Human Genetics

, Volume 136, Issue 4, pp 387–397 | Cite as

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

  • Shigeki Nakagome
  • Hiroshi Chinen
  • Atsushi Iraha
  • Akira Hokama
  • Yasuaki Takeyama
  • Shotaro Sakisaka
  • Toshiyuki Matsui
  • Judith R. Kidd
  • Kenneth K. Kidd
  • Heba S. Said
  • Wataru Suda
  • Hidetoshi Morita
  • Masahira Hattori
  • Tsunehiko Hanihara
  • Ryosuke Kimura
  • Hajime Ishida
  • Jiro Fujita
  • Fukunori Kinjo
  • Shuhei Mano
  • Hiroki Oota
Original Investigation

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.

Supplementary material

439_2017_1764_MOESM1_ESM.docx (286 kb)
Supplementary material 1 (DOCX 285 kb)

References

  1. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Dore J, Antolin M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Merieux A, Melo Minardi R, M’Rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P (2011) Enterotypes of the human gut microbiome. Nature 473:174–180. doi:10.1038/nature09944 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, Unser A, Thacker LR, Sanyal AJ, Kang DJ, Sikaroodi M, Gillevet PM (2015) Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. doi:10.1002/hep.27819 PubMedCentralGoogle Scholar
  3. Bamias G, Martin C 3rd, Marini M, Hoang S, Mishina M, Ross WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT, Wei P, Cominelli F (2003) Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol 171:4868–4874CrossRefPubMedGoogle Scholar
  4. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40:955–962. doi:10.1038/ng.175 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP, Zhernakova DV, Jankipersadsing SA, Jaeger M, Oosting M, Cenit MC, Masclee AA, Swertz MA, Li Y, Kumar V, Joosten L, Harmsen H, Weersma RK, Franke L, Hofker MH, Xavier RJ, Jonkers D, Netea MG, Wijmenga C, Fu J, Zhernakova A (2016) The effect of host genetics on the gut microbiome. Nat Genet. doi:10.1038/ng.3663 Google Scholar
  6. Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15:34–48. doi:10.1038/nrg3575 CrossRefPubMedGoogle Scholar
  7. Danjou F, Zoledziewska M, Sidore C, Steri M, Busonero F, Maschio A, Mulas A, Perseu L, Barella S, Porcu E, Pistis G, Pitzalis M, Pala M, Menzel S, Metrustry S, Spector TD, Leoni L, Angius A, Uda M, Moi P, Thein SL, Galanello R, Abecasis GR, Schlessinger D, Sanna S, Cucca F (2015) Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat Genet 47:1264–1271. doi:10.1038/ng.3307 CrossRefPubMedPubMedCentralGoogle Scholar
  8. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563. doi:10.1038/nature12820 CrossRefPubMedGoogle Scholar
  9. Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint HJ, Lobley GE (2007) Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microbiol 73:1073–1078. doi:10.1128/AEM.02340-06 CrossRefPubMedGoogle Scholar
  10. Fischbach MA, Segre JA (2016) Signaling in Host-Associated Microbial Communities. Cell 164:1288–1300. doi:10.1016/j.cell.2016.02.037 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, Buning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D’Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, Verspaget HW, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panes J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Rioux JD, D’Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, Parkes M (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125. doi:10.1038/ng.717 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, Schwager E, Knights D, Song SJ, Yassour M, Morgan XC, Kostic AD, Luo C, Gonzalez A, McDonald D, Haberman Y, Walters T, Baker S, Rosh J, Stephens M, Heyman M, Markowitz J, Baldassano R, Griffiths A, Sylvester F, Mack D, Kim S, Crandall W, Hyams J, Huttenhower C, Knight R, Xavier RJ (2014) The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15:382–392. doi:10.1016/j.chom.2014.02.005 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hansson GC (2012) Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol 15:57–62. doi:10.1016/j.mib.2011.11.002 CrossRefPubMedGoogle Scholar
