naqvi SA, Rizvi SA, Mehdi SQ (2012) A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan. Gene 502: 133-137.
- Alangari AA (2010) Genomic and non-genomic actions of glucocorticoids in asthma. Ann Thorac Med 5: 133-139.
- Banaszak B, Banaszak P, Adamczyk P, Ziora K (2011) The onset of childhood nephrotic syndrome - clinical characteristics of steroid-sensitive and steroid-resistant patients. Przegląd Pediatr 41: 147-151.
- Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373: 1905-1917.
- Baugh JA, Chitnis S, Donnelly SC, Monteiro J, Lin X, Plant BJ, Wolfe F, Gregersen PK, Bucala R (2002) A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3: 170-176.
- Berdeli A, Mir S, Ozkayin N, Serdaroglu E, Tabel Y, Cura A (2005) Association of macrophage migration inhibitory factor -173C allele polymorphism with steroid resistance in children with nephrotic syndrome. Pediatr Nephrol 20: 1566-1571.
- Berdeli A, Ozyürek AR, Ulger Z, Gürses D, Levent E, Salar K, Gürpinar AR (2006) Association of macrophage migration inhibitory factor gene -173 G/C polymorphism with prognosis in turkish children with juvenile rheumatoid arthritis. Rheumatol Int 26: 726-731.
- Bucala R (2013) MIF, MIF Alleles, and Prospects for Therapeutic Intervention in Autoimmunity. J Clin Immunol 33: S72-S78.
- Choi HJ, Cho HY, Ro H, Lee SH, Han KH, Lee H, Kang HG, Ha IS, Choi Y, Cheong HI (2011) Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome. Pediatr Nephrol 26: 1981-1988.
- Donn R, Alourfi Z, De Benedetti F, Meazza C, Zeggini E, Lunt M, Stevens A, Shelley E, Lamb R, Ollier WE, Thomson W, Ray D (2002) Mutation screening of the macrophage migration inhibitory factor gene positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 46: 2402-2409.
- Donn R, Ray DW (2004) Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule. J Endocrinol 182: 1-9.
- Gao L, Flores C, Fan-Ma S, Miller EJ, Moitra J, Moreno L, Wadgaonkar R, Simon B, Brower R, Sevransky J, Tuder RM, Maloney JP, Moss M, Shanholtz C, Yates CR, Meduri GU, Ye SQ, Barnes KC, Garcia JG (2007) Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations. Transl Res 150: 18-29.
- Gázquez I, Moreno A, Requena T, Ohmen J, Santos-Perez S, Aran I, Soto-Varela A, Pérez-Garrigues H, López-Nevot A, Batuecas A, Friedman RA, López-Nevot MA, López-Escamez JA (2012) Functional variants of MIF, INFG and TFNA genes are not associated with disease susceptibility or hearing loss progression in patients with Ménière's disease. Eur Arch Otorhinolaryngol 270: 1521-1529.
- Grieb G, Merk M, Bernhagen J, Bucala R (2010) Macrophage migration inhibitory factor (MIF): a promising biomarker. Drug News Perspect 23: 257-264.
- Gross KL, Lu NZ, Cidlowski JA (2009) Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 300: 7-16.
- Gómez LM, Sánchez E, Ruiz-Narvaez EA, López-Nevot MA, Anaya JM, Martín J (2007) Macrophage migration inhibitory factor gene influences the risk of developing tuberculosis in northwestern Colombian population. Tissue Antigens 70: 28-33.
- Harambat J, Godron A, Ernould S, Rigothier C, Llanas B, Leroy S (2013) Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome. Pediatr Nephrol 28: 631-638.
- Hodson EM, Knight JF, Willis NS, Craig JC (2000) Corticosteroid therapy in nephrotic syndrome: a meta-analysis of randomised controlled trials. Arch Dis Child 83: 45-51.
