G Model IMLET-5678; No. of Pages 2
ARTICLE IN PRESS Immunology Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Letter to the Editor Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? I read with great interest the paper by Huang et al. [1] regarding the multi-omics analysis of inflammatory bowel disease (IBD). This paper as well as multiple others on this topic [2–4] represented the current mainstream notion that IBD is extremely complex that can only be elucidated through extensive research by sophisticated methods such as the multi-omics (genomics, transcriptomics, proteomics, metabolomics, etc.) and meta-omics analyses of the host and microbiota, to which I have a totally different perception. In fact, at about the same time when the first risk gene of IBD was found more than a decade ago [5,6], I had found evidence suggesting a possible simple cause and mechanism of IBD – impaired inactivation of digestive proteases mediated by deconjugated bilirubin as the result of inhibition of gut bacteria by dietary chemicals such as saccharin [7]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. Later, I further found evidence suggesting sucralose, a new generation of artificial sweetener that was first approved in Canada in 1991 followed by many other countries, may also linked to IBD through a similar mechanism as saccharin, which may have contributed to the recent worldwide increase of IBD [8,9]. This led me eventually coming up with a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD as well as the relationship between ulcerative colitis (UC) and Crohn’s disease (CD) [10]. It provided further explanations for the many puzzles in IBD such as the mysterious remarkable increase of IBD in Alberta of Canada since early 1990s, in Brisbane of Australia since middle 1990s, in north California of the United these since the end of 1990s, and in South-Eastern Norway since middle 2000s, shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004, as well as the especially remarkable recent increase of IBD in children, the shift in the occurrence from UC to CD over time, the increased appearance of CD in the colon, etc. [10,11]. This possible link was further demonstrated by multiple more epidemiological studies published thereafter from countries across the world such as the United States [12], Canada [13], Ireland [14], Sweden [15], Singapore [16], Saudi Arabia [17], China [18], etc. [19]. More importantly, some peculiar changes in IBD such as the recent decrease in CD but increase in UC in the children in Sweden [15] as well as the shared trend of change of pediatric IBD in Sweden with the general population IBD in Denmark but not pediatric IBD in Norway [20], and even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau [19] can also
be easily explained by the unified hypothesis through the pattern of consumption of those dietary chemicals. Thus, the statement in the paper [1] that much of the etiology of IBD remained unexplained seems not accurate. There were indeed simple explanations on the etiology of IBD as shown in the series publications listed above, but all these evidences are just ignored or neglected, intentionally or unintentionally, by the authors of the paper as well as the general society. This is not surprising, as all the evidence presented in my publications was collected by me as an amateur IBD researcher during my spare time from the literature, while the ultimate finding of the nearly 200 risk IBD genes were the result of decade long multiple millions, if not billions, effort of elite IBD professionals all over the world accompanied by series publications in most prestigious scientific journals like Nature [5,6,21–32]. However, time again, the truth usually comes out from theories with the best explanation of the real world rather than those favored by fashion and power. Finding of the 200 risk genes have time and again celebrated as great achievements, but none of these genes, alone or in combinations, can really explain what happened in the real world. This failure may have just reflected the fact that some agents in the environment but not the gene have played a predominant role in the development of IBD, as demonstrated by the fact that IBD emerged and dramatically increased just for about a century. Although it failed to explain what happened in the real world, this tremendous effort indeed made the significant finding of the considerable overlap among these nearly 200 risk genes between susceptibility loci for IBD and mycobacterial infection with pathways shared between host responses to mycobacteria and those predisposing to IBD [21], thus proposed the direction for further