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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061451-08
Application #
7825345
Study Section
Special Emphasis Panel (ZDK1-GRB-R (J2))
Program Officer
Serrano, Jose
Project Start
2002-07-01
Project End
2011-09-20
Budget Start
2010-05-01
Budget End
2011-09-20
Support Year
8
Fiscal Year
2010
Total Cost
$631,541
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Whitcomb, David C (2015) Innovation and hard work: The 2015 George E. Palade Medal Award Lecture. Pancreatology 15:611-5
LaRusch, Jessica; Jung, Jinsei; General, Ignacio J et al. (2014) Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet 10:e1004376

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