| 1. |
- Bonfiglio, F., et al.
(författare)
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Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 155:1, s. 168-179
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 x 10(-8)) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0 x 10(-6)). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 x 10(-10) in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKB-KAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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| 2. |
- Andersson, Johanna, 1974, et al.
(författare)
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Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis
- 2006
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 130:6, s. 1573-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. METHODS: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. RESULTS: KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST
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| 3. |
- Bacq, Yannick, et al.
(författare)
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Efficacy of Ursodeoxycholic Acid in Treating Intrahepatic Cholestasis of Pregnancy: A Meta-analysis.
- 2012
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 143:6, s. 1492-1501
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP). METHODS: We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos. RESULTS: In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01). CONCLUSIONS: Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.
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| 4. |
- Berntsen, N. L., et al.
(författare)
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Association between HLA haplotypes and increased serum levels of IgG4 in patients with primary sclerosing cholangitis
- 2015
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 148:5
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Tidskriftsartikel (refereegranskat)abstract
- Increased serum levels of IgG4 have been reported in 9%-15% of patients with primary sclerosing cholangitis (PSC); it is not clear whether this increase contributes to pathogenesis. We performed genetic analyses of the HLA complex in patients with PSC from Norway, Sweden, and from the United States. We found an association between levels of IgG4 above the upper reference limit and specific HLA haplotypes. These patients had a significantly lower frequency of the strongest PSC risk factor, HLA-B∗08, than patients without increased IgG4, and significantly higher frequencies of HLA-B∗07 and HLA-DRB1∗15. HLA genotype therefore might affect the serum concentration of IgG4, and increased IgG4 might be a marker of a distinct phenotype of PSC. © 2015 AGA Institute.
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| 5. |
- Björk, Jan, et al.
(författare)
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Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis : Cumulative risks and APC gene Mutations
- 2001
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Ingår i: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 121:5, s. 1127-1135
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Patients with familial adenomatous polyposis (FAP) have a high prevalence of duodenal adenomas, and the region of the ampulla of rater is the predilection site for duodenal adenocarcinomas. This study assessed the risk of stage IV periampullary adenomas according to the Spigelman classification and periampullary adenocarcinomas in Swedish FAP patients screened by esophagogastroduodenoscopy (EGD). The genotype of patients with stage IV periampullary adenomas and periampullary adenocarcinomas was also investigated. Methods: A retrospective study of 180 patients screened by EGD in 1982-1999 was undertaken. Kaplan-Meier analysis was performed to evaluate cumulative risk. Mutation analysis was carried out in patients with periampullary adenocarcinomas diagnosed outside the screening program, in addition to patients in the screening group with stage IV periampullary adenomas and adenocarcinomas. Results: Periampullary adenoma stage IV was diagnosed in 14 patients (7.8%), with a cumulative risk of 20% at age 60 years. Periampullary adenocarcinoma was diagnosed in 5 patients (2.8%), with a cumulative risk of 10% at age 60. Three of the adenocarcinomas occurred in patients with stage IV periampullary adenomas compared with 2 in patients with less severe periampullary adenomatosis at screening (odds ratio, 31; 95% confidence interval, 4.6-215). Fifteen (88%) of the APC gene mutations were detected; 12 of these were located downstream from codon 1051 in exon 15. Conclusions: The life time risk of severe periampullary lesions in FAP patients is high, and an association between stage IV periampullary adenomas and a malignant course of the periampullary adenomatosis is strongly suggestive. Mutations downstream from codon 1051 seem to be associated with severe periampullary lesions.
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| 6. |
- Bueter, Marco, et al.
(författare)
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Gastric bypass increases energy expenditure in rats.
- 2010
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 138:5, s. 1845-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Mechanisms underlying weight loss maintenance after gastric bypass are poorly understood. Our aim was to examine the effects of gastric bypass on energy expenditure in rats. METHODS: Thirty diet-induced obese male Wistar rats underwent either gastric bypass (n = 14), sham-operation ad libitum fed (n = 8), or sham-operation body weight-matched (n = 8). Energy expenditure was measured in an open circuit calorimetry system. RESULTS: Twenty-four-hour energy expenditure was increased after gastric bypass (4.50 +/- 0.04 kcal/kg/h) compared with sham-operated, ad libitum fed (4.29 +/- 0.08 kcal/kg/h) and sham-operated, body weight-matched controls (3.98 +/- 0.10 kcal/kg/h, P < .001). Gastric bypass rats showed higher energy expenditure during the light phase than sham-operated control groups (sham-operated, ad libitum fed: 3.63 +/- 0.04 kcal/kg/h vs sham-operated, body weight-matched: 3.42 +/- 0.05 kcal/kg/h vs bypass: 4.12 +/- 0.03 kcal/kg/h, P < .001). Diet-induced thermogenesis was elevated after gastric bypass compared with sham-operated, body weight-matched controls 3 hours after a test meal (0.41% +/- 1.9% vs 10.5% +/- 2.0%, respectively, P < .05). The small bowel of gastric bypass rats was 72.1% heavier because of hypertrophy compared with sham-operated, ad libitum fed rats (P < .0001). CONCLUSIONS: Gastric bypass in rats prevented the decrease in energy expenditure after weight loss. Diet-induced thermogenesis was higher after gastric bypass compared with body weight-matched controls. Raised energy expenditure may be a mechanism explaining the physiologic basis of weight loss after gastric bypass.
