title: LRRK2but notATG16L1is associated with Paneth cell defect in Japanese Crohn's disease patients.
abstract: BACKGROUND.Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associatedATG16L1andNOD2variants. 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,ATG16L1T300A was not associated with Paneth cell defect in Japanese CD (P= 0.20). Among the 56 selected SNPs, onlyLRRK2M2397T 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 ofLRRK2and other candidate genes withPless than 5 × 10-4showed connections with known CD susceptibility genes and links to autophagy and TNF-α networks.CONCLUSIONS.We found dichotomous effects ofATG16L1andLRRK2on 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).
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ta-Chiang
authors.initials: TC
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Naito
authors.affiliation: F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Zhenqiu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: VanDussen
authors.affiliation: F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.affiliation: F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dalin
authors.initials: D
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawai
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: Health Administration Center, Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kinouchi
authors.affiliation: F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dermot Pb
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kakuta
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
mesh_terms: D000328:Adult; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008297:Male; D019879:Paneth Cells / Q000166:cytology*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2