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Okada, Yukinori

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Okada

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Yukinori

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Okada, Yukinori
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    Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis
    (Public Library of Science, 2013) Cui, Jing; Stahl, Eli A.; Saevarsdottir, Saedis; Miceli, Corinne; Diogo, Dorothee; Trynka, Gosia; Raj, Towfique; Mirkov, Maša Umiċeviċ; Canhao, Helena; Ikari, Katsunori; Terao, Chikashi; Okada, Yukinori; Wedrén, Sara; Askling, Johan; Yamanaka, Hisashi; Momohara, Shigeki; Taniguchi, Atsuo; Ohmura, Koichiro; Matsuda, Fumihiko; Mimori, Tsuneyo; Gupta, Namrata; Kuchroo, Manik; Morgan, Ann W.; Isaacs, John D.; Wilson, Anthony G.; Hyrich, Kimme L.; Herenius, Marieke; Doorenspleet, Marieke E.; Tak, Paul-Peter; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Wolbink, Gert Jan; van Riel, Piet L. C. M.; van de Laar, Mart; Guchelaar, Henk-Jan; Shadick, Nancy; Allaart, Cornelia F.; Huizinga, Tom W. J.; Toes, Rene E. M.; Kimberly, Robert P.; Bridges, S. Louis; Criswell, Lindsey A.; Moreland, Larry W.; Fonseca, João Eurico; de Vries, Niek; Stranger, Barbara E.; De Jager, Philip; Raychaudhuri, Soumya; Weinblatt, Michael; Gregersen, Peter K.; Mariette, Xavier; Barton, Anne; Padyukov, Leonid; Coenen, Marieke J. H.; Karlson, Elizabeth; Plenge, Robert M.
    Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10−8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10−11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
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    Genome Wide Association Study of Age at Menarche in the Japanese Population
    (Public Library of Science, 2013) Tanikawa, Chizu; Okada, Yukinori; Takahashi, Atsushi; Oda, Katsutoshi; Kamatani, Naoyuki; Kubo, Michiaki; Nakamura, Yusuke; Matsuda, Koichi
    Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10−7 and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population.