Abstract
Background
Aberrant expression and structural alteration of miRNAs are considered to participate in inflammation and cancer development. It has been suggested that common single-nucleotide polymorphisms (SNPs) in miRNAs are associated with susceptibility to several human diseases.
Methods
In the present preliminary study we evaluated the associations of two SNPs (rs2910164 and rs11614913 in miR-146a and miR-196a2, respectively) with the risk of inflammatory bowel disease (IBD) in a Greek population.
Results
The rs2910164 and rs11614913 SNPs were genotyped in 242 patients with Crohn’s disease (CD), 210 patients with ulcerative colitis (UC) and 300 healthy individuals. No statistically significant differences were found in the genotype or allele distributions of the rs2910164 SNP among UC and control subjects. However, significant differences were found in the genotype or allele distributions of the rs2910164 polymorphism among CD and control subjects (P < 0.0001 and P < 0.0001, respectively). Concerning the rs11614913, no statistically significant differences were found in the genotype or allele distributions among CD and control patients, whereas TT genotype and T allele seem to have a protective role against UC (P = 0.017 and P = 0.007, respectively). The presence of rs2910164 and rs11614913 SNPs did not influence disease phenotype.
Conclusions
Our results demonstrate that the rs2910164 polymorphism has a major role in genetic susceptibility to CD but not to UC, since the rs11614913 polymorphism had a protective role against UC, at least in the population studied here. Independent studies are needed to validate our findings in larger series and in patients of different ethnic origins.
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References
Cosnes J, Gowerrousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–1794.
Hugot JP. Genetic origin of IBD. Inflamm Bowel Dis. 2004;10:S11–S15.
Shanahan F. Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics. Gastroenterology. 2001;120:622–635.
Wei B, Pei G. microRNAs: critical regulators in Th17 cells and players in diseases. Cell Mol Immunol. 2010;7:175–181.
Glinsky GV. Phenotype-defining functions of multiple non-coding RNA pathways. Cell Cycle. 2008;7:1630–1639.
Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev. 2006;16:203–208.
Archanioti P, Gazouli M, Theodoropoulos G, Vaiopoulou A, Nikiteas N. Micro-RNAs as regulators and possible diagnostic bio-markers in inflammatory bowel disease. J Crohns Colitis. 2011;5:520–524.
Seitz H. Redefining microRNA targets. Curr Biol. 2009;19:870–873.
Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113:673–676.
Xiao C, Rajewsky K. MicroRNA control in the immune system: basic principles. Cell. 2009;136:26–36.
Paraskevi A, Theodoropoulos G, Papaconstantinou I, Mantzaris G, Nikiteas N, Gazouli M. Circulating MicroRNA in inflammatory bowel disease. J Crohns Colitis. 2012;6:900–904.
Kanaan Z, Rai SN, Eichenberger MR, et al. Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer. Hum Mutat. 2012;33:551–560.
Hezova R, Kovarikova A, Bienertova-Vasku J, et al. Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World J Gastroenterol. 2012;18:2827–2831.
Liu Z, Li G, Wei S, et al. Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck. Cancer. 2010;116:4753–4760.
Chu YH, Tzeng SL, Lin CW, Chien MH, Chen MK, Yang SF. Impacts of microRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer. PLoS One. 2012;7:e39777. doi:10.1371/journal.pone.0039777.
Glinsky GV. Disease phenocode analysis identifies SNP-guided microRNA maps (MirMaps) associated with human “master” disease genes. Cell Cycle. 2008;7:3680–3694.
Jedlinski DJ, Gabrovska PN, Weinstein SR, Smith RA, Griffiths LR. Single nucleotide polymorphism in hsa-mir-196a-2 and breast cancer risk: a case control study. Twin Res Hum Genet. 2011;14:417–421.
Guo J, Jin M, Zhang M, Chen K. A genetic variant in miR-196a2 increased digestive system cancer risks: a meta-analysis of 15 case-control studies. PLoS One. 2012;7:e30585. doi:10.1371/journal.pone.0030585.
Min KT, Kim JW, Jeon YJ, et al. Association of the miR-146aC>G, 149C>T, 196a2C>T, and 499A>G polymorphisms with colorectal cancer in the Korean population. Mol Carcinog. 2011;51:E65–73. doi:10.1002/mc.21849.
Zhang M, Jin M, Yu Y, et al. Associations of miRNA polymorphisms and female physiological characteristics with breast cancer risk in Chinese population. Eur J Cancer Care (Engl). 2012;21:274–280.
Brest P, Lapaquette P, Mograbi B, et al. Risk predisposition for Crohn disease: a “ménage à trois” combining IRGM allele, miRNA and xenophagy. Autophagy. 2011;7:786–787.
Lung RW, Wang X, Tong JH, et al. A single nucleotide polymorphism in microRNA-146a is associated with the risk for nasopharyngeal carcinoma. Mol Carcinog. 2012. doi:10.1002/mc.21937.
Zhou F, Zhu H, Luo D, et al. A functional polymorphism in pre-miR-146a is associated with susceptibility to gastric cancer in a Chinese population. DNA Cell Biol. 2012;31:1290–1295.
Lian H, Wang L, Zhang J. Increased risk of breast cancer associated with CC genotype of Has-miR-146a rs2910164 polymorphism in Europeans. PLoS One. 2012;7:e31615. doi:10.1371/journal.pone.0031615.
Hung PS, Chang KW, Kao SY, Chu TH, Liu CJ, Lin SC. Association between the rs2910164 polymorphism in pre-mir-146a and oral carcinoma progression. Oral Oncol. 2012;48:404–408.
Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 2006;103:12481–12486.
Pauley KM, Satoh M, Chan AL, et al. R-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10:1–10.
Okubo M, Tahara T, Shibata T, et al. Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis. J Clin Immunol. 2011;31:69–73.
Podolsky DK. Inflammatory bowel disease. N Engl J Med. 1991;325:928–937.
Wu F, Zikusoka M, Trindade A, et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology. 2008;135:1624–1635.
Wu F, Zhang S, Dassopoulos T, et al. Identification of microRNAs associated with ileal and colonic Crohn’s disease. Inflamm Bowel Dis. 2010;16:1729–1738.
Zahm AM, Thayu M, Hand NJ, Horner A, Leonard MB, Friedman JR. Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2011;53:26–33.
Glinsky GV. SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways. Cell Cycle. 2008;7:3564–3576.
Jazdzewski K, Liyanarachchi S, Swierniak M, et al. Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc Natl Acad Sci USA. 2009;106:1502–1505.
Xu B, Feng NH, Li PC, et al. A functional polymorphism in pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate. 2010;70:467–472.
Gao LB, Bai P, Pan XM, et al. The association between two polymorphisms in pre-miRNAs and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2011;125:571–574.
Su XW, Yang Y, Lv ML, et al. Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population. DNA Cell Biol. 2011;30:919–923.
Iborra M, Bernuzzi F, Invernizzi P, Danese S. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun Rev. 2012;11:305–314.
Boldin MP, Taganov KD, Rao DS, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208:1189–1201.
Hoffman AE, Zheng T, Yi C, et al. microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res. 2009;69:5970–5977.
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The study was supported by ELIGAST and by Empeirikion Foundation.
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Gazouli, M., Papaconstantinou, I., Stamatis, K. et al. Association Study of Genetic Variants in miRNAs in Patients with Inflammatory Bowel Disease: Preliminary Results. Dig Dis Sci 58, 2324–2328 (2013). https://doi.org/10.1007/s10620-013-2640-y
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DOI: https://doi.org/10.1007/s10620-013-2640-y