LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn\u27s disease patients

BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn’s disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy. METHODS. We performed a hypothesis-driven analysis of 56 single nucleotide polymorphisms (SNPs) associated with CD susceptibility or known to affect Paneth cell function in 110 Japanese CD patients who underwent ileal resection. We subsequently performed a genome-wide association analysis. Paneth cell phenotype was determined by defensin-5 immunofluorescence. Selected genotype–Paneth cell defect correlations were compared to a Western CD cohort (n = 164). RESULTS. The average percentage of abnormal Paneth cells in Japanese CD was similar to Western CD (P = 0.87), and abnormal Paneth cell phenotype was also associated with early recurrence (P = 0.013). In contrast to Western CD, ATG16L1 T300A was not associated with Paneth cell defect in Japanese CD (P = 0.20). Among the 56 selected SNPs, only LRRK2 M2397T showed significant association with Paneth cell defect (P = 3.62 × 10(–4)), whereas in the Western CD cohort it was not (P = 0.76). Pathway analysis of LRRK2 and other candidate genes with P less than 5 × 10(–4) showed connections with known CD susceptibility genes and links to autophagy and TNF-α networks. CONCLUSIONS. We found dichotomous effects of ATG16L1 and LRRK2 on Paneth cell defect between Japanese and Western CD. Genes affecting Paneth cell phenotype in Japanese CD were also associated with autophagy. Paneth cell phenotype also predicted prognosis in Japanese CD. FUNDING. Helmsley Charitable Trust, Doris Duke Foundation (grant 2014103), Japan Society for the Promotion of Science (KAKENHI grants JP15H04805 and JP15K15284), Crohn’s and Colitis Foundation grant 274415, NIH (grants 1R56DK095820, K01DK109081, and UL1 TR000448)

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn\u27s disease patients

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No association between CEL-HYB hybrid allele and chronic pancreatitis in Asian populations

International audienceA hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL–HYB), generated by non-allelic homologous recombination between CEL intron 10 and CELP intron 10′, was found to increase susceptibility to chronic pancreatitis in a case–control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL–HYB allele in any of these populations. The CEL–HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL–HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis

Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice.

Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys (NUDT15R139C) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys (Nudt15R138C), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15R138C-harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15R138C/R138C HSPCs, but also Nudt15+/R138C HSPCs suffered stronger damage than Nudt15+/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15R139C-harboring patients

Acute Onset Collagenous Colitis with Unique Endoscopic Findings

We experienced a rare case of 72-year-old woman with acute onset collagenous colitis (CC) induced by lansoprazole. The patient developed acute abdominal pain, watery diarrhea, and melena that are quite rare in usual CC. We could find the characteristic colonoscopic findings such as active long liner ulcers in the patient. We also observed the healing courses of these unique findings. Our case indicates two important points of view. (1) CC sometimes develops with acute onset symptoms which resemble those of ischemic colitis. (2) Colonoscopy would be useful and necessary to distinguish acute onset CC and ischemic colitis