Geisinger Obesity Research Institute

Danville, PA, United States

Geisinger Obesity Research Institute

Danville, PA, United States
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Still C.D.,Geisinger Obesity Research Institute | Wood G.C.,Geisinger Obesity Research Institute | Chu X.,Geisinger Obesity Research Institute | Manney C.,Geisinger Obesity Research Institute | And 12 more authors.
Obesity | Year: 2014

Objective Gastric bypass surgery is an effective therapy for extreme obesity. However, substantial variability in weight loss outcomes exists that remains largely unexplained. Our objective was to determine whether any commonly collected preoperative clinical variables were associated with weight loss following Roux-en-Y gastric bypass (RYGB) surgery. Methods The analysis was based on a prospectively recruited observational cohort of 2,365 patients who underwent Roux-en-Y gastric bypass surgery from 2004 to 2009. Weight loss was stratified into three major phases, early (0-6 months), nadir, and long-term (>36 months). Multivariate regression models were constructed using a database of over 350 variables. Results A total of 12-14 preoperative variables were independently associated (P < 0.05) with each of the temporal weight loss phases. Preoperative variables associated with poorer nadir and long-term weight loss included higher baseline BMI, higher preoperative weight loss, iron deficiency, use of any diabetes medication, nonuse of bupropion medication, no history of smoking, age >50 years, and the presence of fibrosis on liver biopsy. Conclusions Several variables previously associated with poorer weight loss after RYGB surgery including age, baseline BMI, and type 2 diabetes were replicated. Several others suggest possible clinical interventions for postoperative management of RYGB patients to improve weight loss outcomes. Copyright © 2013 The Obesity Society.

Parikh M.,New York University | Hetherington J.,New York University | Sheth S.,New York University | Seiler J.,Weis Center for Research | And 4 more authors.
Surgery for Obesity and Related Diseases | Year: 2013

Background: Genetic factors likely play a role in obesity and the outcomes after bariatric surgery. Single nucleotide polymorphisms in or near the insulin-induced gene 2 (INSIG-2), fat mass and obesity-associated gene (FTO), melanocortin 4 receptor gene (MC4R), and proprotein convertase subtilisn/kexin type 1 gene (PCSK-1) have been associated with class III obesity in whites. Minimal data are available regarding the genetic susceptibility to obesity in class III obese nonwhites, especially Hispanics. Our objective was to perform a comparative analysis of 4 common genetic variants (INSIG-2, FTO, MC4R, and PCSK-1) associated with obesity in a diverse population of bariatric surgery patients to determine whether a difference exists by ethnicity (white versus Hispanic). The setting of the study was 2 university hospitals in the United States. Methods: Bariatric surgery patients from 2 different institutions were enrolled prospectively, and genotyping was performed. Differences in the distribution of INSIG-2, FTO, MC4R, and PCSK-1 single nucleotide polymorphisms among the different ethnicities (whites and Hispanics) were compared using an additive model (0, 1, or 2 risk alleles). A propensity-matched analysis was used to account for cohort differences. Results: A total of 1276 bariatric patients were genotyped for the INSIG-2, FTO, MC4R, and PCSK-1 obesity single nucleotide polymorphisms. Statistically significant differences in FTO, INSIG-2, MC4R, and PCSK-1 were seen using an additive model. FTO, PCSK-1, and MC4R (test for trend) remained significantly different in the propensity analysis. Conclusion: Significant differences in the frequencies of several common obesity susceptibility variants in or near FTO, PCSK-1, and MC4R were found in white and Hispanic patients with class III obesity undergoing bariatric surgery. Larger studies in more class III obese Hispanics of different nationalities are needed. © 2013 American Society for Metabolic and Bariatric Surgery. All rights reserved.