research. However, this notion that IBD is caused by an infection would be strongly contradicted by those facts such as the effective treatment of IBD by immune suppressors and anti-TNF-␣ agents [33]. As demonstrated above, the dietary chemicals theory seems also explained more puzzles of IBD than any pathogens can and is supported by the most recent publications in Nature showing saccharin and other dietary chemicals can increase the risk of colitis, diabetes, and even obesity by altering gut microbiota [34,35]. The links between NOD2 and autophagy-related genes and IBD may just reflected the increased infiltration of gut bacteria and their debris secondary of the increased gut permeability as the result of damage of gut barrier by the poorly inactivated digestive proteases, rather than uncontrolled infection of pathogens in the mucosa [36]. Thus, we should realize that many of the changes revealed by omics and meta-omics would be just consequence rather than the cause of the disease, while the crucial primary event may be subtle, transient and yet simple. A superficial explanation of data could be misleading or even detrimental for an easy solution of the disease. In my opinion, we should track down the root toward the primary cause of disease rather than just explore up and likely get lost among the small braches and leaves. Therefore, as suggested
http://dx.doi.org/10.1016/j.imlet.2015.03.007 0165-2478/© 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: X. Qin, Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.03.007
G Model IMLET-5678; No. of Pages 2
ARTICLE IN PRESS Letter to the Editor / Immunology Letters xxx (2015) xxx–xxx
2
years ago [37,38] I advocate here again sparing a little bit more efforts finding out the possible causative factors in the environment. Only then we may found the root mechanism, a cure and ultimate prevention of IBD. References [1] H. Huang, P. Vangay, C.E. McKinlay, D. Knights, Multi-omics analysis of inflammatory bowel disease, Immunol. Lett. 162 (2014) 62–68. [2] C. Fiocchi, Integrating omics: the future of IBD? Dig. Dis. 32 (Suppl. 1) (2014) 96–102. [3] Y. Yau, R.W. Leong, M. Zeng, V.C. Wasinger, Proteomics and metabolomics in inflammatory bowel disease, J. Gastroenterol. Hepatol. 28 (2013) 1076– 1086. [4] A.R. Erickson, B.L. Cantarel, R. Lamendella, Y. Darzi, E.F. Mongodin, C. Pan, et al., Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn’s disease, PLoS ONE 7 (2012) e49138. [5] J.P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J.P. Cezard, J. Belaiche, et al., Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature 411 (2001) 599–603. [6] Y. Ogura, D.K. Bonen, N. Inohara, D.L. Nicolae, F.F. Chen, R. Ramos, et al., A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease, Nature 411 (2001) 603–606. [7] X.F. Qin, Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease, Med. Hypotheses 59 (2002) 159–163. [8] X. Qin, What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can. J. Gastroenterol. 25 (2011) 511. [9] X. Qin, What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm. Bowel Dis. 17 (2011) E139. [10] X. Qin, Etiology of inflammatory bowel disease: a unified hypothesis, World J. Gastroenterol. 18 (2012) 1708–1722. [11] X. Qin, Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children, J. Pediatr. Gastroenterol. Nutr. 54 (2012) 564. [12] X. Qin, When and how was the new round of increase in inflammatory bowel disease in the United States started? J. Clin. Gastroenterol. 48 (2014) 564–565. [13] X. Qin, How to explain recent multiple reports on the decline of inflammatory bowel disease in Canada, Can. J. Gastroenterol. Hepatol. 28 (2014) 620. [14] X. Qin, The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease, Arch. Dis. Child 97 (7) (2012) 590–594. [15] X. Qin, How to explain the discordant change of ulcerative colitis and Crohn disease in adjacent or even the same regions and time periods, J. Pediatr. Gastroenterol. Nutr. 57 (2013) e30. [16] X. Qin, Comment on: paediatric inflammatory bowel disease in a multiracial Asian country, Singap. Med. J. 54 (2013) 716. [17] X. Qin, What might be the cause for the emerging inflammatory bowel disease in Saudi outpatients? Saudi J. Gastroenterol. 20 (2014) 75. [18] X. Qin, May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin. Med. J. 127 (2014) 3196– 3197. [19] X. Qin, Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 145 (2013) 912. [20] X. Qin, Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand. J. Gastroenterol. 49 (2014) 1268–1269. [21] L. Jostins, S. Ripke, R.K. Weersma, R.H. Duerr, D.P. McGovern, K.Y. Hui, et al., Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491 (2012) 119–124.
