Symposium on precision medicine
Individualized Medicine in Gastroenterology and Hepatology

https://doi.org/10.1016/j.mayocp.2017.03.002Get rights and content

Abstract

After the completion of the Human Genome Project, there has been an acceleration in methodologies on sequencing nucleic acids (DNA and RNA) at a high precision and with ever-decreasing turnaround time and cost. Collectively, these approaches are termed next-generation sequencing and are already affecting the transformation of medical practice. In this symposium article, we highlight the current knowledge of the genetics of selected gastrointestinal tract and liver diseases, namely, inflammatory bowel disease, hereditary cholestatic liver disease, and familial colon cancer syndromes. In addition, we provide a stepwise approach to use next-generation sequencing methodologies for clinical practice with the goal to improve the diagnosis as well as management of and/or therapy of the chosen digestive diseases. This early experience of applying next-generation sequencing in the practice of gastroenterology and hepatology will delineate future best practices in the field, ultimately for the benefit of our patients.

Section snippets

Inflammatory Bowel Diseases

Inflammatory bowel diseases, including ulcerative colitis (UC) and Crohn disease (CD), are chronic relapsing and remitting diseases that result in immune-mediated damage to the gut and other organs or systems. The incidence and prevalence of both CD and UC have increased significantly during the 20th century (P<.05).1 For example, in Olmsted County, Minnesota, the incidence of CD increased from 5.8 to 133 cases per 100,000 person-years2 and that of UC increased from 7.6 to 299 cases per 100,000

Hereditary Cholestatic Liver Disease

Chronic cholestasis is a serious and devastating component of both pediatric and adult liver diseases that is either inherited or acquired.24 Clinically, cholestasis is defined by increased serum hyperbilirubinemia and increased alkaline phosphatase levels due to impairment of bile flow. Anatomically, cholestasis is categorized as intrahepatic (caused by a diverse group of hepatobiliary diseases with overlapping clinical presentations) or extrahepatic (largely due to obstructive lesions of the

Familial Colon Cancer Syndromes

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer deaths in the United States. Although most CRCs appear to be sporadic age-related cancers (mean age at diagnosis, 65 years), approximately 20% of CRCs occur in familial aggregates, having varying patterns of apparent disease penetrance and inheritance (Table 5).52 Among the CRCs with a familial component, known genetic conditions account for a small fraction of these patients. The 2

Conclusion

Over the past decade the genetic basis of selected digestive diseases has been elucidated. These advances coupled with the availability of NGS methodologies for clinical testing will further the genomic understanding of several gastrointestinal tract and liver diseases, with the potential to improve prognostication in and therapies for these patients.

References (72)

  • N.A. Molodecky et al.

    Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review

    Gastroenterology

    (2012)
  • E.V. Loftus et al.

    Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival

    Gut

    (2000)
  • C.G. Loftus et al.

    Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000

    Inflamm Bowel Dis

    (2007)
  • J. Cosnes et al.

    Epidemiology and natural history of inflammatory bowel diseases

    Gastroenterology

    (2011)
  • L. Jostins et al.

    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

    Nature

    (2012)
  • H.S. de Souza et al.

    Immunopathogenesis of IBD: current state of the art

    Nat Rev Gastroenterol Hepatol

    (2016)
  • W. Moon et al.

    Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

    Aliment Pharmacol Ther

    (2016)
  • T. Haritunians et al.

    Genetic predictors of medically refractory ulcerative colitis

    Inflamm Bowel Dis

    (2010)
  • L. Henckaerts et al.

    Genetic risk profiling and prediction of disease course in Crohn's disease patients

    Clin Gastroenterol Hepatol

    (2009)
  • E.I. Benchimol et al.

    Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data

    Gut

    (2009)
  • T. Paul et al.

    Distinct phenotype of early childhood inflammatory bowel disease

    J Clin Gastroenterol

    (2006)
  • M. Imielinski et al.

    Common variants at five new loci associated with early-onset inflammatory bowel disease

    Nat Genet

    (2009)
  • S. Kugathasan et al.

    Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

    Nat Genet

    (2008)
  • D.J. Cutler et al.

    Dissecting allele architecture of early onset IBD using high-density genotyping

    PLoS One

    (2015)
  • H.H. Uhlig

    Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

    Gut

    (2013)
  • H.H. Uhlig et al.

    The diagnostic approach to monogenic very early onset inflammatory bowel disease

    Gastroenterology

    (2014)
  • Y.Z. Zhang et al.

    Inflammatory bowel disease: pathogenesis

    World J Gastroenterol

    (2014)
  • K.N. Lazaridis et al.

    Implementing individualized medicine into the medical practice

    Am J Med Genet C Semin Med Genet

    (2014)
  • B. Lo et al.

    Autoimmune disease: patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy

    Science

    (2015)
  • M. Trauner et al.

    Molecular pathogenesis of cholestasis

    N Engl J Med

    (1998)
  • R. Fawaz et al.

    Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)

    J Pediatr Gastroenterol Nutr

    (2017)
  • F.J. Suchy

    Neonatal cholestasis

    Pediatr Rev

    (2004)
  • N. Ovchinsky et al.

    Liver biopsy in modern clinical practice: a pediatric point-of-view

    Adv Anat Pathol

    (2012)
  • K. Johnson et al.

    Evaluation of mebrofenin hepatoscintigraphy in neonatal-onset jaundice

    Pediatr Radiol

    (1998)
  • P. Russo et al.

    Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy

    Clin Gastroenterol Hepatol

    (2011)
  • K. Pittschieler et al.

    Liver involvement in infants with PiSZ phenotype of α1-antitrypsin deficiency

    J Pediatr Gastroenterol Nutr

    (1992)
  • Grant Support: The work was supported by the Mayo Clinic's Center for Individualized Medicine, the Everett J. and Jane M. Hauck Associate Director endowment for the Center for Individualized Medicine, and the William O. Lund, Jr. and Natalie C. Lund Charitable Foundation.

    Individual reprints of this article and a bound reprint of the entire Symposium on Precision Medicine will be available for purchase from our website www.mayoclinicproceedings.org.

    The Symposium on Precision Medicine will continue in an upcoming issue.

    View full text