Abstract
We conducted population-based association tests for the four selected SNPs (rs2240340/padi4_94, rs7528684/fcrl3_3, rs3792876/slc2F2 and rs2268277/runx1) previously reported to be associated with rheumatoid arthritis (RA). The study population consisted of 950 unrelated Japanese subjects with RA and 507 controls, none of whom had previously been tested for these variants. Only the SNP rs2240340/padi4_94 was modestly associated with RA [allele odds ratio (OR) 1.22, 95% confidence interval (CI) 1.04–1.43, P = 0.012]. The most significant association effect was found for genotype contrast between minor and major allele homozygotes (OR 1.53, 95% CI 1.10–2.12, P = 0.010). No other SNPs showed a statistically significant association with RA in our population. Meta-analysis of published studies and our new data confirmed a highly significant association between PADI4 gene SNPs and increased risk of RA in East Asian populations (allele fixed-effects summary OR 1.31, 95% CI 1.22–1.41, P < 0.0001). We found some evidence for an association of either rs7528684/fcrl3_3 or rs3792876/slc2F2 with RA; however, because the magnitudes of effects were apparently much weaker than those reported in the initial positive reports, and there were substantial levels of inter-study OR heterogeneity, we concluded that additional studies are needed to fully understand the present results.
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Acknowledgments
We would like to thank our patients and volunteer blood donors for participating in this study. We thank Dr. Katsunori Ikari (Tokyo Women’s Medical University, Tokyo, Japan), Professor Changwon Kang (Korea Advanced Institute of Science and Technology, Daejeon, Korea) and Professor Sang-Cheol Bae (Hanyang University, Seoul, Korea) for their generosity in providing additional information regarding the genotype information described in their reports. We also thank the many past and present members of our research group for helpful discussions. This study was partially funded by grants from the Ministry of Education, Science and Technology (Knowledge Cluster Initiative).
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ESM Fig. 1a Meta-analysis plots for the genotypic contrasts. Meta-analysis plots for the various genotypic contrasts are shown. Fig. 1A, genotype 11 vs 22; 1B, 11 vs (12+22); 1C, (11+12) vs 22. Black squares indicate the study-specific odds ratios (ORs), with the size of each square being inversely proportional to its variance, and horizontal lines represent the 95% confidence intervals (CIs). The summary ORs and their 95% CI were calculated separately for the “All” and “Replication” studies, using fixed- and random-effects approaches, and are indicated by the unshaded diamonds. (a) PADI4 (rs2240340/padi4_94 or rs874881/padi4_92); (b) FCRL3 (rs7528684/fcrl3_3); (c) SLC22A4 (rs3792876/slc2F2 or rs2073838/slc2F1); and (d) RUNX1 gene (rs2268277/runx1). (AI 2.11 Mb)
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Takata, Y., Inoue, H., Sato, A. et al. 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. J Hum Genet 53, 163–173 (2008). https://doi.org/10.1007/s10038-007-0232-4
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