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We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10−11). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10−15). Subsequent fine-mapping analysis indicated that rs11065828 in CUX2 is the causal variant for colorectal polyps. We found that known colorectal cancer-susceptible SNPs were also associated with colorectal polyps. The genetic correlation between colorectal cancer and polyps is very high (r = 0.98 and p value = 0.0006). We additionally identified 14 significant loci of colorectal polyps and three significant loci of colorectal cancer by applying the multi-trait analysis of GWAS of colorectal cancer and colorectal polyps. We showed very similar germline polygenic features, which gives us the additional insight into potential cancers at polygenic levels for patients with polyps who are followed up at outpatients’ clinic; thus, close observation and polypectomy is critical to prevent colorectal cancers.

We aimed to identify attributing factors to the interindividual variabilities of the infusion rates in unfractionated heparin therapy. We included patients who required unfractionated heparin therapy to achieve the target APTT after cardiac surgery between May 2014 and February 2018. Fifty-nine patients were included, of whom 8 underwent Blalock-Taussig shunt; 27, Glenn procedure; 19, Fontan procedure; 3, mechanical valve replacement; and 2, Rastelli procedure. Previously reported variables that influenced the response to unfractionated heparin treatment were initially compared, which included age; weight; sex; type of surgery; platelet count; fibrinogen, antithrombin III, total protein, albumin, alanine transaminase, and creatinine levels; and use of fresh frozen plasma. The type of surgical procedure was found to be significantly associated with the differences in heparin infusion rate (P = 0.00073). Subsequently, the variance explained by these factors was estimated through a selection based on the minimum Akaike information criterion value; models constructed by various combinations of the surgery types were compared. The model including the Blalock-Taussig shunt, Glenn procedure, and mechanical valve replacement showed the highest summed variance explained (29.1%). More than 70% of the interindividual variability in initial heparin maintenance dosing was unexplained.

CYP2C9*3 and HLA-B alleles are reportedly associated with phenytoin-induced eruption in some East Asian populations; however, this finding is not readily applicable to the Japanese population. Thus, we aimed to investigate the risk alleles using samples and data from BioBank Japan. A total of 747 patients (24 cases and 723 tolerant controls) were selected for analysis. Case-control association studies were conducted, using CYP2C9*3, CYP2C9*27, CYP2C19*2, CYP2C19*3, and HLA-B allele genotype data. CYP2C9*3 carrier status was significantly associated with phenytoin-induced eruption (P = 0.0022, odds ratio 7.05, 95% confidence interval, 2.44-20.4). HLA-B*51:01 showed the most prominent association (P = 0.010, odds ratio 3.19, 95% confidence interval, 1.37-7.48). Including both of these features improved predictive performance, measured as area under the receiver operating characteristic curve, by 10%. CYP2C9*3 and HLA-B*51:01 allele carrier statuses are significantly associated with phenytoin-induced eruption; thus, checking this carrier status before prescription would decrease the incidence of phenytoin-induced eruption in clinical practice.

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15

Background The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. Methods We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. Findings We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. Interpretation We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia. Funding The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001)

No genome-wide association studies (GWAS) were reported for colorectal polyps and the overlap in polygenic backgrounds conferring risk of colorectal cancer and polyps remains unclear. We performed GWAS on subjects with colorectal polyps using the BioBank Japan data with 4447 cases and 157,226 controls. We evaluated genetic correlations between colorectal polyps and cancer, and effects on colorectal polyps of single nucleotide polymorphisms (SNPs) known to be associated with colorectal cancer. We identified CUX2, a known genetic locus to colorectal cancer, as a susceptibility locus to colorectal polyps (p value = 1.1 × 10

It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

Objective The aim of this study was to explore the prescription pattern of antiepileptics and the relationship between antiepileptics and adverse drug reactions (ADRs) in a Japanese population. Methods A retrospective observational cohort study was conducted by reviewing the medical records of patients who visited or were admitted to a single tertiary care center between January 2011 and June 2019, were treated with antiepileptics, and developed allergic ADRs associated with these drugs. Results In total, 14,230 unique patients received antiepileptics during the study period. Diazepam was the most frequently used antiepileptic drug (74.8 %), followed by phenobarbital (14.3 %), valproic acid (11.4 %), fosphenytoin (10.0 %), and carbamazepine (7.3 %). Although a trend of increasing prevalence of newer generation antiepileptics was noted, most patients are still treated with older generation antiepileptics. Thirty-two (0.22 %) unique patients experienced ADRs associated with antiepileptics, and the antiepileptic drug most frequently associated with ADRs was carbamazepine, at a rate of 1.4 %. Three patients developed Stevens-Johnson syndrome/toxic epidermal necrolysis, in two of which carbamazepine was implicated. Most patients experienced ADRs associated with aromatic antiepileptics (84.4 %) or older generation antiepileptics (81.3 %). Significance This is the first study to assess the relationship between ADRs and antiepileptics at a tertiary care center in Japan. Based on our results, most patients were prescribed older generation antiepileptics, and most ADR events were linked to the administration of drugs in this category; thus, identification of patients at risk of developing ADRs is critical in order to prevent such events.

