Human Molecular Genetics Advance Access originally published online on July 7, 2009
Human Molecular Genetics 2009 18(19):3739-3748; doi:10.1093/hmg/ddp301
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Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus
1 Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada 18100, Spain, 2 Hospital Xeral-Calde, Servicio de Reumatología, Lugo 27004, Spain, 3 Hospital Clínico San Cecilio, Unidad de enfermedades sistémicas autoinmunes, Granada 18012, Spain, 4 Hospital Virgen de las Nieves, Servicio de Medicina Interna, Granada 18014, Spain, 5 Hospital Virgen de las Nieves, Servicio de Inmunología, Granada 18014, Spain, 6 Hospital Virgen del Rocío, Servicio de Medicina Interna, Sevilla 41013, Spain, 7 Hospital Carlos Haya, Servicio de Medicina Interna, Málaga 29010, Spain, 8 Hospital Virgen del Rocio, Servicio de Inmunologia, Sevilla 41013, Spain, 9 Sanatorio Parque, Rosario 860, Argentina, 10 Department of Medical Sciences and IRCAD, University of Eastern Piedmont, Novara 28100, Italy, 11 U.O.C. di Reumatologia Ospedale San Camillo, Roma 00151, Italy and 12 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden
* To whom correspondence should be addressed at: Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain. Tel: +34 958181621; Fax: +34 958181632; Email: elena{at}ipb.csic.es
Received April 14, 2009; Accepted June 26, 2009
Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR = 1.37, 95% CI 1.21–1.54, combined P = 3.8E-07, Pc = 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.
Both authors have contributed equally to this work.
B.A.P.-E. is coordinator of the Argentine collaborative group. The list of participants is given in Appendix section along with Italian collaborative group.