No abstract

A 68-year-old Japanese man was monitored for chronic kidney disease (CKD), with unknown primary disease starting in 2014. His serum creatinine (sCr) was stable at ~ 2.5 mg/dL for ~ 2 years. Two weeks before admission, he had bloody sputum, and sCr increased to 4.63 mg/dL. Soon after admission, the patient developed a high fever with pigment spots on the legs. A kidney biopsy was performed. The kidney specimens showed necrotizing and crescentic glomerulonephritis without granuloma formation. An additional blood-sampling test revealed high titers of PR3-ANCA, and we diagnosed PR3-ANCA-positive microscopic polyangiitis (MPA). Treatment with intravenous steroid pulse therapy and intermittent pulse intravenous cyclophosphamide therapy was started for remission induction. With these treatments, sCr improved to ~ 3.0 mg/dL. Azathioprine (AZA) was added for remission-maintenance therapy. Three days later, the dose of AZA was increased from 50 to 100 mg/day, and the number of neutrophils decreased to 30/μL. After withdrawal of AZA, neutrophil levels gradually recovered. We suspected that an abnormal metabolism of AZA was responsible for the neutropenia. Therefore, we analyzed three AZA metabolism-associated genes for mutations: thiopurine -methyltransferase (TPMT), inosine triphosphate pyrophosphohydrolase (ITPA), and nucleoside diphosphate linked moiety X-type motif 15 (NUDT15), and we identified mutation. This was a rare case of PR3-positive MPA with AZA-induced severe neutropenia that was possibly due to an ITPA gene mutation. This case suggests that ITPA gene mutation is related to the adverse reactions of AZA in Japanese patients. We have to pay attention to severe neutropenia when we use AZA, especially in Asian patients with CKD.
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Crohn's disease (CD) development is thought to involve genetic factors related to immune response as well as environmental factors, such as intestinal bacteria and diet, though no clear cause has yet been identified. In our previous study, we found that the concentrations of linoleic acid, stearic acid, and metabolites in erythrocytes differed between CD patients and healthy subjects. These factors related to lipid metabolism are controlled by Δ6 desaturase (fatty acid desaturase 2, FADS2) and elongase 6 (ELOVL6), respectively. In the present study, we analyzed the gene sequences of FADS2 and ELOVL6 in 52 Japanese CD patients, and then compared mutation frequencies with findings in healthy individuals. Nineteen FADS2 mutations and 33 ELOVL6 mutations were found. Furthermore, a new variant in the promoter region was shown in both genes, though no mutation in the coding region was found in either. For the FADS2 intron, the allele frequency of rs227784 (0.3365; 95% CI = 0.0337-0.01460) was higher than that in healthy subjects (0.0190). Furthermore, allele rs227784 had a greater association with CD (odds ratio = 4.4; 95% CI = 2.1-9.3). As compared with healthy Japanese healthy individuals, no mutations were found with a largely deviated allele frequency in the present CD group. However, the number of patients examined was small, thus the reliability of our results is limited. The present findings regarding genetic effects on CD onset and lipid metabolism may be weak.

Background Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. Methods To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. Results The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. Conclusions All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.