[22] K. Cadwell, J.Y. Liu, S.L. Brown, H. Miyoshi, J. Loh, J.K. Lennerz, et al., A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells, Nature 456 (2008) 259–263. [23] Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature 447 (2007) 661–678. [24] Z. Liu, J. Lee, S. Krummey, W. Lu, H. Cai, M.J. Lenardo, The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease, Nat. Immunol. 12 (2011) 1063–1070. [25] M.A. Rivas, M. Beaudoin, A. Gardet, C. Stevens, Y. Sharma, C.K. Zhang, et al., Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease, Nat. Genet. 43 (2011) 1066–1073. [26] C.A. Anderson, G. Boucher, C.W. Lees, A. Franke, M. D’Amato, K.D. Taylor, et al., Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, Nat. Genet. 43 (2011) 246–252. [27] Y. Momozawa, M. Mni, K. Nakamura, W. Coppieters, S. Almer, L. Amininejad, et al., Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease, Nat. Genet. 43 (2011) 43–47. [28] K. Asano, T. Matsushita, J. Umeno, N. Hosono, A. Takahashi, T. Kawaguchi, et al., A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population, Nat. Genet. 41 (2009) 1325–1329. [29] S. Kugathasan, R.N. Baldassano, J.P. Bradfield, P.M. Sleiman, M. Imielinski, S.L. Guthery, et al., Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease, Nat. Genet. 40 (2008) 1211–1215. [30] S.A. Fisher, M. Tremelling, C.A. Anderson, R. Gwilliam, S. Bumpstead, N.J. Prescott, et al., Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease, Nat. Genet. 40 (2008) 710–712. [31] M. Stoll, B. Corneliussen, C.M. Costello, G.H. Waetzig, B. Mellgard, W.A. Koch, et al., Genetic variation in DLG5 is associated with inflammatory bowel disease, Nat. Genet. 36 (2004) 476–480. [32] V.D. Peltekova, R.F. Wintle, L.A. Rubin, C.I. Amos, Q. Huang, X. Gu, et al., Functional variants of OCTN cation transporter genes are associated with Crohn disease, Nat. Genet. 36 (2004) 471–475. [33] X. Qin, Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? J. Crohn’s Colitis 8 (2014) 87. [34] J. Suez, T. Korem, D. Zeevi, G. Zilberman-Schapira, C.A. Thaiss, O. Maza, et al., Artificial sweeteners induce glucose intolerance by altering the gut microbiota, Nature 514 (2014) 181–186. [35] B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley, et al., Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature 519 (2015) 92–96. [36] X. Qin, How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris, J. Crohn’s Colitis 8 (2013) 88. [37] X. Qin, How can we really reduce the morbidity of inflammatory bowel disease – research on genes and cytokines, or find out the causative factors in the environment? J. Crohn’s Colitis 3 (2009) 315. [38] X. Qin, With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm. Bowel Dis. 14 (2008) 1607–1608.
Xiaofa Qin ∗ GI Biopharma Inc, 918 Willow Grove Road, Westfield, NJ 07090, USA ∗ Tel.: +1 908 463 7423. E-mail address: xiaofa [email protected]
14 February 2015 Available online xxx
Please cite this article in press as: X. Qin, Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.03.007
ARTICLE IN PRESS Immunology Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Immunology Letters journal homepage: www.elsevier.com/locate/immlet
Letter to the Editor Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? I read with great interest the paper by Huang et al. [1] regarding the multi-omics analysis of inflammatory bowel disease (IBD). This paper as well as multiple others on this topic [2–4] represented the current mainstream notion that IBD is extremely complex that can only be elucidated through extensive research by sophisticated methods such as the multi-omics (genomics, transcriptomics, proteomics, metabolomics, etc.) and meta-omics analyses of the host and microbiota, to which I have a totally different perception. In fact, at about the same time when the first risk gene of IBD was found more than a decade ago [5,6], I had found evidence suggesting a possible simple cause and mechanism of IBD – impaired inactivation of digestive proteases mediated by deconjugated bilirubin as the result of inhibition of gut bacteria by dietary chemicals such as saccharin [7]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. Later, I further found evidence suggesting sucralose, a new generation of artificial sweetener that was first approved in Canada in 1991 followed by many other countries, may also linked to IBD through a similar mechanism as saccharin, which may have contributed to the recent worldwide increase of IBD [8,9]. This led me eventually coming up with a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD as well as the relationship between ulcerative colitis (UC) and Crohn’s disease (CD) [10]. It provided further explanations for the many puzzles in IBD such as the mysterious remarkable increase of IBD in Alberta of Canada since early 1990s, in Brisbane of Australia since middle 1990s, in north California of the United these since the end of 1990s, and in South-Eastern Norway since middle 2000s, shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004, as well as the especially remarkable recent increase of IBD in children, the shift in the occurrence from UC to CD over time, the increased appearance of CD in the colon, etc. [10,11]. This possible link was further demonstrated by multiple more epidemiological studies published thereafter from countries across the world such as the United States [12], Canada [13], Ireland [14], Sweden [15], Singapore [16], Saudi Arabia [17], China [18], etc. [19]. More importantly, some peculiar changes in IBD such as the recent decrease in CD but increase in UC in the children in Sweden [15] as well as the shared trend of change of pediatric IBD in Sweden with the general population IBD in Denmark but not pediatric IBD in Norway [20], and even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau [19] can also
