NAPS2 Continuation - Genome-Wide Association Study of Pancreatitis

Summary

Principal Investigator: D C Whitcomb
Affiliation: University of Pittsburgh
Country: USA
Abstract: DESCRIPTION (provided by applicant): NAPS2-Continuation: Genome-wide association study for pancreatitis The North American Pancreatitis Study 2 (NAPS2) was a 20-site, prospective molecular genetics study of recurrent acute and chronic pancreatitis. The enrollment target of 1000 subjects was exceeded, and nearly 700 control subjects were also ascertained. The primary purpose of the study was to investigate the role of 6-10 candidate genes, plus the influence of major environmental factors (e.g. tobacco smoking and alcohol consumption). Now, the rapid advances in technology allow for genome-wide association studies (GWAS) to be conducted at a reasonable cost. The goal of this renewal is to conduct a GWAS of subjects with inflammatory diseases of the pancreas. The power of the study will be further advanced by obtaining 5 year follow-up data on 500 of the original subjects, plus the recruitment of an additional 500 patients with chronic pancreatitis as a confirmatory population. The specific aims will be: Aim 1. To conduct a genome-wide association studies on 1000 subjects with recurrent acute pancreatitis and chronic pancreatitis plus 600 controls from the NAPS2 study. Aim 2. To recruit an additional 500 subjects with chronic pancreatitis for confirmatory studies. Aim 3. To re-ascertain 500 subjects with RAP and CP from the original centers with >5 years of follow-up to determine factors associated with rates of diseases progression. We believe that this comprehensive, unbiased approach will uncover multiple important genes and therapeutic targets to prevent recurrent acute pancreatitis, chronic pancreatitis and common complications. This approach will also be important in comparing pathways and key mechanism with other chronic inflammatory disorders with strong genetic basis. Thus, we expect this project to provide major advances in our understanding of pancreatic diseases. PUBLIC HEALTH RELEVANCE: NAPS2 GWAS: Overview and significance. Both recurrent acute and chronic pancreatitis are inflammatory diseases of the pancreas for which there is no effective treatment. In the past, the majority of cases were attributed to alcoholism, which lowered enthusiasm for patient treatment and for research efforts. Our discovery of mutant trypsinogen as a susceptibility gene caused many to reassess the causes of pancreatic inflammation. We organized a 20 site study (NAPS2) to enroll over 1000 cases of recurrent acute and chronic pancreatitis, plus nearly 700 controls and discovered that excessive alcohol drinking is only found in a minority of patients. This means that other culprits (including genetic changes) are important, but remain illusive. The purpose of this study is to use DNA samples from the NAPS2 study to conduct a genome-wide association study (GWAS) to discover the major genetic causes. Knowledge of the genetic basis of pancreatitis will lead to new treatments, and help remove the stigma that chronic pancreatitis is only a disease of drunkards.
Funding Period: ----------------2002 - ---------------2011-
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 Variation in the γ-glutamyltransferase 1 gene and risk of chronic pancreatitis
    Harrison Brand
    Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
    Pancreas 42:836-40. 2013
  3. pmc Physical and mental quality of life in chronic pancreatitis: a case-control study from the North American Pancreatitis Study 2 cohort
    STEPHEN T AMANN
    North Mississippi Medical Center, Tupelo, MS 38801, USA
    Pancreas 42:293-300. 2013
  4. 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
  5. 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
  6. pmc Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?
    Mark Lazarev
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Mol Pain 4:58. 2008
  7. pmc Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2)
    David C Whitcomb
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Pancreatology 8:520-31. 2008
  8. pmc Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol
    Venkata Muddana
    Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh PA 15213, USA
    World J Gastroenterol 14:4486-91. 2008
  9. pmc Validation of reverse phase protein array for practical screening of potential biomarkers in serum and plasma: accurate detection of CA19-9 levels in pancreatic cancer
    Tobias Grote
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, TX, USA
    Proteomics 8:3051-60. 2008
  10. pmc Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis
    Elie Aoun
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 3:e2003. 2008

