Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation

Camilleri, Michael; Carlson, Paula; McKinzie, Sanna; Grudell, April; Busciglio, Irene; Burton, Duane D.; Baxter, Kari; Ryks, Michael; Zinsmeister, Alan R.

doi:10.1152/ajpgi.00371.2007

Cited by 83 publications

(74 citation statements)

References 38 publications

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“…In conclusion, we propose that such studies, as well as a recent report on the effect of genetic control of cannabinoid metabolism on gut functions (8), may usher in studies of endophenotype in IBS and help decipher the role of genetics and candidate mechanisms in the etiology, pathophysiology, or manifestations of IBS.…”

Section: Discussionmentioning

confidence: 86%

Candidate genes and sensory functions in health and irritable bowel syndrome

Camilleri

Busciglio

Carlson

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Zinsmeister AR. Candidate genes and sensory functions in health and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 295: 219 -225, 2008. First published May 29, 2008 doi:10.1152/ajpgi.90202.2008.-Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (GI) function; these effects are mediated through G protein transduction. Candidate genetic variations in ADR-SER were significantly associated with somatic scores in irritable bowel syndrome (IBS) and gastric emptying but not small bowel or colonic transit. Our aim was to assess whether candidate ADR-SER genes are associated with motor and sensory GI functions in IBS and subgroups on the basis of bowel dysfunction. In 122 patients with IBS and 39 healthy controls, we assessed gastrointestinal somatic symptoms and affect by validated questionnaires. We measured: gastric volume (GV), maximum tolerated volume, rectal compliance, sensation thresholds and ratings, and genetic variations including ␣2A (C-1291G), ␣2C (Del 332-325), GN␤3 (C825T), and 5-HTTLPR. Demographics and genotype distributions were similar in the patients with IBS subgrouped on bowel function. There were significant associations between 5-HTTLPR SS genotype and absence of IBS symptoms and between 5-HTTLPR LS/SS genotype and increased rectal compliance and increased pain ratings, particularly at 12 and 24 mmHg distensions. GN␤3 was associated only with fasting GV; we did not detect associations between ␣2A genotype and the gastrointestinal sensory or motor functions tested. We concluded that 5-HTTLPR LS/SS genotype is associated with both increased pain sensation and increased rectal compliance though the latter effect is unlikely to contribute to increased pain sensation ratings with LS/SS genotype. The data suggest the hypotheses that the endophenotype of visceral hypersensitivity in IBS may be partly related to genetic factors, and the association of GN␤3 with fasting GV may explain, in part, the reported association of GN␤3 with dyspepsia. adrenergic; serotonergic; GN␤3; SLC6A4; G protein; receptor ADRENERGIC MECHANISMS alter gastrointestinal reflexes involved in intestinal propulsion, coordinated motor activity in the small bowel and colon, and gastrointestinal tone and fluid secretion (12,46). Norepinephrine is also involved in control of pain including supraspinal inhibition of pain, e.g., due to a change in the behavioral state (37) including stress, which contributes to gut motility disorders (10).Among ␣2 receptors, the ␣2A subtype appears to be critically important for control of motor functions, such as gastrointestinal transit in mice (40) and colonic circular smooth muscle in canine colon (47). The ␣2 receptor agonist, clonidine, inhibits gastric and colonic tone, phasic contractility, and sensation in the rectum and colon in response to balloon distension in healthy humans (4, 43).Serotonergic (5-HT) mechanisms also alter gut absorptive, motor, and sensory functions via actions in the gut, spinal cord, and brain stem (27). Ligand-receptor interaction results in c...

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Section: Discussionmentioning

confidence: 86%

Candidate genes and sensory functions in health and irritable bowel syndrome

Camilleri

Busciglio

Carlson

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…A common SNP is FAAH C385A, which causes reduced cellular expression and activity of FAAH enzyme (27). FAAH C385A was significantly associated with D-IBS, M-IBS, and rapid colon transit in a Mayo Clinic study (21).…”

Section: Neurotransmitter Mechanismsmentioning

confidence: 99%

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Camilleri

Katzka

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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103

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The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, ␣ 2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNF␣, GN␤3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT3 genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klotho␤ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published. adrenergic; serotonergic; solute carrier 6A4; 5-hydroxytryptamine transporter-linked polymorphic region; inflammation; susceptibility; klotho␤; bile acid malabsorption EPIDEMIOLOGICAL STUDIES of familial aggregation (57, 99) and twins (7,70,72,82,83) suggest a genetic contribution to irritable bowel syndrome (IBS). While the data are conflicting, they are generally consistent with the hypothesis that IBS may be a complex genetic disorder. Understanding of genetic variation and its influence on gut motility, secretion, sensation, and inflammation, as it is applied to IBS, has the potential to help elucidate mechanisms of control of a poorly understood syndrome. Similarly, the impact of genetic variation on the targets of therapy in IBS may enhance the efficacy of pharmacological therapies. These targets include receptors and regulators of gut function and variations in drug metabolism.This review addresses the available literature on the role of genetics in IBS. There are no published genome-wide association studies in functional gastrointestinal (GI) or motility disorders specifically focusing on genetic epidemiology and pharmacogenetics. Genetic Epidemiology of IBS: Candidate Gene ApproachAs the general approach followed in genotype association studies (Fig. 1), investigators have sought the relationship between genotype and clinical phenotype, while appreciating that intermediaries, such as th...

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“…Disease gene identification deals with the study of identifying variants which are responsible for genetic disorder [25]. In the process of identification of variants, the detection of changes which are observed on many reads is necessary [26].…”

Section: Variant Identificationmentioning

confidence: 99%

Computational Approaches for Variant Identification

Garg¹,

Jiwan²,

Singh³

2017

IJCA

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Variant identification is a fundamental part in the analysis of genetic diseases. Variants are the alterations which occur in the arrangement of nucleotide in the DNA sequence. Genetic diseases are caused by variations occurring in genes which may cause change in protein, affecting the survival and adaptation of an individual. A number of computational techniques are applied to identify these variant. Precise diagnosis of genetic diseases is important for proper treatment of patients and to determine explicit prevention strategies. Introduction of next generation sequencing (NGS) techniques in the past have made large number of DNA sequences easily available. This has made variant identification using NGS data a area of interest. This paper briefly discussed the analysis steps followed for NGS data analysis. This paper later explains in detail a few approaches that are used for identifying variants such as Support vector machine based approach, Machine learning based approach, MOSAIK: hashbase approach, Bayesian statistical based approach, JointSLM based approach.

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Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation

Cited by 83 publications

References 38 publications

Candidate genes and sensory functions in health and irritable bowel syndrome

Candidate genes and sensory functions in health and irritable bowel syndrome

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Computational Approaches for Variant Identification

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