be easily explained by the unified hypothesis through the pattern of consumption of those dietary chemicals. Thus, the statement in the paper [1] that much of the etiology of IBD remained unexplained seems not accurate. There were indeed simple explanations on the etiology of IBD as shown in the series publications listed above, but all these evidences are just ignored or neglected, intentionally or unintentionally, by the authors of the paper as well as the general society. This is not surprising, as all the evidence presented in my publications was collected by me as an amateur IBD researcher during my spare time from the literature, while the ultimate finding of the nearly 200 risk IBD genes were the result of decade long multiple millions, if not billions, effort of elite IBD professionals all over the world accompanied by series publications in most prestigious scientific journals like Nature [5,6,21–32]. However, time again, the truth usually comes out from theories with the best explanation of the real world rather than those favored by fashion and power. Finding of the 200 risk genes have time and again celebrated as great achievements, but none of these genes, alone or in combinations, can really explain what happened in the real world. This failure may have just reflected the fact that some agents in the environment but not the gene have played a predominant role in the development of IBD, as demonstrated by the fact that IBD emerged and dramatically increased just for about a century. Although it failed to explain what happened in the real world, this tremendous effort indeed made the significant finding of the considerable overlap among these nearly 200 risk genes between susceptibility loci for IBD and mycobacterial infection with pathways shared between host responses to mycobacteria and those predisposing to IBD [21], thus proposed the direction for further research. However, this notion that IBD is caused by an infection would be strongly contradicted by those facts such as the effective treatment of IBD by immune suppressors and anti-TNF-␣ agents [33]. As demonstrated above, the dietary chemicals theory seems also explained more puzzles of IBD than any pathogens can and is supported by the most recent publications in Nature showing saccharin and other dietary chemicals can increase the risk of colitis, diabetes, and even obesity by altering gut microbiota [34,35]. The links between NOD2 and autophagy-related genes and IBD may just reflected the increased infiltration of gut bacteria and their debris secondary of the increased gut permeability as the result of damage of gut barrier by the poorly inactivated digestive proteases, rather than uncontrolled infection of pathogens in the mucosa [36]. Thus, we should realize that many of the changes revealed by omics and meta-omics would be just consequence rather than the cause of the disease, while the crucial primary event may be subtle, transient and yet simple. A superficial explanation of data could be misleading or even detrimental for an easy solution of the disease. In my opinion, we should track down the root toward the primary cause of disease rather than just explore up and likely get lost among the small braches and leaves. Therefore, as suggested
http://dx.doi.org/10.1016/j.imlet.2015.03.007 0165-2478/© 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: X. Qin, Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.03.007
G Model IMLET-5678; No. of Pages 2
ARTICLE IN PRESS Letter to the Editor / Immunology Letters xxx (2015) xxx–xxx
2
years ago [37,38] I advocate here again sparing a little bit more efforts finding out the possible causative factors in the environment. Only then we may found the root mechanism, a cure and ultimate prevention of IBD. References [1] H. Huang, P. Vangay, C.E. McKinlay, D. Knights, Multi-omics analysis of inflammatory bowel disease, Immunol. Lett. 162 (2014) 62–68. [2] C. Fiocchi, Integrating omics: the future of IBD? Dig. Dis. 32 (Suppl. 1) (2014) 96–102. [3] Y. Yau, R.W. Leong, M. Zeng, V.C. Wasinger, Proteomics and metabolomics in inflammatory bowel disease, J. Gastroenterol. Hepatol. 28 (2013) 1076– 1086. [4] A.R. Erickson, B.L. Cantarel, R. Lamendella, Y. Darzi, E.F. Mongodin, C. Pan, et al., Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn’s disease, PLoS ONE 7 (2012) e49138. [5] J.P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J.P. Cezard, J. Belaiche, et al., Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature 411 (2001) 599–603. [6] Y. Ogura, D.K. Bonen, N. Inohara, D.L. Nicolae, F.F. Chen, R. Ramos, et al., A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease, Nature 411 (2001) 603–606. [7] X.F. Qin, Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease, Med. Hypotheses 59 (2002) 159–163. [8] X. Qin, What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can. J. Gastroenterol. 25 (2011) 511. [9] X. Qin, What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm. Bowel Dis. 17 (2011) E139. [10] X. Qin, Etiology of inflammatory bowel disease: a unified hypothesis, World J. Gastroenterol. 18 (2012) 1708–1722. [11] X. Qin, Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children, J. Pediatr. Gastroenterol. Nutr. 54 (2012) 564. [12] X. Qin, When and how was the new round of increase in inflammatory bowel disease in the United States started? J. Clin. Gastroenterol. 48 (2014) 564–565. [13] X. Qin, How to explain recent multiple reports on the decline of inflammatory bowel disease in Canada, Can. J. Gastroenterol. Hepatol. 28 (2014) 620. [14] X. Qin, The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease, Arch. Dis. Child 97 (7) (2012) 590–594. [15] X. Qin, How to explain the discordant change of ulcerative colitis and Crohn disease in adjacent or even the same regions and time periods, J. Pediatr. Gastroenterol. Nutr. 57 (2013) e30. [16] X. Qin, Comment on: paediatric inflammatory bowel disease in a multiracial Asian country, Singap. Med. J. 54 (2013) 716. [17] X. Qin, What might be the cause for the emerging inflammatory bowel disease in Saudi outpatients? Saudi J. Gastroenterol. 20 (2014) 75. [18] X. Qin, May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin. Med. J. 127 (2014) 3196– 3197. [19] X. Qin, Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 145 (2013) 912. [20] X. Qin, Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand. J. Gastroenterol. 49 (2014) 1268–1269. [21] L. Jostins, S. Ripke, R.K. Weersma, R.H. Duerr, D.P. McGovern, K.Y. Hui, et al., Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491 (2012) 119–124.
