Search PubMed⌕ Search

Biomedical subjects

David C Whitcomb

Publications and source records attributed to David C Whitcomb.

At least 19 recordsLinked to original sources
PubMed2024

Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. PERSPECTIVE: Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.

Humans↗
PubMed2007

Human pancreatic digestive enzymes.

A primary function of the pancreas is to produce digestive enzymes that are delivered to the small intestine for the hydrolysis of complex nutrients. Much of our understanding of digestive enzymes comes from studies in animals. New technologies and the availability of the sequence of the human genome allow for a critical review of older reports and assumptions based on animal studies. This report updates our understanding of human pancreatic digestive enzymes with a focus on new insights into the biology of human proteases, lipases and amylases.

Amylases↗
PubMed2006

Chronic alcohol consumption is a major risk factor for pancreatic necrosis in acute pancreatitis.

BACKGROUND: Much of the late morbidity and mortality of acute pancreatitis (AP) is attributed to complications of pancreatic necrosis (PNEC). 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. AIMS: (1) To evaluate a series of preselected clinical factors in a prospectively collected cohort with AP to identify risk factors for PNEC and (2) to verify the relative risk of any newly identified factor(s) by retrospective analysis of a large patient cohort. METHODS: Phase I: 102 AP patients were prospectively ascertained, of which 77 (mean age 49 yr; 35 women, 42 men) underwent contrast-enhanced computerized tomography (CECT) and were studied. Eleven subjects developed PNEC (14%). Binary logistic regression was performed to identify any clinical factors associated with PNEC. Phase II: 1,474 anonymized patients admitted to the hospital with a diagnosis of AP were electronically reviewed to identify 359 subjects (mean age 54 yr; 157 women, 202 men) with AP and CECT. Seventy-six of these patients (21%) exhibited CECT evidence of PNEC. The associations found in the Phase I group were compared with Phase II by logistic regression analysis. RESULTS: In Phase I, only chronic alcohol consumption was identified as a significant new risk factor for the development of PNEC (6/19 vs 5/58, p= 0.02, OR 4.8, CI 1.27-18.2). In Phase II, it was verified that excessive alcohol consumption was a significant risk factor for PNEC (18/52 vs 58/307, p= 0.012, OR 2.27, CI 1.19-4.30). CONCLUSION: Chronic alcohol consumption seems to constitute a strong risk factor for PNEC.

Alcohol Drinking↗
PubMed2006

Role of BRCA1 and BRCA2 mutations in pancreatic cancer.

Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by "allelic" or "phenotypic" heterogeneity, in that they demonstrate differing cancer expressivity between and within pedigrees that segregate their mutations. If the same mutation is present in all our cells, why do some families with a given mutation display predominantly breast cancer? Why do other lineages show a preponderance of ovarian cancer? And why would some families have members who develop mostly or exclusively pancreatic cancer--a cancer that occurs more commonly in men and that lacks consistent evidence for a hormonal basis to its aetiology--which is clearly the case for breast and ovarian cancer? The answer is that other modifying genetic and environmental factors must interact to preferentially incite carcinogenesis in one organ over another. We are just beginning to elucidate what these factors are.

Estrogens↗
PubMed2006

Acute pancreatitis in association with Campylobacter jejuni-associated diarrhea in a 15-year-old with CFTR mutations: is there a link?

CONTEXT: Acute pancreatitis has occasionally been reported in association with Campylobacter jejuni infection in humans. However, the mechanism linking Campylobacter jejuni infection and pancreatitis is unclear. Acute pancreatitis in association with an infectious illness may be related to underlying genetic mutations. For instance, studies show that mutations in the cystic fibrosis transmembrane conductance regulator gene increase the susceptibility for acute and chronic pancreatitis. CASE REPORT: We describe a patient with Campylobacter jejuni infection who developed acute pancreatitis in the setting of an underlying cystic fibrosis transmembrane conductance regulator gene mutation. DISCUSSION: In this patient with an underlying mutation in the CFTR gene, we propose that the interaction between the mutant gene and an environmental factor, Campylobacter jejuni infection, resulted in pancreatitis.

Acute Disease↗
PubMed2006

Obesity increases the severity of acute pancreatitis: performance of APACHE-O score and correlation with the inflammatory response.

BACKGROUND: 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. AIMS: To determine if APACHE-O adds any predictive value to APACHE-II score and to test the hypothesis that obese patients are at increased risk of severe AP (SAP) because of a more intense inflammatory response to pancreatic injury. METHODS: 102 AP patients were prospectively studied. Using a body mass index (BMI) >30, 28% of the subjects were obese. Nineteen patients developed organ dysfunction and were classified as SAP. Receiver-operating curves for prediction of SAP were calculated using admission APACHE-II and APACHE-O scores. Binary logistic regression was performed to assess if obesity is a risk for SAP and to determine the clinical factors associated with severe disease. Serum levels of IL-6, MCP-1 and CRP as well as Ranson's scores were compared between obese and non-obese patients. RESULTS: Admission APACHE-O (area under the curve AUC 0.895) and APACHE-II (AUC 0.893) showed similar accuracy in predicting severe outcome. BMI was identified as a significant risk for SAP (OR 2.8, p = 0.048) and mortality (OR 11.2, p = 0.022). CRP levels were significantly higher in obese AP patients (p = 0.0001) as well as Ranson's score (p = 0.021). IL-6 and MCP-1 levels were higher in obese patients but did not reach statistical significance. CONCLUSIONS: Obesity is an independent risk for SAP. Admission APACHE-O score is not more accurate than APACHE-II. Our study results suggest that obesity increases the severity of AP by amplifying the immune response to injury.

APACHE↗
PubMed2006

The MCP-1 -2518 A/G polymorphism is not a susceptibility factor for chronic pancreatitis.

