An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis

Tokuhiro, Shinya; Yamada, Ryo; Chang, Xiaotian; Suzuki, Akari; Kochi, Yuta; Sawada, Tetsuji; Suzuki, M.; Nagasaki, Masaru; Ohtsuki, Masahiko; Ono, Mariko; Furukawa, Hidehiko; Nagashima, Masakazu; Yoshino, Shinichi; Mabuchi, Akihiko; Sekine, Akihiro; Saito, Susumu; Takahashi, Atsushi; Tsunoda, Tatsuhiko; Nakamura, Yusuke; Yamamoto, Kazuhiko

doi:10.1038/ng1267

Cited by 552 publications

(475 citation statements)

References 41 publications

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“…Obvious candidates in the 19 regions should be investigated first, such as PADI4 on chromosome 1, recently identified in the Japanese population (37), TNFR2 on chromosome 1 (38,39), and RANK on chromosome 18 (8). The Japanese investigators have also recently reported a new RA "susceptibility" gene, SLC22A4 (organic cation transporter) on 5q31 (40), located 20 cM 5Ј to our chromosome 5 suggested locus. This might reflect the limited power of linkage studies compared with association analyses.…”

Section: Discussionmentioning

confidence: 99%

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Fortéa¹,

Bükülmez²,

Petit-Teixeira³

et al. 2004

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan.Methods. In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage.Results. Involvement of the HLA region was strongly confirmed (P ‫؍‬ 6 ؋ 10 ؊5 ), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 ؎ 4 regions (mean ؎ SD) were true-positives. RA covariate-based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA-DRB1 shared epitope as covariates.Conclusion. The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 ؎ 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.

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Section: Discussionmentioning

confidence: 99%

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Fortéa¹,

Bükülmez²,

Petit-Teixeira³

et al. 2004

Arthritis & Rheumatism

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“…1). Identifying non-HLA susceptibility genes remains a challenge, but it was recently reported that a novel RA susceptibility gene, solute carrier 22 member 4 (SLC22A4; OMIM*604190), mapping to chromosome 5q31, had been identified in a Japanese population (2). The 5q31 region was targeted for investigation because it had previously shown linkage in family studies of Crohn's disease (CD), atopic dermatitis, and bronchial asthma, and the region harbors a cytokine gene cluster.…”

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confidence: 99%

“…In the Japanese study, single-marker and haplotype analysis showed convincing association with a singlenucleotide polymorphism (SNP) mapping to intron 2 of the SLC22A4 gene, but the SNP was not thought to play a functional role (2). Studies of an intron 1 SNP in linkage disequilibrium (LD) with it showed that the polymorphism affected binding of a transcription regulator, RUNX-1.…”

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confidence: 99%

Investigation of the SLC22A4 gene (associated with rheumatoid arthritis in a Japanese population) in a United Kingdom population of rheumatoid arthritis patients

Barton¹,

Eyre²,

Ho³

et al. 2005

Arthritis & Rheumatism

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Objective. Recent studies of 2 complex diseases, rheumatoid arthritis (RA) and Crohn's disease (CD), showed associations with genes mapping to the cytokine gene cluster on 5q31. In particular, a functional singlenucleotide polymorphism (SNP) mapping to intron 1 of the organic cation transporter 1 (OCTN1; SLC22A4) gene was associated with RA in a Japanese population, and a haplotype of a different SNP in the same gene and one in an adjacent gene, OCTN2 (SLC22A5), was associated with CD. The purpose of this study was to investigate the association between the OCTN locus and RA in a Caucasian population.Methods. Association with 11 SNPs spanning the SLC22A4 and SLC22A5 genes, including a putative RA-causing functional polymorphism (rs3792876 [slc2f2]) and a functional haplotype previously associated with CD, was investigated in 909 RA cases and 594 population controls in the UK. Genotyping was performed using 5 -allele discrimination assays. Estimated haplotype frequencies were generated using the expectation-maximization algorithm and were compared between cases and controls.Results. All SNPs were in Hardy-Weinberg equilibrium. We found no evidence for an association between RA and either the SNP (rs3792876 [slc2f2]) or the haplotype previously reported to be associated with RA in a Japanese population. Similarly, no association between RA and the haplotype associated with CD was detected.Conclusion. Functional polymorphisms of the OCTN gene locus that have previously been associated with RA and CD were not found to be associated with RA in a UK population. The findings do not provide support for a major role of these genes in the etiology of RA in this population.

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“…12,13 Moreover, SNPs within SLC22A4 were also suggested to be associated with rheumatoid arthritis. 14 At the project's initiation, we selected a total of nineteen genes in the 5q31-33 region to test association with GD, all of which show a strong potential involvement in autoimmune and/or inflammatory diseases. Six known genes located in the region, D5S434-D5S436, were selected, namely LARS, POU4F3, TCERG1, PPP2R2B, DPYSL3 and SPINK1.…”

Section: Introductionmentioning

confidence: 99%

“…SLC22A4 and SLC22A5 had been reported to be associated with Crohn disease and rheumatoid arthritis, which, similar to GD, had the pathogenesis associated with inflammation and autoimmunity. [12][13][14] Given that these genes were chosen within a region with evidence for linkage to GD, and on the basis of our current understanding of GD etiopathology, they should be both positional and functional candidates.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves’ disease in Chinese population

et al. 2009

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Graves' disease (GD) is a common organ-specific autoimmune disorder, which is multifactorial and develops in genetically susceptible individuals. We had earlier mapped a susceptibility locus for GD to chromosome 5q31-33 in a linkage study. Here we used tag single-nucleotide polymorphisms (SNPs) to search for genetic variants associated with GD, and examined 19 functional candidate genes in this chromosomal region. We identified 192 polymorphisms by re-sequencing the candidate genes, and selected 51 tagSNPs to genotype in a case-control collection of 1118 south Han Chinese subjects (428 cases and 690 controls). Initial analysis suggested that a non-synonymous SNP rs40401 (P27S) of interleukin 3 (IL3) was associated with GD, and further fine-mapping showed that rs40401, or its perfect proxy SNP rs31480 in the 5 0 flanking region of IL3, fully accounted for the association signal at this locus. We replicated significant association of rs40401 with GD in an independent sample collection of 839 north Han Chinese subjects. A combined analysis revealed strong validation of this association (odds ratio (OR common ) ¼ 1.63, combined P (P comb ) ¼ 4 Â 10 À6 in the Recessive disease model). This study provides convincing evidence that the IL3 gene is a susceptibility locus for GD in the Chinese population.

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An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis

Cited by 552 publications

References 41 publications

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Investigation of the SLC22A4 gene (associated with rheumatoid arthritis in a Japanese population) in a United Kingdom population of rheumatoid arthritis patients

Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves’ disease in Chinese population

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