Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed Central  Google Scholar 

  • 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 171:4868–4874

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Civelek M, Lusis AJ (2014) Systems genetics approaches to understand complex traits. Nat Rev Genet 15:34–48. doi:10.1038/nrg3575

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Fischbach MA, Segre JA (2016) Signaling in Host-Associated Microbial Communities. Cell 164:1288–1300. doi:10.1016/j.cell.2016.02.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Hunter DJ (2005) Gene-environment interactions in human diseases. Nat Rev Genet 6:287–298. doi:10.1038/nrg1578

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 16:479–492

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  Google Scholar 

  • Todoriki H, Willcox DC, Willcox BJ (2004) The Effects of Post-War Dietary Change on Longevity and Health in Okinawa. Okinawan J Am Studies 1:52–61

    Google Scholar 

  • 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

  • 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

    PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–516S

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 190:73–79

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All of the authors extend their deepest sympathy and condolences to the family of Dr. Hiroshi Chinen, who sadly passed away in the middle of this study. We are very grateful to the anonymous donors of the University of the Ryukyus Hospital, University of the Ryukyus, Fukuoka University, and Chikushi Hospital for their vast cooperation with this study. S.N. was supported as a Grant-in-Aid for the Japan Society for the Promotion of Science (JSPS) Research Fellow (24–3234). This study was supported in part by a Grant-in-Aid for the JSPS No. 22370087 to H.I and Nos. 24370099 and 21370108 to H.O.

Author information

Author notes

    Authors and Affiliations

    1. Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan

      Shigeki Nakagome, Tsunehiko Hanihara & Hiroki Oota

    2. Risk Analysis Research Center, The Institute of Statistical Mathematics, Tachikawa, Tokyo, 190-8562, Japan

      Shigeki Nakagome & Shuhei Mano

    3. School of Medicine, Faculty of Health Sciences, Trinity College Dublin, the University of Dublin, Dublin 2, Ireland

      Shigeki Nakagome

    4. Department of Endoscopy, University of the Ryukyus Hospital, Okinawa, 903-0215, Japan

      Hiroshi Chinen, Atsushi Iraha, Akira Hokama & Fukunori Kinjo

    5. Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, 814-0180, Japan

      Yasuaki Takeyama & Shotaro Sakisaka

    6. Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, 818-8562, Japan

      Toshiyuki Matsui

    7. Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA

      Judith R. Kidd & Kenneth K. Kidd

    8. Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, 277-8561, Japan

      Heba S. Said, Wataru Suda & Masahira Hattori

    9. Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan

      Heba S. Said & Masahira Hattori

    10. Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

      Heba S. Said

    11. Graduate School of Environmental and Life Science, Okayama University, Okayama, 700-8530, Japan

      Hidetoshi Morita

    12. CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan

      Hidetoshi Morita & Shuhei Mano

    13. Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, 903-0215, Japan

      Ryosuke Kimura & Hajime Ishida

    14. 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

      Jiro Fujita

    15. Department of Mathematical Analysis and Statistical Inference, The Institute of Statistical Mathematics, Tokyo, 190-8562, Japan

      Shuhei Mano

    16. Trinity Centre for Health Sciences Room 0.79, St. James’s Hospital, James’s St., Dublin 8, Ireland

      Shigeki Nakagome

    Authors
    1. Shigeki Nakagome
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Hiroshi Chinen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Atsushi Iraha
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Akira Hokama
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yasuaki Takeyama
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Shotaro Sakisaka
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Toshiyuki Matsui
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Judith R. Kidd
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Kenneth K. Kidd
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Heba S. Said
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Wataru Suda
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Hidetoshi Morita
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Masahira Hattori
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Tsunehiko Hanihara
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Ryosuke Kimura
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Hajime Ishida
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Jiro Fujita
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Fukunori Kinjo
      View author publications

      You can also search for this author in PubMed Google Scholar

    19. Shuhei Mano
      View author publications

      You can also search for this author in PubMed Google Scholar

    20. Hiroki Oota
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Shigeki Nakagome.

    Ethics declarations

    Conflict of interest

    On behalf of all authors, the corresponding author states that there is no conflict of interest.

    Additional information

    S. Nakagome and H. Chinen equally contributed to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 285 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Nakagome, S., Chinen, H., Iraha, A. et al. Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn’s disease in the Ryukyu Islands. Hum Genet 136, 387–397 (2017). https://doi.org/10.1007/s00439-017-1764-0

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00439-017-1764-0

    Keywords

    Search

    Navigation