MOLECULAR GENETICS OF HEREDITARY PANCREATITIS

Summary

Principal Investigator: D C Whitcomb
Abstract: Pancreatic diseases represent a major, poorly treated health-care problem in the United States. Unfortunately, once established the devastating effects of severe acute pancreatitis or chronic pancreatitis cannot be reversed. We believe true advances in the treatment of pancreatic disease, as in other diseases, rest in the early identification of at-risk individuals and in the prevention or limitation of the disease. Thus, the goal of our program is to determine the genetic and molecular mechanisms that predispose individuals to recurrent acute pancreatitis and chronic pancreatitis and to identify therapeutic targets. Our Aims are to identify new mutations in susceptibility genes (starting with our chromosome 12 locus), and define the modifier genes and environmental factors that alter phenotypic expression and progression of pancreatic disease through fibrosis, calcifications, diabetes and disabling pain patterns. This will be accomplished by complementary laboratory techniques and statistical analysis and facilitated by expanding and revisiting our valuable family genetic resources. This proposal complements the North American Pancreas Study 2 (NAPS2) grant, a genetic epidemiology study that determines the prevalence of major pancreatitis associated gene mutations in the United States. The NAPS2 focuses on NON-familial pancreatitis, whereas the current hereditary pancreatitis (HP) Study focuses on families. The interaction between these grants occurs through referral of families that are identified in the NAPS2 study to the HP Study, and the determining whether genes found in families in the HP Study are generally important in US populations. The HP and familial pancreatitis studies are especially important because of the statistical power of family studies and the ability to detect modifier genes in a uniform background of susceptibility factors.
Funding Period: 1999-04-01 - 2008-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Polygenetic traits in pancreatic disorders
    David C Whitcomb
    Department of Medicine, University of Pittsburgh, GI Administration, UPMC Presbyterian, Mezzanine Level 2, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Endocrinol Metab Clin North Am 35:255-69, viii. 2006
  2. pmc Genetic risk factors for pancreatic disorders
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Gastroenterology 144:1292-302. 2013
  3. ncbi Genetics of pancreatitis: an update for clinicians and genetic counselors
    Sheila Solomon
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Curr Gastroenterol Rep 14:112-7. 2012
  4. pmc Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Nat Genet 44:1349-54. 2012
  5. pmc What is personalized medicine and what should it replace?
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Medical Arts Building, 3708 Fifth Avenue, Suite 401 5, Pittsburgh, PA 15213, USA
    Nat Rev Gastroenterol Hepatol 9:418-24. 2012
  6. pmc Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred
    Jessica Larusch
    Department of Medicine, University of Pittsburgh Pittsburgh, PA, USA
    JOP 13:258-62. 2012
  7. pmc Genetics of pancreatitis with a focus on the pancreatic ducts
    J Larusch
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
    Minerva Gastroenterol Dietol 58:299-308. 2012
  8. pmc Genetics of alcoholic and nonalcoholic pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Cell Biology and Physiology, and Human Genetics, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania 15213, USA
    Curr Opin Gastroenterol 28:501-6. 2012
  9. pmc Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis
    Alexander Schneider
    Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Gastroenterology 140:162-71. 2011
  10. ncbi Genetic aspects of pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Annu Rev Med 61:413-24. 2010

