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1.  Association of UCP-3-rs1626521 with Obesity and Stomach Functions in Humans 
Obesity (Silver Spring, Md.)  2015;23(4):898-906.
To examine the association of gene variants of uncoupling proteins (UCP)-2 and -3 with obesity and gastrointestinal (GI) traits.
In 255 overweight or obese adults, we studied the associations of gene variants in UCP-2 (−3474, rs659366) and UCP-3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits. Gene variants were genotyped by TaqMan® assay. We assessed the associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) using ANCOVA, corrected for false detection rate (FDR).
We identified a novel UCP-3 gene variant, rs1626521; it was associated with BW (p=0.039), waist circumference (p=0.035), and with significantly higher postprandial gastric volume (p=0.003) and calories ingested at buffet meal (p=0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (p=0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP-3 protein expression (p=0.049). Associations detected between other genotypes and GI traits were non-significant with FDR.
A newly identified functional variant (rs1626521) in UCP-3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.
PMCID: PMC4380685  PMID: 25755013
mitochondria; gastric emptying; accommodation; volume; satiation; satiety; GLP-1; PYY
2.  Quantitative Gastrointestinal and Psychological Traits Associated with Obesity and Response to Weight-loss Therapy 
Gastroenterology  2014;148(3):537-546.e4.
Background & Aims
Weight loss following pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy.
In a prospective study, we measured gastric emptying (GE) of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety following an ad-libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal weight, overweight, or obese adults. We also analyzed data from 181 previously studied adults to assess associations between a subset of traits with body mass index and waist circumference. Latent dimensions associated with overweight or obesity were appraised by principal component analyses. We performed a proof-of-concept, placebo-controlled trial of extended-release phentermine and topiramate in 24 patients, to validate associations between quantitative traits and response to weight-loss therapy.
In the prospective study, obesity was associated with fasting gastric volume (P=.03), accelerated GE (P<.001 for solids and P=.011 for liquids), lower postprandial levels of peptide tyrosine tyrosine (P=.003), and higher postprandial levels of glucagon-like peptide 1 (P<.001). In a combined analysis of data from all studies, obesity was associated with higher volume to fullness (n=509; P=.038) and satiety with abnormal waist circumference (n=271; P=.016). Principal component analysis identified latent dimensions that accounted for ∼81% of the variation among overweight and obese subjects, including satiety or satiation (21%), gastric motility (14%), psychological factors (13%), and gastric sensorimotor factors (11%). The combination of phentermine and topiramate caused significant weight loss, slowed GE, and decreased calorie intake; weight loss in response to phentermine and topiramate was significantly associated with calorie intake at the prior satiety test.
Quantitative traits are associated with high body mass index; they can distinguish obesity phenotypes and, in a proof-of-concept clinical trial, predicted response to pharmacotherapy for obesity.
PMCID: PMC4339485  PMID: 25486131
BMI; incretin; satietyphentermine; topiramate
3.  Exenatide in obesity with accelerated gastric emptying: a randomized, pharmacodynamics study 
Physiological Reports  2015;3(11):e12610.
Obesity is associated with differences in satiety, gastric emptying (GE), gastric volume, and psychological traits. Exenatide, a short-acting glucagon-like peptide 1 (GLP-1) receptor agonist, is associated with variable weight loss. We compared the effects of exenatide, 5 μg, and placebo SQ, twice daily for 30 days on GE of solids and liquids (scintigraphy), satiety (ad libitum buffet meal), satiation (nutrient drink test, maximum tolerated volume [MTV]), and weight loss in 20 participants with documented accelerated GE of solids (T1/2 < 90 min). Exenatide delayed GE of solids (T1/2 [Δ] 86 min relative to placebo, P < 0.001) and reduced calorie intake at buffet meal ([Δ] 129 kcal compared to placebo). Median weight loss was −0.95 kg (IQR −0.7 to −2.1) for exenatide and −0.55 kg (0.3 to −2.1) for placebo (P = 0.23); 80% of exenatide group had documented reduction in weight. In the exenatide treatment group, there was an inverse correlation between gastric emptying T1/2 and MTV (R = −0.548, P = 0.089). The univariate association of weight change with posttreatment MTV was borderline (Rs = 0.43, P = 0.06); in the multiple regression model, posttreatment MTV was associated with weight change (P = 0.047). The effect of the short-acting GLP-1 receptor agonist, exenatide, on GE is associated with the change in food intake, and the latter impacts weight loss in response to exenatide treatment.
PMCID: PMC4632965  PMID: 26542264
Glucagon-like peptide 1; pharmacogenomics; satiation
4.  A Controlled Trial of Gluten-Free Diet in Patients with Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function 
Gastroenterology  2013;144(5):903-911.e3.
Background & Aims
Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).
We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8–negative and 11 HLA-DQ2/8–positive) and 23 on the GFD (12 HLA-DQ2/8−negative and 11 HLA-DQ2/8–positive. We measured bowel function daily, small bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells (PBMCs) following exposure to gluten and rice. We collected rectosigmoid biopsies from 28 patients, analyzed levels of mRNAs encoding tight junction proteins, and performed hematoxylin and eosin staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups.
