المؤلفون: Tavares, Leticia Camargo, Zheng, Tenghao, Kwicklis, Madeline, Mitchell, Emily, Pandit, Anita, Pullapantula, Suraj, Bernard, Cheryl, Teder‐Laving, Maris, Marques, Francine Z., Esko, Tonu, Kuo, Braden, Shulman, Robert J., Chumpitazi, Bruno P., Koch, Kenneth L., Sarosiek, Irene, Abell, Thomas L., McCallum, Richard W., Parkman, Henry P., Pasricha, Pankaj J., Hamilton, Frank A., Tonascia, James, Zawistowski, Matthew, Farrugia, Gianrico, Grover, Madhusudan, D’Amato, Mauro

المصدر: United European Gastroenterology Journal; October 2023, Vol. 11 Issue: 8 p784-796, 13p

مستخلص: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction. Genetic predisposition may play a role; however, investigation at the genome‐wide level has not been performed. We carried out a genome‐wide association study (GWAS) meta‐analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population‐based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non‐gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high‐quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene‐set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls. While no SNP associations were detected at strict significance (p≤ 5 × 10−8), nine independent genomic loci were associated at suggestive significance (p≤ 1 × 10−5), with the strongest signal (rs9273363, odds ratio = 1.4, p= 1 × 10−7) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein‐coding candidate genes. Gene‐set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR≤ 0.05). The GP risk allele rs6984536A (Peroxidasin‐Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p= 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r= 0.8, p= 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p= 0.005 vs. controls). We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory‐motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

المؤلفون: Jarasvaraparn, Chaowapong, Vilar-Gomez, Eduardo, Yates, Katherine P., Wilson, Laura A., Neuschwander-Tetri, Brent, Loomba, Rohit, Cummings, Oscar, Vos, Miriam, Xanthakos, Stavra, Schwimmer, Jeffrey, Molleston, Jean P., Sanyal, Arun, Tonascia, James, Chalasani, Naga

المصدر: Clinical Gastroenterology & Hepatology; May2024, Vol. 22 Issue 5, p1024-1024, 1p

مستخلص: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG). PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16–2.09) and adults (OR, 1.55; 95% CI, 1.16–1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013–1.026), CG (OR, 1.024; 95% CI, 1.018–1.030), and GG (OR, 1.03; 95% CI, 1.023–1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m² was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P <.01 for both). Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD. [ABSTRACT FROM AUTHOR]

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المؤلفون: Sarosiek, Irene, Van Natta, Mark, Parkman, Henry P., Abell, Thomas, Koch, Kenneth L., Kuo, Braden, Shulman, Robert J., Farrugia, Gianrico, Grover, Madhusudan, Hamilton, Frank A., Pasricha, Pankaj J., Yates, Katherine P., Miriel, Laura, Wilson, Laura, Yamada, Goro, Tonascia, James, McCallum, Richard W.

المصدر: Clinical Gastroenterology & Hepatology; Mar2022, Vol. 20 Issue 3, pe452-e464, 13p

مستخلص: The use of domperidone (DOM) for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) Registries (GpR). The GpCRC cohort consisted of patients with GP (75%) and with GP-like symptoms but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and GpR2. Patients who had previously taken or who were on DOM therapy at enrollment were excluded from this analysis. The control group did not use domperidone (non-DOM group) before or after enrollment. The following outcome measures were identified: change from baseline in Gastroparesis Cardinal Symptom Index total score, with 3 subscales, plus Gastroesophageal Reflux Disease and Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life scores. Overall, of 748 patients, 181 (24%) were in the DOM group, whereas 567 were in the non-DOM group. Sixty-three percent of participants had idiopathic GP. At baseline, DOM patients compared with non-DOM patients were significantly younger, had lower body mass index, non-Hispanic ethnicity, a higher annual household income, lower narcotic utilization, lower supplemental and complimentary medication use, and were more likely to have delayed gastric emptying time, as well as worse nausea and fullness scores. Compared with non-DOM patients, DOM patients experienced moderate but significantly more improvement in GP outcome measures: Gastroparesis Cardinal Symptom Index total score (P =.003), nausea (P =.003), and fullness subscales (P =.005), upper abdominal pain score (P =.04), Gastroesophageal Reflux Disease score (P =.05), and Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life score (P =.05). Utilizing the method of pragmatic modeling to evaluate long-term treatment of GP in a large GpCRC database, DOM treatment resulted in moderately but significantly improved GP. This project was based on data generated by 2 GpCRC Registry studies recognized under the Clinicaltrial.gov numbers: NCT00398801 and NCT01696747 symptoms compared with a group receiving standard-of-care but not DOM. [ABSTRACT FROM AUTHOR]

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المؤلفون: Pasricha, Pankaj J., Grover, Madhusudan, Yates, Katherine P., Abell, Thomas L., Bernard, Cheryl E., Koch, Kenneth L., McCallum, Richard W., Sarosiek, Irene, Kuo, Braden, Bulat, Robert, Chen, Jiande, Shulman, Robert J., Lee, Linda, Tonascia, James, Miriel, Laura A., Hamilton, Frank, Farrugia, Gianrico, Parkman, Henry P.