Detail Information

Publications18

  1. ncbi Polygenetic traits in pancreatic disorders
    David C Whitcomb
    Department of Medicine, University of Pittsburgh, GI Administration, UPMC Presbyterian, Mezzanine Level 2, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Endocrinol Metab Clin North Am 35:255-69, viii. 2006
    ..Instead, systems biology-based approaches should be developed to integrate multiple, focused, and mechanistic association studies, with the goal of assisting in the risk assessment of patients on a person-by-person basis...
  2. pmc Genetic risk factors for pancreatic disorders
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Gastroenterology 144:1292-302. 2013
    ..Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms...
  3. ncbi Genetics of pancreatitis: an update for clinicians and genetic counselors
    Sheila Solomon
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Curr Gastroenterol Rep 14:112-7. 2012
    ..This chapter addresses the intricate medical and psychosocial issues that can arise in the setting of treating patients with hereditary pancreatitis...
  4. pmc Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Nat Genet 44:1349-54. 2012
    ..These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07)...
  5. pmc What is personalized medicine and what should it replace?
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Medical Arts Building, 3708 Fifth Avenue, Suite 401 5, Pittsburgh, PA 15213, USA
    Nat Rev Gastroenterol Hepatol 9:418-24. 2012
    ....
  6. pmc Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred
    Jessica Larusch
    Department of Medicine, University of Pittsburgh Pittsburgh, PA, USA
    JOP 13:258-62. 2012
    ....
  7. pmc Genetics of pancreatitis with a focus on the pancreatic ducts
    J Larusch
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
    Minerva Gastroenterol Dietol 58:299-308. 2012
    ..A simple duct cell model is given to illustration the relationship between CFTR, CASR, aquaporins, claudins, and SPINK1, and how they interact. The role of CFTR variants in pancreatic diseases is then discussed...
  8. pmc Genetics of alcoholic and nonalcoholic pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Cell Biology and Physiology, and Human Genetics, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania 15213, USA
    Curr Opin Gastroenterol 28:501-6. 2012
    ..To provide an expert review and expert perspective on important advances related to the genetics of acute and chronic pancreatitis...
  9. pmc Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis
    Alexander Schneider
    Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Gastroenterology 140:162-71. 2011
    ..We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor SPINK1 further increase the risk of pancreatitis in these patients...
  10. ncbi Genetic aspects of pancreatitis
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Annu Rev Med 61:413-24. 2010
    ..Multiple studies are reporting new polymorphisms, as well as complex gene x gene and gene x environmental interactions...
  11. ncbi Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial
    David C Whitcomb
    Department of Medicine, University of Pittsburgh, Pennsylvania, USA
    Am J Gastroenterol 105:2276-86. 2010
    ..Our objective was to assess the efficacy and safety of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules (CREON) in patients with EPI due to CP or PS...
  12. ncbi Evaluation and management of autoimmune pancreatitis: experience at a large US center
    Amit Raina
    Division of Gastroenterology and Hepatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA
    Am J Gastroenterol 104:2295-306. 2009
    ..Systematic evaluation and management of AIP in the United States is reported only from one center. Our aim was to review the evaluation and management of AIP at a large tertiary center...
  13. ncbi A systems biology approach to genetic studies of pancreatitis and other complex diseases
    D C Whitcomb
    Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Cell Mol Life Sci 64:1763-77. 2007
    ....
  14. ncbi Obesity increases the severity of acute pancreatitis: performance of APACHE-O score and correlation with the inflammatory response
    Georgios I Papachristou
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
    Pancreatology 6:279-85. 2006
    ..Obese patients appear to be at risk for complications of acute pancreatitis (AP). APACHE-O score has been suggested to improve APACHE-II accuracy in predicting severe outcome in AP...
  15. ncbi Keratin 8 mutations are not associated with familial, sporadic and alcoholic pancreatitis in a population from the United States
    Alexander Schneider
    Department of Medicine, Division of Gastroenterology, University of Pittsburgh, Pittsburgh, PA, USA
    Pancreatology 6:103-8. 2006
    ..We determined whether mutations in the keratin 8 gene are associated with familial, sporadic and alcoholic recurrent acute or chronic pancreatitis in a population from the United States...
  16. ncbi Acute pancreatitis in association with Campylobacter jejuni-associated diarrhea in a 15-year-old with CFTR mutations: is there a link?
    Leena Kandula
    Department of Pediatrics, University of Pittsburgh, Children s Hospital of Pittsburgh, PA 15213, USA
    JOP 7:482-5. 2006
    ..For instance, studies show that mutations in the cystic fibrosis transmembrane conductance regulator gene increase the susceptibility for acute and chronic pancreatitis...
  17. pmc A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetrance
    A Khalid
    Division of Gastroenterology, Hepatology, and Nutrition, M2, C Wing, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
    Gut 55:728-31. 2006
    ..HP twins study suggests that modifier genes influence severity but not penetrance...
  18. ncbi Genetics of acute and chronic pancreatitis
    Rawad Mounzer
    Division of Gastroenterology, Hepatology and Nutrition, Departments of Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA 15213, USA
    Curr Opin Gastroenterol 29:544-51. 2013
    ..The role of genetics in acute pancreatitis, RAP and progression to chronic pancreatitis within a new framework is needed...