Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study

BMC Medical Genetics

Salvador Resino²  Jesús F Bermejo-Martin³  Juan Miguel García-Gómez⁶  Jesús Bustamante¹  José I Gómez-Herreras⁴  María Heredia⁴  Laura Segura-Roda⁶  Pablo Fernández-Navarro⁵  Eduardo Tamayo⁴  Amanda Fernandez-Rodríguez²  Elisabeth López⁴  Ma Angeles Jimenez-Sousa² 

[1] Departamento de Nefrología, Hospital Clínico Universitario, Valladolid, Spain;Unidad de Epidemiología Molecular de Enfermedades Infecciosas, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda- Pozuelo, Km 2.2, 28220, Majadahonda (Madrid), Spain;Unidad de Investigación Médica en Infección e Inmunidad, Hospital Clínico Universitario-IECSCYL, Valladolid, Spain;Departamento de Anestesiología y Reanimación, Hospital Clínico Universitario, Valladolid, Spain;CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain;IBIME, Instituto de Aplicaciones de las Tecnologías de la Información y de las Comunicaciones Avanzadas (ITACA), Universitat Politècnica de València, València, Spain

关键词: Immunity;    Inflammation;    Genetic polymorphism;    Kidney;    ESRD;   

Others  :  1177831
DOI  :  10.1186/1471-2350-13-58

 received in 2012-01-30, accepted in 2012-07-20,  发布年份 2012

【 摘 要 】

Background

Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem.

Objective

To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development.

Design and methods

A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD.

Results

Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance.

Conclusion

Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.

【 授权许可】

   
2012 Jiménez-Sousa et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Otero A, de Francisco A, Gayoso P, Garcia F: Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia 2010, 30(1):78-86.
• [2]Kottgen A: Genome-wide association studies in nephrology research. Am J Kidney Dis 2010, 56(4):743-758.
• [3]Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, Jong PE, Coresh J, de Jong PE, El-Nahas M, et al.: Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes in both general and high-risk populations. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011, 80(1):93-104.
• [4]Reich HN, Gladman DD, Urowitz MB, Bargman JM, Hladunewich MA, Lou W, Fan SC, Su J, Herzenberg AM, Cattran DC, et al.: Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus. Kidney Int 2011, 9(8):914-920.
• [5]Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DS: Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int 2007, 72(5):549-556.
• [6]Munshi R, Hsu C, Himmelfarb J: Advances in understanding ischemic acute kidney injury. BMC Med 2011, 9(1):11. BioMed Central Full Text
• [7]Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, et al.: New loci associated with kidney function and chronic kidney disease. Nat Genet 2010, 42(5):376-384.
• [8]Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, et al.: Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 2010, 42(5):373-375.
• [9]Ribases M, Ramos-Quiroga JA, Sanchez-Mora C, Bosch R, Richarte V, Palomar G, Gastaminza X, Bielsa A, Arcos-Burgos M, Muenke M, et al.: Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study. Genes Brain Behav 2010, 10(2):149-157.
• [10]Sole X, Guino E, Valls J, Iniesta R, Moreno V: SNPStats: a web tool for the analysis of association studies. Bioinformatics 2006, 22(15):1928-1929.
• [11]Fried L, Solomon C, Shlipak M, Seliger S, Stehman-Breen C, Bleyer AJ, Chaves P, Furberg C, Kuller L, Newman A: Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. J Am Soc Nephrol 2004, 15(12):3184-3191.
• [12]Wolkow PP, Niewczas MA, Perkins B, Ficociello LH, Lipinski B, Warram JH, Krolewski AS: Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol 2008, 19(4):789-797.
• [13]Nakamura E, Megumi Y, Kobayashi T, Kamoto T, Ishitoya S, Terachi T, Tachibana M, Matsushiro H, Habuchi T, Kakehi Y, et al.: Genetic polymorphisms of the interleukin-4 receptor alpha gene are associated with an increasing risk and a poor prognosis of sporadic renal cell carcinoma in a Japanese population. Clin Cancer Res 2002, 8(8):2620-2625.
• [14]Burgos PI, Causey ZL, Tamhane A, Kelley JM, Brown EE, Hughes LB, Danila MI, van Everdingen A, Conn DL, Jonas BL, et al.: Association of IL4R single-nucleotide polymorphisms with rheumatoid nodules in African Americans with rheumatoid arthritis. Arthritis Res Ther 2010, 12(3):R75. BioMed Central Full Text
• [15]Tachdjian R, Mathias C, Al Khatib S, Bryce PJ, Kim HS, Blaeser F, O'Connor BD, Rzymkiewicz D, Chen A, Holtzman MJ, et al.: Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. J Exp Med 2009, 206(10):2191-2204.
• [16]Zheng G, Wang Y, Xiang SH, Tay YC, Wu H, Watson D, Coombes J, Rangan GK, Alexander SI, Harris DC: DNA vaccination with CCL2 DNA modified by the addition of an adjuvant epitope protects against "nonimmune" toxic renal injury. J Am Soc Nephrol 2006, 17(2):465-474.
• [17]Kang YS, Lee MH, Song HK, Ko GJ, Kwon OS, Lim TK, Kim SH, Han SY, Han KH, Lee JE, et al.: CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice. Kidney Int 2010, 78(9):883-894.
• [18]Dai R, Ahmed SA: MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases. Transl Res 2011, 157(4):163-179.
• [19]Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM: PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 2002, 18(2):333-334.
• [20]Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, Messeguer X: Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res 2003, 31(13):3651-3653.
• [21]Wei L, Vahedi G, Sun HW, Watford WT, Takatori H, Ramos HL, Takahashi H, Liang J, Gutierrez-Cruz G, Zang C, et al.: Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 2010, 32(6):840-851.
• [22]Nakayama T, Sato W, Kosugi T, Zhang L, Campbell-Thompson M, Yoshimura A, Croker BP, Johnson RJ, Nakagawa T: Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse. Am J Physiol Renal Physiol 2009, 296(2):F317-327.
• [23]Webber JL, Tooze SA: New insights into the function of Atg9. FEBS Lett 2010, 584(7):1319-1326.
• [24]Kullo IJ, Greene MT, Boerwinkle E, Chu J, Turner ST, Kardia SL: Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. Atherosclerosis 2008, 196(2):905-912.
• [25]Popov AF, Hinz J, Schulz EG, Schmitto JD, Wiese CH, Quintel M, Seipelt R, Schoendube FA: The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction. Eur J Cardiothorac Surg 2009, 36(4):651-656.
• [26]Wang CH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, Takahashi N: A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Proc Natl Acad Sci U S A 2011, 108(5):2070-2075.
• [27]Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C: Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009, 37(9):e67.
• [28]Sironi M, Menozzi G, Riva L, Cagliani R, Comi GP, Bresolin N, Giorda R, Pozzoli U: Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res 2004, 32(5):1783-1791.
• [29]Perneger TV: What's wrong with Bonferroni adjustments. BMJ 1998, 316(7139):1236-1238.
• [30]Sterne JA, Davey Smith G: Sifting the evidence-what's wrong with significance tests? BMJ 2001, 322(7280):226-231.