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Role of SLC22A4, SLC22A5, and RUNX1 Genes in Rheumatoid

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Role of SLC22A4, SLC22A5, and RUNX1 Genes in Rheumatoid Role of SLC22A4, SLC22A5, and RUNX1 Genes in Rheumatoid Arthritis ALFONSO MARTÍNEZ, ANTONIO VALDIVIA, DORA PASCUAL-SALCEDO, ALEJANDRO BALSA, BENJAMÍN FERNÁNDEZ-GUTIÉRREZ, EMILIO G. de la CONCHA, and ELENA URCELAY ABSTRACT. Objective. Excessively suppressed expression of the SLC22A4 gene by RUNX1 is associated with the pathogenesis of rheumatoid arthritis (RA). Two etiological polymorphisms in the RUNX1 and SLC22A4 genes have been defined in a Japanese population. We studied additional polymorphisms to ascertain whether any SLC22A4/SLC22A5 haplotype is relevant for RA predisposition in a Spanish population. Method. We performed a case-control study comprising 416 patients with RA and 501 healthy subjects. Results. The etiologic SLC22A4 mutation was rarely found in homozygosis (0.72% patients vs 0.40% controls). None of the 4 haplotypes present in the SLC22A4/SLC22A5 region in 5q31 showed signifi- cant association with RA in our Spanish cohort. The causative RUNX1 variant found in a Japanese cohort displayed the same genotype distribution in our population. However, no difference was observed when allele or genotype frequencies were compared between Spanish patients with RA and controls. Conclusion. The SLC22A4 and RUNX1 polymorphisms described as etiological in the Japanese study did not show a significant role in RA susceptibility in our population. The mechanism proposed by these Japanese investigators could underlie RA susceptibility irrespective of ethnicity, but the lower mutation rate present in our population hampered detection of a significant effect. Most probably the lack of mutated SLC22A4 substrate explains the absence of RUNX1 association with RA observed in our pop- ulation. (J Rheumatol 2006;33:842–6) Key Indexing Terms: RHEUMATOID ARTHRITIS SUSCEPTIBILITY SLC22A4/SLC22A5/RUNX1 POLYMORPHISMS The interplay of both genetic and environmental factors con- used for detecting genes contributing to susceptibility or tributes to the development of rheumatoid arthritis (RA). resistance to multifactorial diseases: nonparametric linkage Clinical manifestations of RA are a consequence of localiza- analysis, case-control association study, and transmission dis- tion of lymphocytes in synovial tissue initiating inflammation equilibrium test (TDT). Case-control association study has the through the production of mediators1,2. Genetic analysis of highest power for detecting disease genes if there is no popu- human populations clearly contributes to the understanding of lation stratification between patients and controls. autoimmune diseases. RA is a common complex genetic dis- Human chromosomal region 5q31 has been recently relat- ease and HLA-DRB1 has been clearly shown to be associated ed to autoimmune disorders with an inflammatory component, with the disease3. However, this association accounts for less like RA and Crohn’s disease4,5. In this bowel disease, associ- than half the overall genetic susceptibility. Identifying specif- ation was found with functional variants in 2 nearby genes, ic genetic mechanisms involved in RA continues to present SLC22A4 and SLC22A5, encoding the organic cation trans- considerable challenges. There are 3 genetic methods often porters OCTN1 and OCTN2, respectively. Tokuhiro, et al4 mapped RA susceptibility to the SLC22A4 gene and also From the Departments of Clinical Immunology and Rheumatology, located the causative variant in this gene, slc2F2 (rs3792876). Hospital Clinico San Carlos; and the Departments of Clinical The mutant allele of this single nucleotide polymorphism Immunology and Rheumatology, Hospital La Paz, Madrid, Spain. (SNP) within a Runt-related transcription factor 1 (RUNX1) Dr. Urcelay is the recipient of a Ramón y Cajal contract of the Spanish Government. Dr. Martínez is the recipient of a research contract from the binding site further suppresses the expression of the SLC22A4 Spanish Health Ministry (CP04/00175). gene. In this Japanese work, the RUNX1 gene was associated A. Martínez, PhD; A. Valdivia, MSc, Department of Clinical Immunology, with RA as well. The SLC22A4 gene is expressed in hemato- Hospital Clinico San Carlos; D. Pascual-Salcedo, PhD, Department of logical tissues6 and a 2-fold increase in its expression in cul- Clinical Immunology; A. Balsa, MD, PhD, Department of Rheumatology, Hospital La Paz; B. Fernández-Gutierrez, MD, PhD, Department of tured synovial fibroblasts was observed upon treatment with Rheumatology; E.G. de la Concha, MD, PhD; E. Urcelay, PhD, proinflammatory cytokines. Moreover, the collagen induced Department of Clinical Immunology, Hospital Clinico San Carlos. arthritis mouse model expresses the counterpart of the human Address reprint requests to Dr. E. Urcelay, Department of Immunology, Hospital Clinico San Carlos, C/ Martin Lagos sn, Madrid, 28040, Spain. SLC22A4 gene in the joints, adding evidence in favor of its 4 E-mail: [email protected] role in the disease . RUNX1 regulates the expression of vari- Accepted for publication January 13, 2006. ous genes implicated in hematopoiesis and myeloid differen- Personal non-commercial use only. The Journal of Rheumatology Copyright © 2006. All rights reserved. 