Background Albuterol is one of the most frequently used medications in clinical practice and seeing varying responses to albuterol between individuals is not uncommon. Multiple studies have been conducted to investigate the associations of differing responses due to albuterol, particularly with regards to the two nonsynonymous single nucleotide polymorphisms (SNPs) at positions 16 (Arg16Gly: substitution of arginine to glycine at position 16; rs1042713) and 27 (Glu27Gln: substitution of glutamic acid to glutamine at position 27; rs1042714) on the β-2 adrenergic receptor (ADRB2) gene. However, the directions of the correlations are conflicting. Objective The objective of this systematic review and meta-analysis is to assess the effect of the two SNPs on the ADRB2 gene, in terms of the responses that present in asthmatic patients shortly after albuterol inhalation. Methods The primary outcome of this work is a detailed study of the associations of the two SNPs in the ADRB2 gene with treatment response and lung function testing shortly after administration of albuterol to asthmatic patients. A comprehensive literature search, using the OVID platform, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, will be conducted by a specialized librarian without language restrictions. We will include both prospective and retrospective original observational studies, and we will exclude nonhuman or in vitro studies. All abstracts will be reviewed by two authors who will also individually perform data extraction from each eligible study. Any arising disagreements will be resolved through discussion with a third party. Risk of bias for all included studies will be independently assessed using the quality of genetic association studies tool. We will report the systematic review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A narrative synthesis of study results or meta-analyses will be undertaken when appropriate. Results At the moment of writing, we have already started the preliminary literature search and piloting of the study selection process. The anticipated completion date is September 30, 2019. Conclusions Our systematic review and meta-analysis aims to clarify the current evidence of associations between the two nonsynonymous SNPs in the ADRB2 gene and the responses that present in asthmatic patients shortly after albuterol inhalation. If positive correlations are found, this knowledge may be used to improve personalized pharmacotherapy of albuterol use. Trial Registration PROSPERO CRD42019074554; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=74554 International Registered Report Identifier (IRRID) PRR1-10.2196/14759

In this study, we aimed to understand the gap in coverage of pharmacogenomic (PGx) biomarkers between Japan and the US. PGx biomarkers (1) in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines; (2) that are CPIC level A or B; or (3) have US Food and Drug Administration (FDA)-approved drug labels, were determined. Subsequently, their coverage by US health insurance companies and the National Health Insurance (NHI) in Japan was investigated. We identified the top six health insurance companies with the largest market shares in the US and investigated the coverage for the PGx biomarkers by these health insurers, Medicare, Medicaid, and the NHI in Japan. We found that 19.9% of these biomarkers are covered by the six companies (10.0%, the CPIC guidelines; 25.1%, the FDA-approved drug labels). The coverage of somatic and germline biomarkers was respectively 86.8% and 8.5% in the US and 56.3% and 0.6% in Japan. A few germline PGx biomarkers are covered both in Japan and the US, but the coverage of both somatic and germline biomarkers was lower in Japan. Therefore, more coverage should be considered to improve patient outcomes after prescribing medications in Japan.

The purpose of this study was to compare the benefit of neck computed tomography (CT) of identifying important cervical spine injuries (CSIs) with its harm of radiation exposure and cancer risk.A PubMed search for published studies relating to CSI in trauma, cervical spine imaging, CT, and cancer risk was conducted. Article abstracts were reviewed, and selected published studies relating to the study objective were retrieved.Of 100,000 trauma patients, neck CT scans were obtained in 3,767 to 26,785 patients. Of 100,000 patients with trauma on whom a neck CT scan was performed, a CSI was identified in 2,470 to 33,898 patients. Clinically important CSI ranged from 4,724 to 27,119 per 100,000 CT scans. For every 100,000 neck CT scans performed, additional cancer cases occur in a low end estimate of a thyroid cancer cases to a high end estimate of 100 male and 700 female cancer cases. In females, cancer risks are higher than in males, and these are closer to, but still less than, the incidence of clinically important CSI found by CT.CT's benefit of identifying important CSIs in the published studies exceeds its cancer harm risk. However, at their extremes, the numbers are disturbingly close. Limiting neck CT scanning to a higher-risk group would increase the gap between benefit and harm, whereas performing CT routinely on low-risk cases approaches a point where its harm equals or exceeds its benefit.Systematic review, level IV.

5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are used in the prevention of chemotherapy- induced, radiation-induced and postoperative nausea and vomiting. CYP2D6 polymorphisms can influence the metabolism of some of these drugs (i.e. ondansetron and tropisetron) thereby affecting drug efficacy. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for ondansetron and tropisetron based on CYP2D6 genotype (updates at www.pharmgkb.org ).