Citation: Clinical and Translational Gastroenterology (2016) 7, e189; doi:10.1038/ctg.2016.45
& 2016 the American College of Gastroenterology 2155-384X/16 www.nature.com/ctg
EDITORIAL
Inflammatory Bowel Disease: Changing Associations to Mechanisms Benjamin Click, MD1,2 and David C. Whitcomb, MD, PhD1,2,3,4
Managing the health of individual patients suffering from complex disorders is a challenge and is costly. Inflammatory bowel disease (IBD) is a prototypic complex disorder of the small and large intestines. Susceptibility is complex, severity is variable, and response to treatment is unpredictable. Di Narzo et al. (Clin Transl Gastroenterol 7: e177; doi:10.1038/ ctg.2016.34) bring diverse teams of physicians and scientists together to break down the mechanisms of IBD by linking pathogenic genetic variants with altered gene expression in specific cell types causing IBD. Framing new findings in the context of other complex diseases provides a roadmap for predictive medicine. Clinical and Translational Gastroenterology (2016) 7, e189; doi:10.1038/ctg.2016.45; published online 8 September 2016
Inflammatory bowel disease (IBD) is classified generally as Crohn’s disease (CD) and ulcerative colitis (UC) on the basis of endoscopic, radiographic, and pathologic criteria. A diagnosis is usually clear, but less clear is the answer to our patient’s three primary questions: (1) “Why did this happen to me?” (2) “What is going to happen to me?” and (3) “What can I do to avoid horrible natural history of this disease?” To truly answer these questions with high confidence, the physician needs three types of information that currently elude us: (1) what is the mechanism of disease in this patient (mechanistic diagnosis); (2) what is the mechanism of disease progression and complications? (prognostic model); and (3) which therapies can be directed to alter the pathogenic disease trajectory (targeted therapy). To address the three primary questions of the patient and physician, there needs to be a framework shift from association studies in populations to mechanistic models in individual patients. Of course the two frameworks are not mutually exclusive and can inform each other. As new insights into complex diseases emerge, new methods of managing data evolve, but the basic elements remain the same. However, complex problems are complex, and a personalized precision medicine approach requires a paradigm shift toward complex disease modeling. Furthermore, in complex diseases such as
CD and UC, the models include multiple systems with features that overlap with other disorders, which may help in understanding each individual disease. The manuscript by Di Narzo et al. (Clin Transl Gastroenterol 2016) represents a massive team effort in changing the information obtained from genome-wide association studies to cell-specific mechanism using multiple steps and approaches. Although methodologically dense, it is a valuable “reverse engineering” project, where great value may be gained from studying components of the overall project that are of particular interest to different investigators at different times. Several important features should be highlighted. First, the authors link specific genetic variants (often far away from any coding exons) with the gene products that they regulate. The gene that is “expressed” in variable amounts on the basis of underlying genetics and the noncoding genetic “locus” that regulates it, is called the “expressional quantitative trait loci.” These DNA variants are often very important for acquired diseases (rather than congenital disorders) as they may alter the normal response to injury, inflammation, healing, and/or regeneration rather than the development or function of a cell, or organ under nonstress conditions. Second, the authors identify the cell types in which the altered gene expression takes place. This information is needed for disease modeling where the specific problems in an individual patient can be identified and the altered responses predicted. Further support of the concept and opportunities for multi-disease treatments is the fact that some, but not all genetic loci are found in other specific diseases. Third, some of the genetic variants are in protein-coding areas. The effect of the pathogenic variant that directly affects protein function under all conditions cannot be overlooked. Fourth, the authors conducted this project on patients who are resistant to anti-tumor necrosis factor therapy—suggesting that there may be multiple diseases that have common pathologic appearance, but different prognosis and therapeutic responses possibly owing to underlying mechanistic differences on a genetic level. Finally, this paper should serve as an important reference paper for many single-nucleotide polymorphisms or variants, for IBD, and other diseases. This is an important step in discovering molecular etiologies of multiple IBD risk alleles, taking us one step closer to personalized precision medicine.
1 Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 2University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 3Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA and 4Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Correspondence: David C. Whitcomb, MD, PhD, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. E-mail: [email protected]
Received 5 July 2016; accepted 15 July 2016
Editorial
2
The work of Di Narzo et al. should be commended as well as studied. We believe that these efforts are serving the scientific and clinical communities in many ways. We hope to see an acceleration of new findings like these that changes the weak associations into disease mechanisms that solves the question of Dx, Px, and Rx in individual patients. CONFLICT OF INTEREST Guarantor of the article: David C. Whitcomb, MD, PhD. Specific author contributions: Both authors contributed to the writing of the editorial and approved the final draft submitted.
