Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands

Shigeki Nakagome^{1 2 3 4}, Hiroshi Chinen⁵, Atsushi Iraha⁵, Akira Hokama⁵, Yasuaki Takeyama⁶, Shotaro Sakisaka⁶, Toshiyuki Matsui⁷, Judith R Kidd⁸, Kenneth K Kidd⁸, Heba S Said^{9 10 11}, Wataru Suda⁹, Hidetoshi Morita^{12 13}, Masahira Hattori^{9 10}, Tsunehiko Hanihara¹⁴, Ryosuke Kimura¹⁵, Hajime Ishida¹⁵, Jiro Fujita¹⁶, Fukunori Kinjo⁵, Shuhei Mano^{17 13 18}, Hiroki Oota¹⁴

Affiliations

¹ Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan. nakagoms@tcd.ie.
² Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan. nakagoms@tcd.ie.
³ School of Medicine, Faculty of Health Sciences, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland. nakagoms@tcd.ie.
⁴ Trinity Centre for Health Sciences Room 0.79, St. James's Hospital, James's St., Dublin 8, Ireland. nakagoms@tcd.ie.
⁵ Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
⁶ Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, 814-0180, Japan.
⁷ Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, 818-8562, Japan.
⁸ Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁹ Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan.
¹⁰ Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
¹¹ Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
¹² Graduate School of Environmental and Life Science, Okayama University, Okayama, 700-8530, Japan.
¹³ CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
¹⁴ Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan.
¹⁵ Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan.
¹⁶ 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.
¹⁷ Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan.
¹⁸ Department of Mathematical Analysis and Statistical Inference, The Institute of Statistical Mathematics, Tokyo, 190-8562, Japan.

PMID:28197769
DOI: 10.1007/s00439-017-1764-0

Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands

Shigeki Nakagome et al. Hum Genet.2017 Apr.

.2017 Apr;136(4):387-397.

doi: 10.1007/s00439-017-1764-0. Epub 2017 Feb 14.

Authors

Affiliations

¹ Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan. nakagoms@tcd.ie.
² Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan. nakagoms@tcd.ie.
³ School of Medicine, Faculty of Health Sciences, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland. nakagoms@tcd.ie.
⁴ Trinity Centre for Health Sciences Room 0.79, St. James's Hospital, James's St., Dublin 8, Ireland. nakagoms@tcd.ie.
⁵ Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan.
⁶ Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, 814-0180, Japan.
⁷ Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, 818-8562, Japan.
⁸ Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁹ Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan.
¹⁰ Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
¹¹ Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
¹² Graduate School of Environmental and Life Science, Okayama University, Okayama, 700-8530, Japan.
¹³ CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
¹⁴ Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan.
¹⁵ Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan.
¹⁶ 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.
¹⁷ Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan.
¹⁸ Department of Mathematical Analysis and Statistical Inference, The Institute of Statistical Mathematics, Tokyo, 190-8562, Japan.

PMID:28197769
DOI: 10.1007/s00439-017-1764-0

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.

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Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands

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Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands

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