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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.  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
4.  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 1-4 (4)