المصدر: Gastroenterology (00165085); May2021, Vol. 160 Issue 6, p2006-2017, 12p

مستخلص: The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206⁺ macrophages in both groups compared with obese controls. A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. NCT00398801 , NCT01696747 [ABSTRACT FROM AUTHOR]

: Copyright of Gastroenterology (00165085) is the property of W B Saunders and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Price, Jennifer, Naggie, Susanna, Vilar-Gomez, Eduardo, Chalasani, Naga P., Gawrieh, Samer, Heath, Sonya, Loomba, Rohit, Sterling, Richard K., Sulkowski, Mark S., Tonascia, James, Wilson, Laura, Woreta, Tinsay A., Lake, Jordan

المصدر: Gastroenterology (00165085); 2023 Supplement, Vol. 164 Issue 6, pS-1050-S-1050, 1p

المؤلفون: Pasricha, Pankaj J., Grover, Madhusudan, Yates, Katherine P., Abell, Thomas L., Koch, Kenneth L., McCallum, Richard W., Sarosiek, Irene, Bernard, Cheryl E., Kuo, Braden, Bulat, Robert, Shulman, Robert J., Chumpitazi, Bruno P., Tonascia, James, Miriel, Laura A., Wilson, Laura A., Van Natta, Mark L., Mitchell, Emily, Hamilton, Frank, Farrugia, Gianrico, Parkman, Henry P.

المصدر: Clinical Gastroenterology & Hepatology; Dec2022, Vol. 20 Issue 12, p2684-2684, 1p

مستخلص: The Gastroparesis Clinical Research Consortium is a multicenter coalition created and funded by the National Institutes of Diabetes and Digestive and Kidney Disorders, with a mission to advance understanding of the pathophysiology of gastroparesis and develop an effective treatment for patients with symptomatic gastroparesis. In this review, we summarize the results of the published Gastroparesis Clinical Research Consortium studies as a ready and convenient resource for gastroenterologists and others to provide a clear understanding of the consortium's experience and perspective on gastroparesis and related disorders. [ABSTRACT FROM AUTHOR]

: Copyright of Clinical Gastroenterology & Hepatology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Parkman, Henry P., Blackford, Amanda L., Yates, Katherine P., Grover, Madhusudan, Malik, Zubair A., Schey, Ron, Bulat, Robert S., Koch, Kenneth L., Sarosiek, Irene, Kuo, Braden, Shulman, Robert J., Farrugia, Gianrico, Miriel, Laura A., Tonascia, James, Hamilton, Frank A., Pasricha, Pankaj J., McCallum, Richard W., Abell, Thomas

المصدر: Gastroenterology (00165085); 2022 Supplement, Vol. 162 Issue 7, pS-274-S-275, 1p

المؤلفون: Murray, Helen Burton, Mitchell, Emily P., Edwards, Robert, McCallum, Richard W., Sarosiek, Irene, Koch, Kenneth L., Grover, Madhusudan, Farrugia, Gianrico, Parkman, Henry P., Tonascia, James, Shulman, Robert J., Hamilton, Frank A., Abell, Thomas, Pasricha, Pankaj J., Kuo, Braden

المصدر: Gastroenterology (00165085); 2022 Supplement, Vol. 162 Issue 7, pS-247-S-248, 1p

المؤلفون: Wei, Lai, Jessen, Erik, Bernard, Cheryl, Chikkamenahalli, Lakshmikanth, Breen-Lyles, Margaret K., Ghanem, Omar, Mckenzie, Travis J., Yates, Katherine P., Kuo, Braden, Shulman, Robert J., Chumpitazi, Bruno P., Koch, Kenneth L., Sarosiek, Irene, Abell, Thomas, McCallum, Richard W., Parkman, Henry P., Pasricha, Pankaj J., Hamilton, Frank A., Tonascia, James, Farrugia, Gianrico

المصدر: Gastroenterology (00165085); 2022 Supplement, Vol. 162 Issue 7, pS-247-S-247, 1p

المؤلفون: Parkman, Henry P., Sharkey, Emily, McCallum, Richard W., Hasler, William L., Koch, Kenneth L., Sarosiek, Irene, Abell, Thomas L., Kuo, Braden, Shulman, Robert J., Grover, Madhusudan, Farrugia, Gianrico, Schey, Ron, Tonascia, James, Hamilton, Frank, Pasricha, Pankaj J.

المصدر: Clinical Gastroenterology & Hepatology; Mar2022, Vol. 20 Issue 3, p546-546, 1p

مستخلص: Constipation can be an important symptom in some patients with gastroparesis. The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; and 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and wireless motility capsule (WMC). Patients with symptoms of gastroparesis underwent gastric emptying scintigraphy (GES), wireless motility capsule (WMC) assessing gastric emptying, small bowel transit, and colonic transit, and questionnaires assessing symptoms using a modified Patient Assessment of Upper GI Symptoms [PAGI-SYM] and Rome III functional GI disorder questionnaire. Of 338 patients with symptoms of gastroparesis, 242 (71.5%) had delayed gastric emptying by scintigraphy; 298 (88.2%) also met criteria for functional dyspepsia. Severity of constipation was severe/very severe in 34% patients, moderate in 24%, and none/very mild/mild in 42%. Increasing severity of constipation was associated with increasing symptoms of gastroparesis and presence of irritable bowel syndrome (IBS). Severity of constipation was not associated with gastric retention on GES or WMC. Delayed colonic transit was present in 108 patients (32% of patients). Increasing severity of constipation was associated with increasing small bowel transit time, colonic transit time, and whole gut transit time. Severe/very severe constipation and delayed colon transit occurs in a third of patients with symptoms of gastroparesis. The severity of constipation is associated with severity of gastroparesis symptoms, presence of IBS, small bowel and colon transit delay, but not delay in gastric emptying. ClinicalTrials.gov Identifier: NCT01696747 [ABSTRACT FROM AUTHOR]

: Copyright of Clinical Gastroenterology & Hepatology is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)