SLC22A4 polymorphisms implicated in rheumatoid arthritis and Crohn's disease are not associated with rheumatoid arthritis in a Canadian Caucasian population

Abstract

Objective Single‐nucleotide polymorphisms (SNPs) in the SLC22A4 gene encoding the organic cation transporter OCTN1 have been associated with rheumatoid arthritis (RA) in the Japanese population and with Crohn's disease in a Canadian cohort. The RA‐associated and Crohn's disease–associated SNPs include, respectively, an intronic variant (slc2F2) and an exonic variant (1672T). We used a case–control approach to investigate the prevalence of these variants in a Canadian RA cohort and to determine whether RA and Crohn's disease share SLC22A4 susceptibility alleles. Methods Nine hundred eighteen unrelated patients with RA, 507 patients with Crohn's disease, and 623 healthy controls were genotyped for the putatively RA‐associated slc2F1 and slc2F2 variants and the Crohn's disease–associated SLC22A4 1672T variant. Results Neither slc2F1 nor slc2F2 showed evidence for association with RA, the allele frequencies of these variants being significantly different in the Canadian population compared with those reported in the Japanese population, but not significantly different between patients with RA and controls. In addition, associations between the 1672T Crohn's disease risk allele and RA or between the slc2F1‐A and slc2F2‐T risk alleles and Crohn's disease were not detected in this study cohort, and the latter 2 alleles were not in linkage disequilibrium with the 1672T variant. Conclusion These observations do not support roles for any of the previously identified SLC22A4 disease risk alleles in RA susceptibility in the Canadian population. The slc2F1/slc2F2 risk alleles were not associated with Crohn's disease nor in linkage disequilibrium with the Crohn's disease–associated 1672T variant, and accordingly, also appear to be irrelevant to Crohn's disease susceptibility in the population under study.

Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations

“…Interestingly, the Crohn's disease-associated CARD15 and SLC22A4/SLC22A5 alleles do not appear to confer risk for RA, at least in Caucasian populations (32,33), and the data reported here suggest that the PTPN22 1858T variant also is not involved in Crohn's disease susceptibility. These findings raise the possibility that Crohn's disease and psoriatic arthritis are genetically similar conditions, while RA is genetically distinct from these disorders and instead has genetic overlap with other conditions, such as lupus and type 1 diabetes.…”

Ethnic differences in allele frequency of autoimmune-disease-associated SNPs

“…a British data derived from Barton et al (2004) b Canadian data derived from Newman et al (2005) c European data derived from Peltekova et al(2004) d Swedish data derived from Prokunina et al (2004) and Prokunina et al (2002) e European American data derived from Prokunina et al (2004) f Danish data derived from Nielsen et al (2003) g North American data derived from Begovich et al (2004) h North American data derived from Kyogoku et al (2004) i North Amerian data derived from Bottini et al (2004) j Japanese data from our group, reported by Suzuki et al (2003) k Japanese data derived from Yamazaki et al (2004) * P value calculated by Fisher's exact test: P < 0.01 ences in allele frequency less outstanding than L503F in SLC22A4/5, it was of note that PD-1.3A in PDCD1 and R620W in PTPN22 were only polymorphic in Caucasians and in the African-descent population, as for L503F in SLC22A4/5. Populations of African descent, Caucasians, and Japanese (an ethnic subgroup from fareast islands), should have different population histories of mutation, migration, isolation, and genetic drift, and there is no doubt that there should be substantial differences in allele frequencies among these ethnic groups.…”

Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies

“…Intriguingly, a genetic variant of the RUNX1 gene itself was also found to be implicated in RA susceptibility, where an intronic SNP, designated runx1, was strongly associated with RA risk (maximum OR 1.48, P = 0.00035, under a dominant model) . To date, the findings of Tokuhiro and colleagues have not been replicated in either Japanese or Caucasian populations Barton et al 2005b;Newman et al 2005;Martinez et al 2006b;Orozco et al 2006), while it is interesting to note that, in Caucasian populations, a nonsynonymous substitution (1672C [ T; rs1050152) causing an amino-acid change (L503F) in the SLC22A4 was proposed as a potential causal variant for Crohn's disease, a chronic inflammatory bowel disease with immunologically mediated processes (Fisher et al 2006).…”