BACKGROUND AND AIMS: Chronic pancreatitis (CP) is an inflammatory process initiated by recurrent acute pancreatitis and characterized by progressive parenchyma destruction and fibrosis. 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. METHODS: A genetic association study was performed on 177 CP patients and 116 healthy controls from the NAPS2 Study. The MCP-1 A/G genotype was determined by RFLP and confirmed by DNA sequencing. RESULTS: Compared to the control group the MCP-1 -2518 genotypes were similar: A/A (57% vs. 50%), A/G (34.5% vs. 40%) and G/G (8.5% vs. 10%). These allele frequencies were not statistically different (p = 0.267). CONCLUSIONS: Although the pro-inflammatory chemokine MCP-1 -2518 G allele is a severity factor for AP, it does not significantly alter susceptibility to CP.

Adolescent↗
PubMed2006

Molecular overlap of fly circadian rhythms and human pancreatic cancer.

Circumstantial evidence demonstrating a role for circadian rhythms in cancer has been presented but there is little direct molecular evidence to support this idea in human cancer. Herein, we report a significant similarity between fly genes with strong circadian rhythms and human genes under expressed in pancreatic cancer. The list of genes includes both circadian regulator genes, such as period 1 and DEC1, and downstream effectors, such as ubiquitin specific protease 30. This observation may indicate that the pancreas peripheral clock is disrupted in pancreatic cancer and are consistent with the recent proposals that circadian genes act as tumor suppressors.

Animals↗
PubMed2006

Genetic issues in pediatric pancreatitis.

The number of hospitalizations in children with acute and chronic pancreatitis is increasing and accounts for significant morbidity. Acute pancreatitis is a reversible event involving diffuse inflammation of the pancreas with variable involvement of other regional tissues, remote organs, or both, whereas chronic pancreatitis is a process that produces irreversible changes in the pancreatic structure and function. Mutations in the gene encoding cationic trypsinogen have recently been identified to be associated with hereditary pancreatitis. Genetic mutations in the pancreatic secretory trypsin inhibitor and the cystic fibrosis transmembrane conductance regulator have been described to play a role in the development of pancreatitis as well. Mutations in the cytokine target genes relating to regulation of inflammation are likely to be important in determining the severity of pancreatitis. These findings, along with the advances in cell biology, have contributed to a better understanding of the pathophysiology of pancreatic diseases.

Carrier Proteins↗
PubMed2006

Polygenetic traits in pancreatic disorders.

Rapid advances in information and technology provide opportunities to discover the risks or causes for various disorders within individual patients. The availability of new data and new technology has outstripped the conceptual framework of simple disorders,however, and challenges current statistical approaches. The author addresses the issues surrounding study design and sample size for complex genetic traits with special attention to meta-analysis and systems biology. The author concludes that meta-analysis should play a limited role in evaluating studies of complex genetic diseases. 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.

Genetic Diseases, Inborn↗
PubMed2006

Gene-environment factors that contribute to alcoholic pancreatitis in humans.

Alcohol-associated acute and chronic pancreatitis occur in a minority of alcohol users, suggesting that most drinkers are protected from pancreatic diseases while a subset is susceptible. Ongoing studies suggest that the pathophysiology is complex and can involve multiple genetic and environmental pathways and stochastic events. Both rat models and human genetic epidemiology studies have been used to understand susceptibility and modifying factors in humans. Rat studies suggest that different types of altered pancreatic physiology occur depending on dose, they occur rapidly and that alcohol changes the immune response to recurrent pancreatic injury. Human studies suggest that PRSS1 and SPINK1 mutation increase the pancreas' susceptibility to alcohol-associated pancreatitis, and that tobacco smoking, and some factors, affect disease progression.

Disease Progression↗
PubMed2006

Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.

BACKGROUND: Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32-34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. METHODS AND FINDINGS: A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. CONCLUSIONS: These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.

Actinin↗
PubMed2005

Keratin 8 mutations are not associated with familial, sporadic and alcoholic pancreatitis in a population from the United States.

BACKGROUND AND AIMS: Genetic predispositions play a major role in the development of chronic pancreatitis. Recently, a mutation in the keratin 8 gene (G62C) was reported to be associated with chronic pancreatitis in Italy. 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. METHODS: We investigated the relevant genomic region of the keratin 8 gene in 80 patients with familial pancreatitis without a cationic trypsinogen (PRSS1) gene mutation from 52 different families, 21 patients with familial hereditary pancreatitis and a PRSS1 mutation from 20 different families, 126 patients with sporadic pancreatitis without a PRSS1 mutation, 61 patients with alcoholic pancreatitis and 271 controls by direct DNA sequencing. RESULTS: We found the heterozygous G62C mutation in n = 3/80 patients (n = 2/52 patients from different families, 3.8%) with familial pancreatitis without PRSS1 mutation and in n = 3/126 patients (2.4%) with sporadic pancreatitis. We detected an adjacent heterozygous I63V mutation in n = 2/80 patients (n = 2/52 patients from different families, 3.8%) with familial pancreatitis without PRSS1 mutation and in n = 1/61 patients (1.6%) with alcoholic pancreatitis. We found the G62C mutation in n = 2/271 controls (0.7%) and the I63V mutation in n = 2/271 controls (0.7%). There were no statistically significant differences in the genotype frequencies between patients and controls (p > 0.05). Screening of additional available family members revealed that these variants did not segregate with the disease phenotype. There was no statistically significant difference in the frequency of these keratin 8 variants between patients with chronic pancreatitis and controls (p > 0.05). CONCLUSION: These keratin 8 variants are not associated with familial, sporadic or alcoholic pancreatitis.

Adult↗