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Summary: Inherited genetic variation is associated with 6‐mercaptopurine (6‐MP) dose reduction and frequent toxicities induced by 6‐MP. However, the tolerable dose for 6‐MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome‐wide association study (GWAS) related to 6‐MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome‐wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6‐MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene‐coding regions, among which only variants at 13q14.2 were significant and replicated genome‐wide (rs116855232, NUDT15, β = −10.99, p = 3.7 × 10−13). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10−6) and CHST11 (rs1148407, p = 2.09 × 10−6), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6‐MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (padjust = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6‐MP tolerable dose in children in Japan. [ABSTRACT FROM AUTHOR]

α 1 -antitrypsin deficiency (AATD) is a hereditary disorder with a global prevalence that differs across regions. AATD is highly prevalent in Europe and North America but rarely found in Asian countries, including Japan, possibly because of the founder effect of the pathogenic SERPINA1 variants PI*Z and PI*S. However, AATD remains underdiagnosed even in high-prevalence and low-prevalence regions, possibly because of lack of awareness. In this study, we surveyed open Japanese genetic variation databases to estimate AATD prevalence in Japan. We identified allelic frequencies (AFs) of 5 among the 14 major pathogenic SERPINA1 variants from three datasets, collectively derived from 63,119 Japanese participants. The mean AF was determined to be 8.56 × 10 -4 (95% confidence interval [CI]: 6.43 × 10 -4 to 1.12 × 10 -3 ). Given that this represents the entire Japanese population, one AATD patient was speculated to be born per 1.37 × 10 6 births (95% CI: 7.97 × 10 5 to 2.42 × 10 6 ) in Japan. Our results support the prevailing notion that AATD is extremely rare in Japan., Competing Interests: Declaration of competing interest Susumu Sato received honoraria for lectures from Nippon Boehringer Ingelheim and AstraZeneca; Susumu Sato received a research grant from Nippon Boehringer Ingelheim, Philips-Respironics, Fukuda Denshi, Fukuda Lifetec, and ResMed; Susumu Sato endowed departments by commercial entitles from Philips-Respironics, Fukuda Denshi, Fukuda Lifetec, and ResMed; Kuniaki Seyama, Tadashi Sato, and Toyohiro Hirai have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cardiovascular disease (CVD) is a major cause of mortality worldwide. High-sensitivity cardiac troponin T (hs-cTnT) is released into the bloodstream due to cardiomyocyte damage and is associated with a high CVD risk. This study aimed to investigate hs-cTnT-related genetic variation and to examine whether this is an associated risk factor for CVD in the Japanese general population., Methods: This was a genome-wide association study (GWAS) based on a cohort from the 2013 Tohoku Medical Megabank Project community study. The GWAS was performed using a HumanOmniExpressExome BeadChip array with 914,035 autosomal single-nucleotide polymorphisms. The Framingham Risk Score and the Suita score were used to evaluate the future risk of CVD., Results: The GWAS identified 10 loci reaching suggestive significance in the discovery cohort. A replication analysis confirmed that one of the 10 loci, rs7798496, is associated with elevated hs-cTnT levels. The combined P value in the discovery and replication cohorts for the association between the rs7798496 and hs-cTnT levels was 3.4 × 10 -8 , which indicates that the novel variant reached genome-wide significance. The rs7798496 loci was located at an intergenic region between the retinoblastoma gene product (RB)-associated Krüppell-associated box (KRAB) zinc finger, zinc finger protein 890, and pseudogene (ZNF890P). Logistic regression analysis revealed that the presence of the rs7798496 T allele was strongly associated with a high risk for CVD., Conclusions: This study provides insights into a link between a novel genetic variant, T allele of rs7798269, and elevated hs-cTnT levels as a future risk for CVD in the general Japanese population., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)