title: Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands.
abstract: Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan. nakagoms@tcd.ie.|Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan. nakagoms@tcd.ie.|School of Medicine, Faculty of Health Sciences, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland. nakagoms@tcd.ie.|Trinity Centre for Health Sciences Room 0.79, St. James's Hospital, James's St., Dublin 8, Ireland. nakagoms@tcd.ie.
authors.forename: Shigeki
authors.identifier: 0000-0001-9613-975X
authors.initials: S
authors.lastname: Nakagome
authors.affiliation: Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chinen
authors.affiliation: Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iraha
authors.affiliation: Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hokama
authors.affiliation: Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, 814-0180, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Takeyama
authors.affiliation: Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, 814-0180, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakisaka
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, 818-8562, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kidd
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan.|Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.|Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
authors.forename: Heba S
authors.initials: HS
authors.lastname: Said
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Suda
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama, 700-8530, Japan.|CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Morita
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan.|Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
authors.forename: Masahira
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan.
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Hanihara
authors.affiliation: Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujita
authors.affiliation: Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
authors.forename: Fukunori
authors.initials: F
authors.lastname: Kinjo
authors.affiliation: Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan.|CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.|Department of Mathematical Analysis and Statistical Inference, The Institute of Statistical Mathematics, Tokyo, 190-8562, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Mano
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oota
mesh_terms: D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D016015:Logistic Models; D064307:Microbiota; D020641:Polymorphism, Single Nucleotide; D012463:Saliva / Q000382:microbiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human