The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature ...and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).
Objective: To estimate the disease activity score (DAS)28-C-reactive protein (CRP) threshold values that correspond to DAS28-erythrocyte sedimentation rate (ESR) values for remission, low disease ...activity and high disease activity in patients with rheumatoid arthritis. Methods: DAS28 data were analysed using a large observational study (Institute of Rheumatology Rheumatoid Arthritis) database of 6729 patients with rheumatoid arthritis. Firstly, the relationship between the DAS28-ESR and the DAS28-CRP values was analysed. Secondly, the best DAS28-CRP trade-off values for each threshold were calculated using receiver operating characteristic (ROC) curves. Results: The correlation coefficient of ESR versus CRP was 0.686, whereas that of DAS28-ESR versus DAS28-CRP was 0.946, showing the strong linear relationship between DAS28-ESR and DAS28-CRP values. DAS28-CRP threshold values corresponding to remission, low disease activity and high disease activity were 2.3, 2.7 and 4.1, respectively. The sensitivity and specificity from the ROC curves were gradually reduced as DAS28 values became lower. Conclusions: This study showed that DAS28-CRP and DAS28-ESR were well correlated, but the threshold values should be reconsidered. As the results were derived from only Japanese patients, it is essential to compare DAS28-CRP threshold values in people of other ethnic groups.
Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients ...with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease.
To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls.
We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 × 10⁻⁹, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 × 10⁻⁸ and 7.44 × 10⁻⁸, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold.
We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC.
A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA).
The PMS study was performed for ...all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly.
Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab.
This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.
Warfarin is a commonly used anticoagulant, whose dose needs to be determined for each individual patient owing to large inter-individual variability in its therapeutic dose. Although several clinical ...and genetic variables influencing warfarin dose have been identified, uncovering additional factors are critically important for safer use of warfarin. Through a genome-wide association study, we identified single-nucleotide polymorphism (SNP) rs2108622 cytochrome P450, family 4, subfamily F, polypeptide 2 (CYP4F2) as a genetic determinant of warfarin responsiveness for Japanese. Stratifying subjects who have been pre-classified according to the genotypes of SNP rs10509680 cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) and SNP rs9923231 vitamin K epoxide reductase complex subunit 1 (VKORC1), based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin. Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age, body surface area, status of amiodarone co-administration and genotypes of SNPs in the CYP2C9 and VKORC1 genes improved the model's predictability to 43.4%. In this study, the association of CYP4F2 with warfarin dose of the Japanese has been established for the first time. Besides, a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co-administration status was suggested for the Japanese. Our study also implied that common SNPs other than those in the CYP2C9, VKORC1 and CYP4F2 genes that show strong effect on the therapeutic warfarin dose might not exist.
Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association ...studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.
A number of recent studies have shown that human polymorphisms near the IL28B type III interferon (IFNλ) gene influence the response to peg-interferon plus ribavirin combination therapy for infection ...with chronic hepatitis C virus (HCV). Viral polymorphisms, including substitutions within the HCV core and NS5A proteins, have also been shown to influence treatment outcome, but it is not known whether these factors act independently of the IL28B polymorphism or if they reflect the same or a different underlying mechanism. Multiple logistic regression was used to determine whether host and viral polymorphisms independently predict sustained virological response (SVR).
Two single nucleotide polymorphisms were genotyped in the IL28B locus (rs12979860 and rs8099917) from 817 patients with chronic HCV infection, and substitutions at amino acids 70 and 91 of the HCV core protein and within the NS5A interferon sensitivity-determining region (ISDR) were analysed.
It was found that independent predictors of an SVR included IL28B rs12979860 CC genotype (OR=4.98; p=4.00E-08), core amino acid 70 substitutions (OR=0.53; p=0.016), age and baseline viral load. For non-virological response, the IL28B rs12979860 CT/TT genotype (OR=0.23; p=1.96E-8) and age were independent predictors. IL28B rs12979860 genotype (p=1.4E-8), core amino acid 70 substitutions (p=0.0013), ISDR substitutions (p=0.0019), baseline viral load, γ-glutamyltranspeptidase, alanine aminotransferase and platelet count were independent predictors for change in viral load by week 4 of treatment.
IL28B polymorphisms and HCV core amino acid 70 substitutions contribute independently to an SVR to peg-interferon plus ribavirin combination therapy.
In order to identify a gene(s) susceptible to idiopathic pulmonary fibrosis (IPF), we conducted a genome-wide association (GWA) study by genotyping 159 patients with IPF and 934 controls for 214 508 ...tag single-nucleotide polymorphisms (SNPs). We further evaluated selected SNPs in a replication sample set (83 cases and 535 controls) and found a significant association of an SNP in intron 2 of the TERT gene (rs2736100), which encodes a reverse transcriptase that is a component of a telomerase, with IPF; a combination of two data sets revealed a p value of 2.9 x 10(-8) (GWA, 2.8 x 10(-6); replication, 3.6 x 10(-3)). Considering previous reports indicating that rare mutations of TERT are found in patients with familial IPF, we suggest that the common genetic variation within TERT may contribute to the risk of sporadic IFP in the Japanese population.
A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive ...disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻⁶). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻⁵). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.
Objective. Polymorphisms and haplotypes of the peptidylarginine deiminase type 4 gene (PADI4) have been reported to be associated with rheumatoid arthritis (RA) in a Japanese population. However, ...subsequent replication studies showed conflicting results. The aim of this study was to determine whether meta-analysis would prove the existence of the association. Methods. PubMed was searched using the term ‘PADI4’ for articles from the publication of the first study to December 2005. Replication studies that tested the association between PADI4 and RA were reviewed for meta-analysis. The Breslow–Day test for homogeneity across the studies was calculated. The Mantel–Haenszel procedure was used to pool odds ratios (OR) with 95% confidence intervals (CI) to evaluate the association. Results. Six replication studies, one from Japan and five from Europe and North America, fulfilled the selection criteria for inclusion in the meta-analysis. Homogeneity was confirmed across the replication studies. The common OR was 1.14 (95% CI = 1.07–1.21) for allelic distribution. The association was confirmed when only five replication studies in the European descent populations were combined (P = 0.0096, common OR = 1.10). Conclusions. Our meta-analysis showed a positive association between PADI4 and RA not only in the Japanese population but also in populations of European descent.
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