[22] K. Cadwell, J.Y. Liu, S.L. Brown, H. Miyoshi, J. Loh, J.K. Lennerz, et al., A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells, Nature 456 (2008) 259–263. [23] Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature 447 (2007) 661–678. [24] Z. Liu, J. Lee, S. Krummey, W. Lu, H. Cai, M.J. Lenardo, The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease, Nat. Immunol. 12 (2011) 1063–1070. [25] M.A. Rivas, M. Beaudoin, A. Gardet, C. Stevens, Y. Sharma, C.K. Zhang, et al., Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease, Nat. Genet. 43 (2011) 1066–1073. [26] C.A. Anderson, G. Boucher, C.W. Lees, A. Franke, M. D’Amato, K.D. Taylor, et al., Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, Nat. Genet. 43 (2011) 246–252. [27] Y. Momozawa, M. Mni, K. Nakamura, W. Coppieters, S. Almer, L. Amininejad, et al., Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease, Nat. Genet. 43 (2011) 43–47. [28] K. Asano, T. Matsushita, J. Umeno, N. Hosono, A. Takahashi, T. Kawaguchi, et al., A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population, Nat. Genet. 41 (2009) 1325–1329. [29] S. Kugathasan, R.N. Baldassano, J.P. Bradfield, P.M. Sleiman, M. Imielinski, S.L. Guthery, et al., Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease, Nat. Genet. 40 (2008) 1211–1215. [30] S.A. Fisher, M. Tremelling, C.A. Anderson, R. Gwilliam, S. Bumpstead, N.J. Prescott, et al., Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease, Nat. Genet. 40 (2008) 710–712. [31] M. Stoll, B. Corneliussen, C.M. Costello, G.H. Waetzig, B. Mellgard, W.A. Koch, et al., Genetic variation in DLG5 is associated with inflammatory bowel disease, Nat. Genet. 36 (2004) 476–480. [32] V.D. Peltekova, R.F. Wintle, L.A. Rubin, C.I. Amos, Q. Huang, X. Gu, et al., Functional variants of OCTN cation transporter genes are associated with Crohn disease, Nat. Genet. 36 (2004) 471–475. [33] X. Qin, Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? J. Crohn’s Colitis 8 (2014) 87. [34] J. Suez, T. Korem, D. Zeevi, G. Zilberman-Schapira, C.A. Thaiss, O. Maza, et al., Artificial sweeteners induce glucose intolerance by altering the gut microbiota, Nature 514 (2014) 181–186. [35] B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley, et al., Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature 519 (2015) 92–96. [36] X. Qin, How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris, J. Crohn’s Colitis 8 (2013) 88. [37] X. Qin, How can we really reduce the morbidity of inflammatory bowel disease – research on genes and cytokines, or find out the causative factors in the environment? J. Crohn’s Colitis 3 (2009) 315. [38] X. Qin, With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm. Bowel Dis. 14 (2008) 1607–1608.
Xiaofa Qin ∗ GI Biopharma Inc, 918 Willow Grove Road, Westfield, NJ 07090, USA ∗ Tel.: +1 908 463 7423. E-mail address: xiaofa [email protected]
14 February 2015 Available online xxx
Please cite this article in press as: X. Qin, Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses? Immunol Lett (2015), http://dx.doi.org/10.1016/j.imlet.2015.03.007