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| 7. |
- Böhn, Lena, et al.
(författare)
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Diet Low in FODMAPs Reduces Symptoms of Irritable Bowel Syndrome as Well as Traditional Dietary Advice: A Randomized Controlled Trial.
- 2015
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 149:6
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Tidskriftsartikel (refereegranskat)abstract
- A diet with reduced content of fermentable short-chain carbohydrates (fermentable oligo-, di-, monosaccharides, and polyols [FODMAPs]) has been reported to be effective in the treatment of patients with irritable bowel syndrome (IBS). However, there is no evidence of its superiority to traditional dietary advice for these patients. We compared the effects of a diet low in FODMAPs with traditional dietary advice in a randomized controlled trial of patients with IBS.
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| 8. |
- Drossman, D. A., et al.
(författare)
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Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut−Brain Interaction): A Rome Foundation Working Team Report
- 2018
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 154:4
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Central neuromodulators (antidepressants, antipsychotics, and other central nervous system−targeted medications) are increasingly used for treatment of functional gastrointestinal disorders (FGIDs), now recognized as disorders of gut−brain interaction. However, the available evidence and guidance for the use of central neuromodulators in these conditions is scanty and incomplete. In this Rome Foundation Working Team report, a multidisciplinary team summarized available research evidence and clinical experience to provide guidance and treatment recommendations. Methods: The working team summarized the literature on the pharmacology of central neuromodulators and their effects on gastrointestinal sensorimotor function and conducted an evidence-based review on their use for treating FGID syndromes. Because of the paucity of data for FGIDs, we included data for non-gastrointestinal painful disorders and specific symptoms of pain, nausea, and vomiting. This information was combined into a final document comprising a synthesis of available evidence and recommendations for clinical use guided by the research and clinical experience of the experts on the committee. Results: The evidence-based review on neuromodulators in FGID, restricted by the limited available controlled trials, was integrated with open-label studies and case series, along with the experience of experts to create recommendations using a consensus (Delphi) approach. Due to the diversity of conditions and complexity of treatment options, specific recommendations were generated for different FGIDs. However, some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone α2δ ligand agents) is recommended when a single medication is unsuccessful or produces side effects at higher dosages; (3) treatment should be continued for 6−12 months to potentially prevent relapse; and (4) implementation of successful treatment requires effective communication skills to improve patient acceptance and adherence, and to optimize the patient−provider relationship. Conclusions: Based on systematic and selectively focused review and the consensus of a multidisciplinary panel, we have provided summary information and guidelines for the use of central neuromodulators in the treatment of chronic gastrointestinal symptoms and FGIDs. Further studies are needed to confirm and refine these recommendations.
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| 9. |
- Gwynne, Rachel M, et al.
(författare)
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Cholera toxin induces sustained hyperexcitability in submucosal secretomotor neurons in guinea pig jejunum.
- 2009
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 136:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Neural mechanisms underlying cholera toxin (CT)-induced intestinal hypersecretion remain unclear. We investigated long-term excitability changes in vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) secretomotor neurons after prolonged luminal exposure to CT. METHODS: Isolated segments of guinea pig jejunum were incubated with saline or CT +/- neurotransmitter antagonist in the lumen; the submucosal plexus was then dissected clear, circumferentially adjacent to intact mucosa. Synaptic inputs and firing properties of S neurons in ganglia next to the mucosa in control saline were studied using intracellular recording. Neurons were processed for VIP and NPY immunoreactivity. RESULTS: Thirty S neurons (20 VIP(+), 7 NPY(+), 3 VIP(-)/NPY(-)) from CT-treated preparations and 27 control S neurons (19 VIP(+), 4 NPY(+), 4 VIP(-)/NPY(-)) in ganglia adjacent to intact mucosa were analyzed. VIP(+) and NPY(+) neurons in CT-treated preparations fired significantly more action potentials and for longer periods during injected depolarizing current pulses (50-350 pA) than control neurons. Addition of tetrodotoxin, hexamethonium, granisetron, or the neurokinin-1 (NK1) antagonist SR140333 during the CT incubation blocked CT-induced effects in both neuron types. The NK3 antagonist SR142801 blocked CT-induced effects in NPY(+) neurons and reduced the number of action potentials in VIP(+) neurons. Synaptic activity was unaffected by CT. CONCLUSIONS: CT induces specific and sustained hyperexcitability of secretomotor neurons in enteric pathways. CT acts in the mucosa. Its effect is neurally mediated and depends on 5-hydroxytryptamine-3, nicotinic, and NK1 receptors. This system represents a unique model to understand the neural mechanisms of action of CT and to identify therapeutic targets.
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| 10. |
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