Scientific Experts

  • D C Whitcomb
  • Julia B Greer
  • Gregory A Cote
  • Adam Slivka
  • Georgios I Papachristou
  • Venkata Muddana
  • Janette Lamb
  • Dhiraj Yadav
  • Randall E Brand
  • M Michael Barmada
  • Robert H Hawes
  • STEPHEN T AMANN
  • Jessica Larusch
  • Mary E Money
  • Michelle A Anderson
  • Elie Aoun
  • Amit Raina
  • Peter A Banks
  • Timothy B Gardner
  • Stuart Sherman
  • Brenda Diergaarde
  • John Baillie
  • Andres Gelrud
  • Harrison Brand
  • Faraz Bishehsari
  • J Larusch
  • Michele D Lewis
  • Michael O'Connell
  • Alexander Schneider
  • F Burton
  • Frank R Burton
  • Randall Brand
  • James DiSario
  • Asif Khalid
  • Beth Elinoff
  • Alyssa M Krasinskas
  • Tobias Grote
  • Mark Lazarev
  • Peter B Cotton
  • Yasser M Bhat
  • David A Sass
  • Dionysios J Papachristou
  • Leena Kandula
  • Samer Alkaade
  • Joseph Romagnuolo
  • Michael R O'Connell
  • Michelle Anderson
  • Elizabeth D Kennard
  • M Micheal Barmada
  • Arun Sharma
  • Anna C Evans
  • Michael Richard O'Connell
  • Kimberly Stello
  • Chad Toth
  • S T Amann
  • S Alkaade
  • R E Brand
  • E D Kennard
  • A Slivka
  • Xiumei Sun
  • C E Forsmark
  • Jeremy Martinson
  • S Sherman
  • RAYMOND FRIZZELL
  • P A Banks
  • D Yadav
  • M A Anderson
  • Robert Hawes
  • V Muddana
  • J Baillie
  • Peter Cotton
  • A Gelrud
  • T B Gardner
  • D Collins
  • C Lawrence
  • Sirvart Kassabian
  • Nevin Oruc
  • M O'CONNELL
  • J G Lieb
  • J Romagnuolo
  • Ryan George
  • Amy Aloe
  • M D Lewis
  • Matthew J Rockacy
  • James Park
  • Soo Yeon Cheong
  • Eleanor Feingold
  • Kim Stello
  • Kevin M McGrath
  • Christopher Lawrence