- Lan HY (2008) Role of macrophage migration inhibition factor in kidney disease. Nephron Exp Nephrol 109: e79-e83.
- Li Y, Zeng Z, Deng S (2012) Study of the relationship between human MIF level, MIF-794CATT5-8 microsatellite polymorphism, and susceptibility of tuberculosis in Southwest China. Braz J Infect Dis 16: 383-386.
- Li Y, Wang J, Zhu X, Feng Q, Li X, Feng X (2012) Urinary protein markers predict the severity of renal histological lesions in children with mesangial proliferative glomerulonephritis. BMC Nephrol 13: 29.
- Li Y, Yuan T, Lu W, Chen M, Cheng X, Deng S (2012) Association of tuberculosis and polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) in a Southwestern China Han population. Cytokine 60: 64-67.
- Liu R, Xu N, Wang X, Shen L, Zhao G, Zhang H, Fan W (2012) Influence of MIF, CD40, and CD226 polymorphisms on risk of rheumatoid arthritis. Mol Biol Rep 39: 6915-6922.
- Lolis E (2011) Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Curr Opin Pharmacol 1: 662-668.
- Matsumoto K, Maruyama N, Maruyama T, Ohnishi Y, Nonaka S, Inoshita A, Ito K, Kitajima S, Abe M, Satomura A, Fujita T (2005) Elevated macrophage migration inhibitory factor (MIF) levels in the urine of patients with focal glomerular sclerosis. Clin Exp Immunol 139: 338-347.
- Mehls O, Hoyer PF (2011) Dosing of glucocorticosteroids in nephrotic syndrome. Pediatr Nephrol 26: 2095-2098.
- Renner P, Roger T, Calandra T (2005) Macrophage migration inhibitory factor: gene polymorphisms and susceptibility to inflammatory diseases. Clin Infect Dis 41: S513-S519.
- Shiroeda H, Tahara T, Nakamura M, Shibata T, Nomura T, Yamada H, Hayashi R, Saito T, Yamada M, Fukuyama T, Otsuka T, Yano H, Ozaki K, Tsuchishima M, Tsutsumi M, Arisawa T (2010) Association between functional promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene and ulcerative colitis in Japan. Cytokine 51: 173-177.
- Smoak KA, Cidlowski JA (2004) Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev 125: 697-706.
- Sreih A, Ezzeddine R, Leng L, LaChance A, Yu G, Mizue Y, Subrahmanyan L, Pons-Estel BA, Abelson AK, Gunnarsson I, Svenungsson E, Cavett J, Glenn S, Zhang L, Montgomery R, Perl A, Salmon J, Alarcón-Riquelme ME, Harley JB, Bucala R (2011) Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus. Arthritis Rheum 63: 3942-3951.
- Stahn C, Buttgereit F (2008) Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol 4: 525-533.
- Stosic-Grujicic S, Stojanovic I, Nicoletti F (2009) MIF in autoimmunity and novel therapeutic approaches. Autoimmun Rev 8: 244-249.
- Van Husen M, Kemper MJ (2011) New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol 26: 881-892.
- Vivarelli M, D'Urbano LE, Stringini G, Ghiggeri GM, Caridi G, Donn R, Tozzi A, Emma F, De Benedetti F (2008) Association of the macrophage migration inhibitory factor −173*C allele with childhood nephrotic syndrome. Pediatr Nephrol 23: 743-748.
- Xie Q, Wang SC, Bian G, Zhan FL, Xie JK, Li J (2012) Association of MIF-173G/C and MBL2 codon 54 gene polymorphisms with rheumatoid arthritis: A meta-analysis. Hum Immunol 73: 966-971.
- Zheng X, Wang D, Hou S, Zhang C, Lei B, Xiao X, Kijlstra A, Yang P (2012) Association of macrophage migration inhibitory factor gene polymorphisms with Behçet's disease in a han chinese population. Ophthalmology 119: 2514-2518.
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