Volume 139, Issue 4, Pages e3 (October 2010)

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Volume 139, Issue 4, Pages 1190-1197.e3 (October 2010) ITPA Polymorphism Affects Ribavirin-Induced Anemia and Outcomes of Therapy—A Genome-Wide Study of Japanese HCV Virus Patients Hidenori Ochi, Toshiro Maekawa, Hiromi Abe, Yasufumi Hayashida, Rikita Nakano, Michaki Kubo, Tatsuhiko Tsunoda, C. Nelson Hayes, Hiromitsu Kumada, Yusuke Nakamura, Kazuaki Chayama Gastroenterology Volume 139, Issue 4, Pages 1190-1197.e3 (October 2010) DOI: 10.1053/j.gastro.2010.06.071 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Depiction of the haplotype structure around the top locus. P value plots in linear regression analysis in genome-wide association study (GWAS)-1 stage (middle panel), fine-mapping using GWAS-1, GWAS-2, and Replication-1 samples (upper panel), and linkage disequilibrium (LD) map around DDRGK1 and inosine triphosphate pyrophosphatase (ITPA) using HapMap JPT datasets. Dark gray: regions with high r2 values, light gray: regions with low r2 values (lower panel). Dashed line and arrow represent the top single nucleotide polymorphism (SNP) rs6051639 identified by GWAS. The solid line and arrow represent the missense variant rs1127354 in the ITPA gene. Gastroenterology 2010 139, 1190-1197.e3DOI: (10.1053/j.gastro.2010.06.071) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 Inosine triphosphate pyrophosphatase (ITPA) variants and hemoglobin (Hb) level at baseline and 4-week. All the samples enrolled in the present study were stratified based on rs1127354 genotype. Markers represent means and each error bar represents 1 standard deviation. Gastroenterology 2010 139, 1190-1197.e3DOI: (10.1053/j.gastro.2010.06.071) Copyright © 2010 AGA Institute Terms and Conditions

Figure 3 Inosine triphosphate pyrophosphatase (ITPA) expression level and ribavirin-induced anemia. Among genome-wide association study (GWAS)-1 and GWAS-2 patients, 124 white blood cell samples were collected and analyzed. The y-axis represents hemoglobin (Hb) level change at week 4 compared with baseline, and the x-axis represents relative messenger RNA (mRNA) expression levels of ITPA standardized by glyceraldehyde-3-phosphate dehydrogenase. The thick solid line represents the overall least squares best fit line and the other 3 lines represent best fit stratified by missense single-nucleotide polymorphism rs1127354 genotypes. Gastroenterology 2010 139, 1190-1197.e3DOI: (10.1053/j.gastro.2010.06.071) Copyright © 2010 AGA Institute Terms and Conditions

Supplementary Figure 1 Results of the genome-wide association study-1 (GWAS-1). (A) log10 P value plot at the first stage. Each P value was calculated by linear regression. The large dot corresponds to the single nucleotide polymorphism (SNP) with the strongest association, located in the DDRGK1 gene. (B) Quantile-quantile plot for GWAS-1. Dots represent P values of each SNP that passed the quality control filters. Only one SNP (large dot) in the DDRGK1 gene attained genome-wide significance after GWAS-2. The inflation factor λ was estimated to be 1.004. Gastroenterology 2010 139, 1190-1197.e3DOI: (10.1053/j.gastro.2010.06.071) Copyright © 2010 AGA Institute Terms and Conditions