Detail Information

Publications32

  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 Variation in the γ-glutamyltransferase 1 gene and risk of chronic pancreatitis
    Harrison Brand
    Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
    Pancreas 42:836-40. 2013
    ....
  3. pmc Physical and mental quality of life in chronic pancreatitis: a case-control study from the North American Pancreatitis Study 2 cohort
    STEPHEN T AMANN
    North Mississippi Medical Center, Tupelo, MS 38801, USA
    Pancreas 42:293-300. 2013
    ..The objective of this study was to define the quality of life (QOL) in patients with chronic pancreatitis (CP)...
  4. 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...
  5. 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...
  6. pmc Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?
    Mark Lazarev
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Mol Pain 4:58. 2008
    ....
  7. pmc Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2)
    David C Whitcomb
    Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Pancreatology 8:520-31. 2008
    ..We developed the North American Pancreatitis Study 2 (NAPS2) to be sufficiently powered to understand the complex environmental, metabolic and genetic mechanisms underlying RAP and CP...
  8. pmc Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol
    Venkata Muddana
    Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh PA 15213, USA
    World J Gastroenterol 14:4486-91. 2008
    ....
  9. pmc Validation of reverse phase protein array for practical screening of potential biomarkers in serum and plasma: accurate detection of CA19-9 levels in pancreatic cancer
    Tobias Grote
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, TX, USA
    Proteomics 8:3051-60. 2008
    ..75%). As RPPA is a high-throughput method that shows results comparable to that of ELISA, we propose that RPPA is a viable technique for rapid experimental screening and validation of candidate biomarkers in blood samples...
  10. pmc Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis
    Elie Aoun
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 3:e2003. 2008
    ..We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis...
  11. ncbi Chronic alcohol consumption is a major risk factor for pancreatic necrosis in acute pancreatitis
    Georgios I Papachristou
    Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Am J Gastroenterol 101:2605-10. 2006
    ..Early diagnosis of PNEC in high-risk patients is critical to management. Hemoconcentration is one risk factor for PNEC, but additional risk factors are likely implicated...
  12. 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...
  13. ncbi The MCP-1 -2518 A/G polymorphism is not a susceptibility factor for chronic pancreatitis
    David A Sass
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Pancreatology 6:297-300. 2006
    ..Genetic factors influence susceptibility and modify progression. The monocyte chemotactic protein-1 (MCP-1) -2518 G allele, which modifies the severity of acute pancreatitis, was investigated as a susceptibility factor for CP...
  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 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
    ....
  16. ncbi Functional polymorphisms of the GSTT-1 gene do not predict the severity of acute pancreatitis in the United States
    Yasser M Bhat
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Pancreatology 7:180-6. 2007
    ..Our aim was to determine whether the same GSTT-1 polymorphism affects the severity of AP in a population from Pittsburgh, Pa., USA...
  17. doi Serum immunoglobulin G fraction 4 levels in pancreatic cancer: elevations not associated with autoimmune pancreatitis
    Amit Raina
    Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
    Arch Pathol Lab Med 132:48-53. 2008
    ..A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis...
  18. ncbi TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis
    Faraz Bishehsari
    Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
    Pancreatology 12:113-8. 2012
    ..Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS...
  19. pmc Going MAD: development of a "matrix academic division" to facilitate translating research to personalized medicine
    David C Whitcomb
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    Acad Med 86:1353-9. 2011
    ..The author illustrates this approach by describing its successful application to the reverse engineering of chronic pancreatitis...
  20. pmc Genetics of pancreatitis
    Jessica Larusch
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Curr Opin Gastroenterol 27:467-74. 2011
    ..This review highlights recent advances and future directions in genetic research...
  21. pmc ABO blood group and chronic pancreatitis risk in the NAPS2 cohort
    Julia B Greer
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Pancreas 40:1188-94. 2011
    ..Our goal was to determine whether ABO blood group may affect the risk of chronic pancreatitis...
  22. pmc Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States
    F Burton
    St Louis University, MO, USA
    Aliment Pharmacol Ther 33:149-59. 2011
    ..Effectiveness of medical therapies in chronic pancreatitis has been described in small studies of selected patients...
  23. pmc Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis
    Gregory A Cote
    Department of Medicine, Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Clin Gastroenterol Hepatol 9:266-73; quiz e27. 2011
    ..We investigated the epidemiology of alcohol-related CP at tertiary US referral centers...
  24. 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...
  25. pmc Are genetic variants in the platelet-derived growth factor [beta] gene associated with chronic pancreatitis?
    Venkata Muddana
    Division of Gastroenterology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
    Pancreas 39:1215-9. 2010
    ..We also tested the hypothesis that PDGF-[beta] polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP...
  26. doi 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...
  27. pmc Pooling-based genome-wide association study implicates gamma-glutamyltransferase 1 (GGT1) gene in pancreatic carcinogenesis
    Brenda Diergaarde
    Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
    Pancreatology 10:194-200. 2010
    ..Knowledge regarding genetic factors that influence pancreatic cancer risk is currently limited. To identify novel pancreatic cancer susceptibility loci, we conducted a two-stage genome-wide association study...
  28. 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...
  29. 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...
  30. doi Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis
    Dhiraj Yadav
    Department of Medicine, University of Pittsburgh, 3708 Fifth Ave, Pittsburgh, PA 15213, USA
    Arch Intern Med 169:1035-45. 2009
    ..We examined the current prevalence of alcohol use and smoking and their association with RAP and CP in patients evaluated at US referral centers...
  31. doi Elevated serum creatinine as a marker of pancreatic necrosis in acute pancreatitis
    Venkata Muddana
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, UPMC Presbyterian Hospital, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Am J Gastroenterol 104:164-70. 2009
    ..This study focuses on the association between routine laboratory tests and the development of pancreatic necrosis in patients with acute pancreatitis...
  32. doi SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event
    Elie Aoun
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
    Am J Gastroenterol 105:446-51. 2010
    ..Our aim was to study the prevalence of the SPINK1 N34S polymorphism in patients with sentinel and recurrent AP (RAP)...