Clinical and Translational Gastroenterology
Financial support: None. Potential competing interests: None. Clinical and Translational Gastroenterology is an openaccess journal published by Nature Publishing Group. This work is licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-sa/4.0/
& 2016 the American College of Gastroenterology 2155-384X/16 www.nature.com/ctg
EDITORIAL
Inflammatory Bowel Disease: Changing Associations to Mechanisms Benjamin Click, MD1,2 and David C. Whitcomb, MD, PhD1,2,3,4
Managing the health of individual patients suffering from complex disorders is a challenge and is costly. Inflammatory bowel disease (IBD) is a prototypic complex disorder of the small and large intestines. Susceptibility is complex, severity is variable, and response to treatment is unpredictable. Di Narzo et al. (Clin Transl Gastroenterol 7: e177; doi:10.1038/ ctg.2016.34) bring diverse teams of physicians and scientists together to break down the mechanisms of IBD by linking pathogenic genetic variants with altered gene expression in specific cell types causing IBD. Framing new findings in the context of other complex diseases provides a roadmap for predictive medicine. Clinical and Translational Gastroenterology (2016) 7, e189; doi:10.1038/ctg.2016.45; published online 8 September 2016
Inflammatory bowel disease (IBD) is classified generally as Crohn’s disease (CD) and ulcerative colitis (UC) on the basis of endoscopic, radiographic, and pathologic criteria. A diagnosis is usually clear, but less clear is the answer to our patient’s three primary questions: (1) “Why did this happen to me?” (2) “What is going to happen to me?” and (3) “What can I do to avoid horrible natural history of this disease?” To truly answer these questions with high confidence, the physician needs three types of information that currently elude us: (1) what is the mechanism of disease in this patient (mechanistic diagnosis); (2) what is the mechanism of disease progression and complications? (prognostic model); and (3) which therapies can be directed to alter the pathogenic disease trajectory (targeted therapy). To address the three primary questions of the patient and physician, there needs to be a framework shift from association studies in populations to mechanistic models in individual patients. Of course the two frameworks are not mutually exclusive and can inform each other. As new insights into complex diseases emerge, new methods of managing data evolve, but the basic elements remain the same. However, complex problems are complex, and a personalized precision medicine approach requires a paradigm shift toward complex disease modeling. Furthermore, in complex diseases such as
CD and UC, the models include multiple systems with features that overlap with other disorders, which may help in understanding each individual disease. The manuscript by Di Narzo et al. (Clin Transl Gastroenterol 2016) represents a massive team effort in changing the information obtained from genome-wide association studies to cell-specific mechanism using multiple steps and approaches. Although methodologically dense, it is a valuable “reverse engineering” project, where great value may be gained from studying components of the overall project that are of particular interest to different investigators at different times. Several important features should be highlighted. First, the authors link specific genetic variants (often far away from any coding exons) with the gene products that they regulate. The gene that is “expressed” in variable amounts on the basis of underlying genetics and the noncoding genetic “locus” that regulates it, is called the “expressional quantitative trait loci.” These DNA variants are often very important for acquired diseases (rather than congenital disorders) as they may alter the normal response to injury, inflammation, healing, and/or regeneration rather than the development or function of a cell, or organ under nonstress conditions. Second, the authors identify the cell types in which the altered gene expression takes place. This information is needed for disease modeling where the specific problems in an individual patient can be identified and the altered responses predicted. Further support of the concept and opportunities for multi-disease treatments is the fact that some, but not all genetic loci are found in other specific diseases. Third, some of the genetic variants are in protein-coding areas. The effect of the pathogenic variant that directly affects protein function under all conditions cannot be overlooked. Fourth, the authors conducted this project on patients who are resistant to anti-tumor necrosis factor therapy—suggesting that there may be multiple diseases that have common pathologic appearance, but different prognosis and therapeutic responses possibly owing to underlying mechanistic differences on a genetic level. Finally, this paper should serve as an important reference paper for many single-nucleotide polymorphisms or variants, for IBD, and other diseases. This is an important step in discovering molecular etiologies of multiple IBD risk alleles, taking us one step closer to personalized precision medicine.
1 Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 2University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 3Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA and 4Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Correspondence: David C. Whitcomb, MD, PhD, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. E-mail: [email protected]
Received 5 July 2016; accepted 15 July 2016
Editorial
2
The work of Di Narzo et al. should be commended as well as studied. We believe that these efforts are serving the scientific and clinical communities in many ways. We hope to see an acceleration of new findings like these that changes the weak associations into disease mechanisms that solves the question of Dx, Px, and Rx in individual patients. CONFLICT OF INTEREST Guarantor of the article: David C. Whitcomb, MD, PhD. Specific author contributions: Both authors contributed to the writing of the editorial and approved the final draft submitted.
Clinical and Translational Gastroenterology
Financial support: None. Potential competing interests: None. Clinical and Translational Gastroenterology is an openaccess journal published by Nature Publishing Group. This work is licensed under a Creative Commons AttributionNonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-sa/4.0/
