Ida J. Hatoum

A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort

To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.

Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery

CONTEXT Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. OBJECTIVE Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. METHODS AND RESULTS Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. CONCLUSIONS MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.

Common body mass index-associated variants confer risk of extreme obesity

To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at approximately 550,000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of risk-conferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

Capacity for Physical Activity Predicts Weight Loss After Roux-en-Y Gastric Bypass

Despite its overall excellent outcomes, weight loss after Roux‐en‐Y gastric bypass (RYGB) is highly variable. We conducted this study to identify clinical predictors of weight loss after RYGB. We reviewed charts from 300 consecutive patients who underwent RYGB from August 1999 to November 2002. Data collected included patient demographics, medical comorbidities, and diet history. Of the 20 variables selected for univariate analysis, 9 with univariate P values ≤ 0.15 were entered into a multivariable regression analysis. Using backward selection, covariates with P < 0.05 were retained. Potential confounders were added back into the model and assessed for effect on all model variables. Complete records were available for 246 of the 300 patients (82%). The patient characteristics were 75% female, 93% white, mean age of 45 years, and mean initial BMI of 52.3 kg/m2. One year after surgery, patients lost an average of 64.8% of their excess weight (s.d. = 20.5%). The multivariable regression analysis revealed that limited physical activity, higher initial BMI, lower educational level, diabetes, and decreased attendance at postoperative appointments had an adverse effect on weight loss after RYGB. A model including these five factors accounts for 41% of the observed variability in weight loss (adjusted r2 = 0.41). In this cohort, higher initial BMI and limited physical activity were the strongest predictors of decreased excess weight loss following RYGB. Limited physical activity may be particularly important because it represents an opportunity for potentially meaningful pre‐ and postsurgical intervention to maximize weight loss following RYGB.

Heritability of the weight loss response to gastric bypass surgery.

CONTEXT The use of Roux-en-Y gastric bypass (RYGB) surgery to treat severe obesity has grown dramatically. RYGB is highly effective, but the response in individual patients varies widely, and clinical predictors have been able to explain only a fraction of this variation. OBJECTIVE Our objective was to determine whether there is a significant genetic contribution to weight loss after RYGB. METHODS We genotyped 848 patients undergoing RYGB. Using identity-by-descent methods, we identified 13 pairs of first-degree relatives. We identified an additional 10 pairs of individuals who were living together but are not genetically related and randomly paired the remaining 794 individuals. We then compared weight loss within and across pairs. RESULTS First-degree relative pairs had a similar response to surgery, with a 9% mean difference in excess weight loss between members of each pair. This similarity was not seen with cohabitating individuals (26% mean difference; P = 0.005 vs. first-degree pairs) or unrelated individuals (25% mean difference; P = 0.001). Cohabitating individuals had within-pair differences in weight loss no more similar than randomly paired individuals (P = 0.60). The pair relationship explained a significant portion of the variation in weight loss in first-degree relatives [intraclass correlation coefficient (ICC) = 70.4%; P = 0.02] but not in random subjects (ICC = 0.9%; P = 0.48) or genetically unrelated cohabitating individuals (ICC = 14.3%; P = 0.67). CONCLUSIONS Genetic factors strongly influence the effect of RYGB on body weight. Identification of the specific genes that mediate this effect will advance our understanding of the biological mechanisms of weight loss after RYGB and should help identify patients who will benefit the most from this intervention.

Advantages of Percent Weight Loss as a Method of Reporting Weight Loss after Roux-en-Y Gastric Bypass

Although Roux‐en‐Y gastric bypass (RYGB) is an effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (ΔBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively, it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB‐induced WL.

Weight Loss after Gastric Bypass Is Associated with a Variant at 15q26.1

The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB.

Clinical Factors Associated With Remission of Obesity-Related Comorbidities After Bariatric Surgery.

