We also demonstrate that polymorphism is functionally relevant for CML cell growth and viability, and that blockade is cytotoxic to CML cells. Material and methods Discovery and validation data sets We performed a GWAS on peripheral blood samples from 202 CML patients with East Asian ethnicity as a discovery set. imatinib (IM) therapy. We also demonstrate that polymorphism is functionally relevant for CML cell growth and viability, and that blockade is cytotoxic to CML cells. Material and methods Discovery and validation data sets We performed a GWAS on Flopropione peripheral blood samples from 202 CML patients with East Asian ethnicity as a discovery set. The discovery set had been utilized in a previous study to identify a germline polymorphism marker associated with increased susceptibility to CML. A separate set of samples from 272 CML patients of European descent recruited in Canada was used as validation set. All patients in the discovery and validation sets were treated with IM frontline therapy [6C9, 40]. The study was approved by the Institutional Review Boards. Genotyping and quality control in the? discovery and validation sets In the discovery set, 906,530 SNPs were genotyped using Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA, USA). SNPs showing erroneous genotype clustering patterns were filtered out. One sample with a missing genotype rate of? ?5% was excluded from the analysis. BSG In addition, 39,033 SNPs were excluded owing to low genotyping (with? ?5% missing genotypes per marker) and 198,553 SNPs, owing to minor allele frequency of? ?1%. A total of 637,886 autosomal SNPs in the discovery set (values of? ?5.0??10C5, and? ?five SNPs with based on in vitro methods We performed functional analysis of in order to investigate the effects of isoform type 3 blockade on cell lines expressing experiments are described in the Supplementary Information. Statistical analysis Cumulative incidence of responses to IM therapy including CCyR, MMR, and DMR were calculated considering competing risks (i.e., switch to other TKI or death or progression). Grays test was used for comparison according to TCGAATAC haplotype. The Fine-Gray model was adopted for multivariate analysis. Students test was used for independent samples, and the Wilcoxon rank sum or KruskalCWallis rank sum test was used to calculate Flopropione difference in cell viability or for eQTL analysis. All statistical analyses were performed using PLINK Version 1.07 [41],?R (R Foundation for Statistical Computing, Austria), Flopropione and EZR software (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html) [18]. Results GWAS identified a locus of 6p12.1 as a predictive marker for DMR following IM therapy In the discovery set of CML patients (values of 2.25??10?5 for 6p12.1 and 4.64??10?6 for 16q23.3 were observed. Candidate genes included near the 6p12.1 locus?and and near the 16q23.3?locus. Open in a separate window Fig. 1 Results of genome-wide association analysis. a Manhattan plot shows the genome-wide value identified in the discovery set of 201 chronic myeloid leukemia (CML) patients following imatinib (IM) therapy. Two loci (i.e., 6p12.1 and 16q23.2) were selected as candidate loci, each including more than five SNPs with values of less than 5.0??10?5. b and c The plots show cumulative incidence of deep molecular response (DMR; defined as a molecular response with 4 or 4.5-log reduction) in the discovery and validation sets, respectively. The red line indicates the Flopropione group with TCGAATAC. TT indicates TCGAATAC/TCGAATAC homozygote haplotype. TG represents TCGAATAC/GTCTGCGT heterozygote haplotype. GG indicates GTCTGCGT/GTCTGCGT homozygote haplotype. Two cases in the discovery set and three cases in the validation set did not have haplotype information due to missing data of genotype or different haplotype constructed. One case in the validation.