  14. Hatzikotoulas K, Gilly A, Zeggini E (2014) Using population isolates in genetic association studies. Brief Funct Genomics 13:371–377. doi:10.1093/bfgp/elu022 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hunter DJ (2005) Gene-environment interactions in human diseases. Nat Rev Genet 6:287–298. doi:10.1038/nrg1578 CrossRefPubMedGoogle Scholar
  16. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124. doi:10.1038/nature11582 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Khor CC, Hibberd ML (2012) Host-pathogen interactions revealed by human genome-wide surveys. Trends Genet 28:233–243. doi:10.1016/j.tig.2012.02.001 CrossRefPubMedGoogle Scholar
  18. Knights D, Silverberg MS, Weersma RK, Gevers D, Dijkstra G, Huang H, Tyler AD, van Sommeren S, Imhann F, Stempak JM, Vangay P, Al-Ghalith GA, Russell C, Sauk J, Knight J, Daly MJ, Huttenhower C, Xavier RJ (2014) Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med 6:107. doi:10.1186/s13073-014-0107-1 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lee MN, Ye C, Villani AC, Raj T, Li W, Eisenhaure TM, Imboywa SH, Chipendo PI, Ran FA, Slowikowski K, Ward LD, Raddassi K, McCabe C, Lee MH, Frohlich IY, Hafler DA, Kellis M, Raychaudhuri S, Zhang F, Stranger BE, Benoist CO, De Jager PL, Regev A, Hacohen N (2014) Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343:1246980. doi:10.1126/science.1246980 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Liu JZ, Anderson CA (2014) Genetic studies of Crohn’s disease: past, present and future. Best Pract Res Clin Gastroenterol 28:373–386. doi:10.1016/j.bpg.2014.04.009 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, Abedian S, Cheon JH, Cho J, Daryani NE, Franke L, Fuyuno Y, Hart A, Juyal RC, Juyal G, Kim WH, Morris AP, Poustchi H, Newman WG, Midha V, Orchard TR, Vahedi H, Sood A, Sung JJ, Malekzadeh R, Westra HJ, Yamazaki K, Yang SK, Barrett JC, Franke A, Alizadeh BZ, Parkes M, Daly MJ, Kubo M, Anderson CA, Weersma RK (2015) Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47:979–986. doi:10.1038/ng.3359 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517CrossRefPubMedGoogle Scholar
  23. Lukens JR, Gurung P, Vogel P, Johnson GR, Carter RA, McGoldrick DJ, Bandi SR, Calabrese CR, Vande Walle L, Lamkanfi M, Kanneganti TD (2014) Dietary modulation of the microbiome affects autoinflammatory disease. Nature 516:246–249. doi:10.1038/nature13788 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P (2002) TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16:479–492CrossRefPubMedGoogle Scholar
  25. Moltke I, Grarup N, Jorgensen ME, Bjerregaard P, Treebak JT, Fumagalli M, Korneliussen TS, Andersen MA, Nielsen TS, Krarup NT, Gjesing AP, Zierath JR, Linneberg A, Wu X, Sun G, Jin X, Al-Aama J, Wang J, Borch-Johnsen K, Pedersen O, Nielsen R, Albrechtsen A, Hansen T (2014) A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 512:190–193. doi:10.1038/nature13425 CrossRefPubMedGoogle Scholar
  26. Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonzalez A, Fontana L, Henrissat B, Knight R, Gordon JI (2011) Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332:970–974. doi:10.1126/science.1198719 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Nakagome S, Takeyama Y, Mano S, Sakisaka S, Matsui T, Kawamura S, Oota H (2010) Population-specific susceptibility to Crohn’s disease and ulcerative colitis; dominant and recessive relative risks in the Japanese population. Ann Hum Genet 74:126–136. doi:10.1111/j.1469-1809.2010.00567.x CrossRefPubMedGoogle Scholar
