宇田川 智野

Similar to that in Europe and the United States, the need for forensic DNA identification in dogs is increasing in Japan. As few studies have used commercial genotyping kits, the effectiveness of the Canine GenotypesTM Panel 2.1 Kit for individual DNA identification in dogs bred in Japan was examined. We genotyped 150 unrelated dogs (50 Golden Retrievers, 50 Miniature Dachshunds, and 50 Shiba Inu) at 18 canine short tandem repeat loci by the Kit. The allele frequency, expected heterozygosity, observed heterozygosity, p-value, power of the discriminant, and of exclusion, polymorphic information content, and random matching probability were calculated for each marker. The random matching probability was subsequently estimated to be 4.394×10-22 in the 150 dogs of the three pure-bred groups based on 18 STR loci; 3.257 × 10-16 in the Golden Retriever, 3.933 × 10-18 in the Miniature Dachshund, and 2.107 × 10-18 in the Shiba Inu breeds. In addition, principal component analysis based on genotype data revealed the Golden Retrievers, Miniature Dachshunds, and Shiba Inus separated into three clusters. The results of the genotype analysis showed that the Canine GenotypesTM Panel 2.1 Kit could be useful for identity testing and tool of population study of canines in Japan.

Aim: We sought to identify the variants that could predict the risk of nivolumab-induced immune-related adverse events (irAEs) in patients with cancer. Patients & methods: We enrolled 622 Japanese patients and carried out a genome-wide association study. The associations for 507 single nucleotide polymorphisms (SNPs) showing p < 0.001 were further investigated using an independent cohort. Results: In the combined analysis, possible associations were found for a total of 90 SNPs. Although no SNPs were identified to be significantly associated with nivolumab-induced irAEs, the SNP most strongly associated with nivolumab-induced irAEs was rs469490. Conclusion: This study is an important hypothesis-generating study to guide future studies in larger and/or other ethnic cohorts.

Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (Pcombined = 4.92 × 10-5 and 5.50 × 10-5, respectively). These data suggest that rs8032978 and rs7406710 could be predictive markers of trastuzumab-induced cardiotoxicity in Japanese and Singaporean populations, and support their potential use in clinical risk assessment. These findings offer a first step toward the development of clinically available markers for the potential risk of trastuzumab-induced cardiotoxicity as well as an improved understanding of the pathogenesis of this complication.

Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real-time PCR. The relationships between the risk alleles and low toxicity (non-ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3-4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.

The feline AB blood group system (blood types A, B, and AB) encoding the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (<italic>CMAH</italic>) gene is the most significant in transfusion medicine and hemolysis of the newborn for cats. Blood typing and cross-matching in pre-transfusion testing are crucial to determining blood compatibility and thus prevent hemolytic transfusion reactions. We here performed serological and genetic investigations to characterize blood samples from cats with discordant results for card agglutination (CARD) and the alloantibody agglutination test for blood typing in two cats (subjects K and R). Subject K showed incompatible cross-matching in pre-transfusion testing. Red blood cells from subjects K and R determined blood type B from the CARD method showed blood type AB by alloanti-A and alloanti-B antibodies in agglutination testing. Genomic DNA sequencing of the coding region (exons 1a to 14) for the cat <italic>CMAH</italic> gene showed that subject K had four mutations with heterozygosity at c.139C&amp;gt;T, c.179G&amp;gt;T, c.327A&amp;gt;C, and c.364C&amp;gt;T. Similarly, the <italic>CMAH</italic> gene of subject R carried six mutations with heterozygosity at c.142G&amp;gt;A, c.187A&amp;gt;G, c.268T&amp;gt;A, c.327A&amp;gt;C, c.773G&amp;gt;A and c.1603G&amp;gt;A, representing a new diplotype including a novel synonymous single nucleotide polymorphism (SNP) in exon 7 (c.773 G&amp;gt;A: Arg258Gln). The <italic>CMAH</italic> diplotype in subjects K and R was different from major diplotype in blood type B cats. This study is the first to report <italic>CMAH</italic> variants in cats with discordant blood types between CARD and TUBE methods. These results could assist in the classification of feline AB blood types for transfusion medicine to avoid blood incompatibilities.