842 The Journal of Rheumatology 2006; 33:5 Downloaded on September 27, 2021 from www.jrheum.org tiation7, and its defective binding to target genes has been first tested the rate of linkage disequilibrium of SLC22A4 associated with 2 other autoimmune disorders: systemic lupus polymorphisms by analyzing 2, slc2F2 (rs3792876) and erythematosus and psoriasis8,9. RUNX1 also plays a role as a slc2F11 (rs2306772). Both SNP were in complete disequilib- negative regulator of GATA3 expression, thereby inhibiting rium as previously shown, but allelic distribution in the Th2 cell differentiation10. Spanish population was clearly different from that present in In summary, the exacerbated suppression of the SLC22A4 Japan (p < 10-42), with the minor allele frequency ranging gene by RUNX1 has been associated with RA in a Japanese from about 31% in the Japanese cohort to 7.5% in Spain. population, but these risk factors should be confirmed in dif- A total of 416 patients with RA and 501 ethnically matched ferent ethnic groups. For instance, none of the 3 mutations in controls were then studied for association of the intronic the NOD2/CARD15 gene was found in 483 Japanese patients slc2F2 polymorphism. This SNP was originally described in a with Crohn’s disease11, which provides evidence for the pres- Japanese study as the etiological variant, being the mutant ence of genetic heterogeneity among patients of different eth- homozygous genotype associated with RA. The susceptible nicity. Indeed, no association of the Japanese putative slc2F2*T within a RUNX1 transcription factor-binding site in SLC22A4 etiological variant has been replicated in Canadian the SLC22A4 gene further diminished the expression of the or British cohorts with RA12,13. We studied the association gene. Table 1A shows the genotype distribution in the Spanish of both SLC22A4 and SLC22A5 genes with RA in a patients with RA and control cohorts and no significant dif- Mediterranean population to assess the impact of these 2 func- ference was observed. Analysis by TDT of 12 informative het- tionally and physically closely related genes. To our knowl- erozygous progenitors showed no distorted transmission of edge, there is only one replication study in a Caucasian popu- the alleles (allele C transmitted 6 times; allele T 6 times; p = lation14 of the RUNX1 gene, which was associated with RA in 0.61). When we analyzed the etiologic RUNX1 intronic poly- the Japanese report. morphism (rs2268277) tested by Tokuhiro, et al4, similar genotype distribution to that found in Japan was observed in MATERIALS AND METHODS the Spanish controls. However, this SNP did not increase the Patients. Four hundred sixteen consecutively recruited patients with RA and risk for RA in the Spanish population in contrast to the signif- 501 ethnically matched controls from the same Madrid area were included; all icant association found in the Japanese report (Table 1B). gave informed consent according to the Helsinki Declaration. Clinical data Again, no preferential transmission of any allele was found by for most of the patients have been described15: female:male ratio 3:1, age at onset 54 ± 14 years, 83% of patients presented erosive disease, and 62% and TDT analysis of 30 heterozygous progenitors (allele G and 76% were positive for shared epitope (SE) and rheumatoid factor (RF), allele C were transmitted 14 and 16 times respectively; p = respectively. TDT was performed with 56 RA patients who belonged to the 0.43). Previous stratification for the well-established major European Consortium of RA Families (ECRAF): 84% were women aged 32 histocompatibility complex (MHC) risk factor for RA, the ± 9 years, 78% had erosive disease, and 64% were positive for SE and 86% SE17, did not modify the observed absence of association of for RF. The Hospital Ethical Board approved the design of the study. either polymorphism (data not shown). Genotyping. SNP of the SLC22A4, SLC22A5, and RUNX1 genes were geno- typed by TaqMan Assays on Demand under conditions recommended by the Both organic cation transporters OCTN1 (SLC22A4) and manufacturer (Applied Biosystems, Foster City, CA, USA), with the follow- OCTN2 (SLC22A5) show 88% homology and 77% identity ing identification numbers: C_3170428_10 for slc2F2 (rs3792876), in their sequences; the latter is physiologically important for C_3170458_1_ for slc2F11 (rs2306772), C_3170445_1_
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