Subjects on the GCD had more bowel movements/day (P=.04); the GCD had a greater effect on bowel movements/day of HLA-DQ2/8–positive than −negative patients (P=.019). The GCD was associated with higher SB permeability (based on 0–2 hr levels of mannitol and lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than −negative patients (P=.018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of ZO-1 in SB mucosa and significant decreases in expression of ZO-1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. GCD vs GFD had no significant effects on transit or histology. PBMCs produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-a in response to gluten than rice (unrelated to HLA genotype).
Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder.
PMCID: PMC3633663  PMID: 23357715
permeability; transit; immunity; cytokines
5.  Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults 
Genes & Nutrition  2014;9(2):384.
Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m2 (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) − CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median Δ total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median Δ 6.7 %, p = 0.008) and 4 h (median Δ 3.2 %, p = 0.006), and longer t½ (median Δ 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.
PMCID: PMC3968288  PMID: 24458996
Melanocortin 4 receptor (MC4R); rs17782313; Satiation; Gastric emptying; Obesity
6.  Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation 
Gut  2011;61(8):10.1136/gutjnl-2011-301181.
To differentiate dys-synergic defaecation (DD) from normal function and slow transit constipation (STC).
The medical records of 1411 patients evaluated by a single gastroenterologist over a 16-year period at a tertiary medical centre were reviewed. DD was characterised by anorectal manometry and balloon expulsion test. There were 390 patients with DD, and 61 with STC without DD. Transit data from 211 healthy individuals served as controls. The primary endpoints were overall colonic transit (geometric centre) at 24 h and 48 h (GC24 and GC48). Regional transit was measured as ascending colon half-emptying time (AC t1/2) and residual content in descending rectosigmoid colon and stool (DRS).
Age and body mass index were similar in the STC and DD groups. DD was associated with smaller perineal descent and a greater difference in rectoanal pressure than STC. Both STC and DD were associated with lower GC24 and GC48 and slower AC t1/2 than controls. GC48 differentiated DD from healthy controls (p<0.001) and DD from STC (p=0.007). AC t1/2 values differentiated healthy controls from DD (p=0.006) and STC (p<0.001) and were associated with constipation (DD vs STC, p=0.007). The regional content of DRS at 48 h discriminated DD from STC (AUC=0.82) and stool content at 48 h, increasing the odds for DD over STC (OR per 5% in stool 2.4, 95% CI 1.1 to 5.5, p=0.03).
DD is associated with delayed overall colonic transit at 48 h and AC t1/2 compared with healthy controls. Regional scintigraphic transit profiles differentiate DD from STC and facilitate identification of a subgroup of patients with constipation.
PMCID: PMC3813955  PMID: 22180057
7.  Randomized Pharmacodynamic and Pharmacogenetic Trial of Dronabinol Effects on Colon Transit in Irritable Bowel Syndrome-Diarrhea 
Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO’s effects on colonic motility. Our aims were: 1) To compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D; and 2) To examine influence of genetic variations in CB mechanisms on DRO’s transit effects.
36 IBS-D volunteers were randomized (double-blind, concealed allocation) to twice daily PLA (n=13), DRO 2.5mg (n=10), or DRO 5mg (n=13) for two days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model.
Key Results
Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24h compared to CC (p=0.13 for differential treatment effects on post- minus pre-treatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected.
Overall, DRO 2.5mg or 5mg twice daily for two days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.
PMCID: PMC3775711  PMID: 22288893
cannabinoid; anandamide; FAAH; motility; nonselective; receptor; gastric; small bowel
8.  A Controlled Pharmacogenetic Trial of Sibutramine on Weight Loss and Body Composition in Obese or Overweight Adults 
Gastroenterology  2008;135(4):1142-1154.
Background/ Aim
Weight loss in response to sibutramine is highly variable. We assessed the association of specific markers of polymorphisms of candidate a2A adrenoreceptor, 5-HT transporter and GNβ3 genes and weight loss with sibutramine.
We conducted a randomized, double-blind, pharmacogenetic study of behavioral therapy and sibutramine (10 or 15 mg daily) or placebo for 12 weeks in 181 overweight or obese participants. We measured body weight, BMI, body composition, gastric emptying and genetic variation (α2A C1291G, 5-HTTLPR, and GNβ3 C825T genotypes). ANCOVA was used to assess treatment effects on, and associations of the specific markers of candidate genes with weight loss and body composition.
Sibutramine, 10 and 15 mg, caused significant weight loss (p = 0.009); there was a statistically significant gene by dose interaction for GNβ3 genotype. For each candidate gene, significant treatment effects at 12 weeks were observed (p<0.017) for all specific genotype variants (delta weight loss in the 2 sibutramine doses versus placebo): α2A CC genotype ( Δ ~5kg), GNβ3 TC/TT genotype (Δ ~6kg), and 5-HTTLPR LS/SS (Δ ~4.5kg). Gene pairs resulted in significantly greater sibutramine treatment effects on weight (both p<0.002): in participants with 5-HTTLPR LS/SS with GNβ3 TC/TT, Δ ~6kg and those with a2A CC with GNβ3 TC/TT, Δ ~8kg; however, effects were not synergistic. Treatment with sibutramine also resulted in significantly greater reduction of body fat for specific α2A CC and GNβ3 TC/TT genotype variants individually (both p<0.02).
Selection of patients with obesity based on candidate genes may enhance response to multidimensional sibutramine and behavioral therapy.
PMCID: PMC2629484  PMID: 18725220
Adrenergic; norepinephrine; serotonin; transporter; SLC6A4

Results 1-8 (8)