IMPORTANCE Little is known about comorbidity remission after bariatric surgery during typical clinical care across diverse and geographically distributed populations. OBJECTIVE To estimate the improvement in obesity-related comorbidities after bariatric surgery and to identify clinical factors associated with these responses using a large representative population of patients. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included all patients (N = 33,718) with a recorded Current Procedural Terminology code for Roux-en-Y gastric bypass (RYGB) or adjustable gastric banding (AGB) in the MarketScan Commercial Claims and Encounters Medicare Supplemental Databases from January 1, 2005, to June 30, 2010, and who had continuous enrollment from 6 months or more before to 12 months after surgery. MAIN OUTCOMES AND MEASURES Comorbidities before and after surgery were identified using both diagnoses (from International Classification of Diseases, Ninth Revision [ICD-9] codes) and prescription drug fills. Remission was based on a record of the comorbidity within 6 months before surgery, without record of the condition 18 months after surgery, using both ICD-9 codes and medication fills, as applicable. Multivariable logistic regression models were developed to identify factors associated with remission of diabetes and hypertension. RESULTS Among the 33,718 patients, 13 comorbidities with at least 1% prevalence before surgery were identified. Both RYGB and AGB led to statistically and clinically significant reductions in these comorbidities; remission rates for all comorbidities were higher after RYGB than AGB. For comorbidities that could be defined using both ICD-9 and prescription drug fill codes, prevalence was higher before and lower after surgery when measured by fill codes. Diagnoses using ICD-9 codes, but not prescription fill codes, increased in the 3 months before surgery. In multivariable logistic regression models for remission of diabetes mellitus after RYGB and AGB, age (RYGB: odds ratio [OR], 0.976; 95% CI, 0.965-0.988 and AGB: OR, 0.982; 95% CI, 0.971-0.933), procedure year (RYGB: OR, 1.11; 95% CI, 1.012-1.218 and AGB: OR, 1.185; 95% CI, 1.039-1.351), preoperative insulin use (RYGB: OR, 0.14; 95% CI, 0.114-0.171; AGB: OR, 0.174; 95% CI, 0.131-0.230), preoperative sulfonylurea use (RYGB: OR, 0.616; 95% CI, 0.505-0.752 and AGB: OR, 0.449; 95% CI, 0.357-0.566), and other antidiabetic medication use (RYGB: OR, 0.747; 95% CI, 0.568-0.981 and AGB: OR, 0.506; 95% CI, 0.359-0.715) were significantly associated with response after both procedures. For remission of hypertension, age (RYGB: OR, 0.964; 95% CI, 0.957-0.972 and AGB: OR, 0.968; 95% CI, 0.959-0.977), number of preoperative antihypertensive medications (RYGB: OR, 0.104; 95% CI, 0.067-0.161 and AGB: OR, 0.239; 95% CI, 0.140-0.408), and preoperative diuretic use (RYGB: OR, 1.729; 95% CI, 1.462-2.045 and AGB: OR, 1.648; 95% CI, 1.380-1.967) were significantly associated with response after both procedures. CONCLUSIONS AND RELEVANCE Analysis of a large, representative administrative database confirmed established predictors and revealed novel variables associated with comorbidity remission after bariatric surgery. Incorporating these factors into clinical tools to assess an individual patients risk-to-benefit profile for these procedures could enhance patient selection and the overall use of surgery for the treatment of obesity and metabolic disease.

Intensive Prenatal Nutrition Counseling in a Community Health Setting: A Randomized Controlled Trial

OBJECTIVE To assess the effect of a culturally appropriate nutritional intervention delivered to overweight and obese patients in a community health setting on gestational weight gain and postpartum weight retention. MATERIALS AND METHODS We conducted a randomized controlled trial of an intensive nutrition counseling intervention for overweight and obese women by a registered dietitian throughout pregnancy and 6 months postpartum. The primary outcome was likelihood of gestational weight gain within Institute of Medicine (IOM, now known as the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine) guidelines. Secondary outcomes included birth weight and maternal and neonatal complications. RESULTS Three hundred patients were randomized. In intent-to-treat analyses, assignment to the intervention group did not have a significant effect on maintenance of gestational weight gain within IOM guidelines (34.2% compared with 27.5%, odds ratio [OR] 1.4, 95% CI 0.8-2.4). Among obese women, assignment to the intervention group was associated with fewer large-for-gestational-age (LGA) neonates (7% compared with 17%; OR 0.3, 95% CI 0.1-0.99). Neither primary nor secondary outcomes were significantly different among overweight women in the intervention group in intent-to-treat analyses. In as-treated analyses, women in the intervention group had lower neonatal birth weights (3,343 g compared with 3,500 g; difference -157.4 g, 95% CI -298.4 to -16.5) and lower likelihood of LGA (6% compared with 14%; OR 0.4, 95% CI 0.2-0.96). Among overweight women, participation in the intervention was associated with lower gestational weight gain (26.1 pounds compared with 31.4 pounds; difference -5.3 pounds, 95% CI -10.0 to -0.6), lower neonatal birth weights (3,237 g compared with 3,467 g; difference -230, 95% CI -452.8 to -7.8), and lower percent of initial body mass index at 6 months postpartum (101% compared with 106%; difference -4.9, 95% CI -8.8 to -0.9). CONCLUSION Our intervention did not result in a significant improvement in our primary outcome, the proportion of obese and overweight women who had gestational weight gain within IOM guidelines. However, intensive prenatal nutrition counseling offered in an urban community health setting may decrease LGA births among a group of overweight and obese women from culturally diverse backgrounds at risk for adverse maternal and neonatal outcomes. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT01056406.