  28. Nakayama J, Watanabe K, Jiang J, Matsuda K, Chao SH, Haryono P, La-Ongkham O, Sarwoko MA, Sujaya IN, Zhao L, Chen KT, Chen YP, Chiu HH, Hidaka T, Huang NX, Kiyohara C, Kurakawa T, Sakamoto N, Sonomoto K, Tashiro K, Tsuji H, Chen MJ, Leelavatcharamas V, Liao CC, Nitisinprasert S, Rahayu ES, Ren FZ, Tsai YC, Lee YK (2015) Diversity in gut bacterial community of school-age children in Asia. Scientific reports 5:8397. doi:10.1038/srep08397 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Nedelec Y, Sanz J, Baharian G, Szpiech ZA, Pacis A, Dumaine A, Grenier JC, Freiman A, Sams AJ, Hebert S, Page Sabourin A, Luca F, Blekhman R, Hernandez RD, Pique-Regi R, Tung J, Yotova V, Barreiro LB (2016) Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Cell 167(657–669):e21. doi:10.1016/j.cell.2016.09.025 Google Scholar
  30. Nishijima S, Suda W, Oshima K, Kim SW, Hirose Y, Morita H, Hattori M (2016) The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res 23:125–133. doi:10.1093/dnares/dsw002 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. doi:10.1086/519795 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Said HS, Suda W, Nakagome S, Chinen H, Oshima K, Kim S, Kimura R, Iraha A, Ishida H, Fujita J, Mano S, Morita H, Dohi T, Oota H, Hattori M (2014) Dysbiosis of salivary microbiota in inflammatory bowel disease and its association with oral immunological biomarkers. DNA Res 21:15–25. doi:10.1093/dnares/dst037 CrossRefPubMedGoogle Scholar
  33. Sato T, Nakagome S, Watanabe C, Yamaguchi K, Kawaguchi A, Koganebuchi K, Haneji K, Yamaguchi T, Hanihara T, Yamamoto K, Ishida H, Mano S, Kimura R, Oota H (2014) Genome-wide SNP analysis reveals population structure and demographic history of the ryukyu islanders in the southern part of the Japanese archipelago. Mol Biol Evol 31:2929–2940. doi:10.1093/molbev/msu230 CrossRefPubMedGoogle Scholar
  34. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989. doi:10.1086/319501 CrossRefPubMedPubMedCentralGoogle Scholar
  35. The GTEx Consortium (2015) The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660. doi:10.1126/science.1262110 CrossRefGoogle Scholar
  36. Todoriki H, Willcox DC, Willcox BJ (2004) The Effects of Post-War Dietary Change on Longevity and Health in Okinawa. Okinawan J Am Studies 1:52–61Google Scholar
  37. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Science translational medicine 1:6ra14. doi:10.1126/scitranslmed.3000322
  38. Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A, Xu L, Shestopaloff K, Moreno-Hagelsieb G, Paterson AD, Croitoru K (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet. doi:10.1038/ng.3693 PubMedGoogle Scholar
  39. Walker AW, Ince J, Duncan SH, Webster LM, Holtrop G, Ze X, Brown D, Stares MD, Scott P, Bergerat A, Louis P, McIntosh F, Johnstone AM, Lobley GE, Parkhill J, Flint HJ (2011) Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J 5:220–230. doi:10.1038/ismej.2010.118 CrossRefPubMedGoogle Scholar
  40. Wang J, Thingholm LB, Skieceviciene J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen FA, Ruhlemann MC, Szymczak S, Holm K, Esko T, Sun J, Pricop-Jeckstadt M, Al-Dury S, Bohov P, Bethune J, Sommer F, Ellinghaus D, Berge RK, Hubenthal M, Koch M, Schwarz K, Rimbach G, Hubbe P, Pan WH, Sheibani-Tezerji R, Hasler R, Rosenstiel P, D’Amato M, Cloppenborg-Schmidt K, Kunzel S, Laudes M, Marschall HU, Lieb W, Nothlings U, Karlsen TH, Baines JF, Franke A (2016) Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet. doi:10.1038/ng.3695 Google Scholar
  41. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, Parkinson H (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–D1006. doi:10.1093/nar/gkt1229 CrossRefPubMedGoogle Scholar
  42. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, Zhernakova A, Zhernakova DV, Veldink JH, Van den Berg LH, Karjalainen J, Withoff S, Uitterlinden AG, Hofman A, Rivadeneira F, Hoen PA, Reinmaa E, Fischer K, Nelis M, Milani L, Melzer D, Ferrucci L, Singleton AB, Hernandez DG, Nalls MA, Homuth G, Nauck M, Radke D, Volker U, Perola M, Salomaa V, Brody J, Suchy-Dicey A, Gharib SA, Enquobahrie DA, Lumley T, Montgomery GW, Makino S, Prokisch H, Herder C, Roden M, Grallert H, Meitinger T, Strauch K, Li Y, Jansen RC, Visscher PM, Knight JC, Psaty BM, Ripatti S, Teumer A, Frayling TM, Metspalu A, van Meurs JB, Franke L (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45:1238–1243. doi:10.1038/ng.2756 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Willcox DC, Willcox BJ, Hsueh WC, Suzuki M (2006) Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study. Age 28:313–332. doi:10.1007/s11357-006-9020-x CrossRefPubMedPubMedCentralGoogle Scholar
  44. Willcox DC, Willcox BJ, Todoriki H, Suzuki M (2009) The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load. J Am Coll Nutr 28(Suppl):500S–516SCrossRefPubMedGoogle Scholar
  45. Wlodarska M, Kostic AD, Xavier RJ (2015) An integrative view of microbiome-host interactions in inflammatory bowel diseases. Cell Host Microbe 17:577–591. doi:10.1016/j.chom.2015.04.008 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Wright DP, Rosendale DI, Robertson AM (2000) Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin. FEMS Microbiol Lett 190:73–79CrossRefPubMedGoogle Scholar
  47. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105–108. doi:10.1126/science.1208344 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Yamaguchi-Kabata Y, Nakazono K, Takahashi A, Saito S, Hosono N, Kubo M, Nakamura Y, Kamatani N (2008) Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am J Hum Genet 83:445–456. doi:10.1016/j.ajhg.2008.08.019 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, Cardon L, Takazoe M, Tanaka T, Ichimori T, Saito S, Sekine A, Iida A, Takahashi A, Tsunoda T, Lathrop M, Nakamura Y (2005) Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 14:3499–3506. doi:10.1093/hmg/ddi379 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Shigeki Nakagome
    • 1
    • 2
    • 3
    • 16
  • Hiroshi Chinen
    • 4
  • Atsushi Iraha
    • 4
  • Akira Hokama
    • 4
  • Yasuaki Takeyama
    • 5
  • Shotaro Sakisaka
    • 5
  • Toshiyuki Matsui
    • 6
  • Judith R. Kidd
    • 7
  • Kenneth K. Kidd
    • 7
  • Heba S. Said
    • 8
    • 9
    • 10
  • Wataru Suda
    • 8
  • Hidetoshi Morita
    • 11
    • 12
  • Masahira Hattori
    • 8
    • 9
  • Tsunehiko Hanihara
    • 1
  • Ryosuke Kimura
    • 13
  • Hajime Ishida
    • 13
  • Jiro Fujita
    • 14
  • Fukunori Kinjo
    • 4
  • Shuhei Mano
    • 2
    • 12
    • 15
  • Hiroki Oota
    • 1
  1. 1.Department of AnatomyKitasato University School of MedicineSagamiharaJapan
  2. 2.Risk Analysis Research CenterThe Institute of Statistical MathematicsTachikawaJapan
  3. 3.School of Medicine, Faculty of Health SciencesTrinity College Dublin, the University of DublinDublin 2Ireland
  4. 4.Department of EndoscopyUniversity of the Ryukyus HospitalOkinawaJapan
  5. 5.Department of Gastroenterology and MedicineFukuoka University Faculty of MedicineFukuokaJapan
  6. 6.Department of GastroenterologyFukuoka University Chikushi HospitalFukuokaJapan
  7. 7.Department of GeneticsYale University School of MedicineNew HavenUSA
  8. 8.Department of Computational BiologyGraduate School of Frontier Sciences, University of TokyoChibaJapan
  9. 9.Graduate School of Advanced Science and EngineeringWaseda UniversityTokyoJapan
  10. 10.Department of Microbiology and ImmunologyFaculty of Pharmacy, Mansoura UniversityMansouraEgypt
  11. 11.Graduate School of Environmental and Life ScienceOkayama UniversityOkayamaJapan
  12. 12.CREST, Japan Science and Technology AgencyKawaguchiJapan
  13. 13.Department of Human Biology and AnatomyGraduate School of Medicine, University of the RyukyusOkinawaJapan
  14. 14.Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Graduate School of MedicineUniversity of the RyukyusOkinawaJapan
  15. 15.Department of Mathematical Analysis and Statistical InferenceThe Institute of Statistical MathematicsTokyoJapan
  16. 16.Trinity Centre for Health Sciences Room 0.79St. James’s HospitalDublin 8Ireland

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