Mirshahi U.L.,Weis Center for Research | Still C.D.,Geisinger Obesity Research Institute | Masker K.K.,Weis Center for Research | Gerhard G.S.,Weis Center for Research | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Factors that influence long-term weight loss after Roux-en Y gastric bypass (RYGB) surgeries are poorly defined. The melanocortin system plays an important role in regulating energy homeostasis, satiety, and glucose metabolism. Variations of the MC4R comprise the most prevalent monogenetic obesity disorder. Objective: The objective of the study was to examine the role of MC4R variants and diabetic status in long-term weight loss after RYGB. Participants and Methods: In 1433 extremely obese patients who underwent RYGB, we sequenced for genetic variants of MC4R. We examined the MC4R genotype and its relationship with weight loss profile, and clinical phenotypes accumulated during a 48-month period before and after surgery. Results: We found 80 subjects with rare and common variants of MC4R in the RYGB cohort. Among these, 26 and 36 patients carry the I251L and V103I variants, respectively. These common alleles are negatively associated with obesity. Remarkably, after the 12-month presurgery caloric restriction and RYGB, I251L allele carriers lost 9% more weight (∼9 kg) compared with the noncarriers, continued rapid weight loss longer, regained less weight, and had lower presurgery homeostatic model assessment for insulin resistance values. Normoglycemic, I251L allele carriers lost more weight compared with their diabetic and prediabetic counterparts and maintained their weight loss. Among noncarriers, normoglycemic individuals initially lost more weight compared with dysglycemics, but this difference was not maintained in the long term. Conclusions: Individuals carrying the I251L common allele are predisposed to better clinical outcome, reduced risk of type 2 diabetes, and better weight loss during diet and surgical interventions. Diabetic status has only a small, short -term effect on weight loss after RYGB. Copyright © 2011 by The Endocrine Society.

Benotti P.,Geisinger Obesity Research Institute | Wood G.C.,Geisinger Obesity Research Institute | Winegar D.A.,Surgical Review Corporation | Petrick A.T.,Geisinger Clinic | And 3 more authors.
Annals of Surgery | Year: 2014

OBJECTIVE: We sought to identify the major risk factors associated with mortality in Roux-en-Y gastric bypass (RYGB) surgery. BACKGROUND: Bariatric surgery has become an established treatment for extreme obesity. Bariatric surgery mortality has steadily declined with current rates of less than 0.5%. However, significant variation in the mortality rates has been reported for specific patient cohorts and among bariatric centers. METHODS: Clinical outcome data from 185,315 bariatric surgery patients from the Bariatric Outcome Longitudinal Database were reviewed. Of these, 157,559 patients had either documented 30 or more day follow-up data, including mortality. Multiple demographic, socioeconomic, and clinical factors were analyzed by univariate analysis for their association with 30-day mortality after gastric bypass. Variables found to be significant were entered into a multiple logistic regression model to identify factors independently associated with 30-day mortality. On the basis of these results, a RYGB mortality risk score was developed. RESULTS: The overall 30-day mortality rate for the entire bariatric surgery cohort was 0.1%. Of the 81,751 RYGB patients, the mortality rate was 0.15%. Factors significantly associated with 30-day gastric bypass mortality included increasing body mass index (BMI) (P < 0.0001), increasing age (P < 0.005), male gender (P < 0.001), pulmonary hypertension (P < 0.0001), congestive heart failure (P = 0.0008), and liver disease (P = 0.038). When the RYGB risk score was applied, a significant trend (P < 0.0001) between increasing risk score and mortality rate is found. CONCLUSIONS: Increasing BMI, increasing age, male gender, pulmonary hypertension, congestive heart failure, and liver disease are risk factors for 30-day mortality after RYGB. The RYGB risk score can be used to determine patients at greater risk for mortality after RYGB surgery. Copyright © 2013 by Lippincott Williams & Wilkins.

Still C.D.,Geisinger Obesity Research Institute | Wood G.C.,Geisinger Obesity Research Institute | Wood G.C.,Center for Health Research | Chu X.,Weis Center for Research | And 9 more authors.
Obesity | Year: 2011

Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI 35kg/m 2) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre-and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P≤0.0006) and excess body weight (P≤0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P≤0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI 50kg/m 2, with evidence of a dosage effect, which was not present in individuals with initial BMI 50kg/m 2. Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI. © 2011 The Obesity Society.

Lee C.J.,Johns Hopkins University | Wood G.C.,Geisinger Obesity Research Institute | Lazo M.,Johns Hopkins University | Brown T.T.,Johns Hopkins University | And 3 more authors.
Obesity | Year: 2016

Objective: The epidemiology of post-gastric bypass surgery hypoglycemia (PGBH) is incompletely understood. This study aimed to evaluate the risk of PGBH among nondiabetic patients and associated factors. Methods: A cohort study of nondiabetic patients who underwent Roux-en-Y gastric bypass (RYGB) was conducted. PGBH was defined by any postoperative record of glucose < 60 mg/dL, diagnosis of hypoglycemia, or any medication use for treatment of PGBH. Kaplan-Meier analysis was used to describe PGBH occurrence, log-rank tests, and Cox regression to examine associated factors. Results: Of the 1,206 eligible patients, 86% were female with mean age of 43.7 years, mean preoperative BMI of 48.7 kg/m2, and a mean follow-up of 4.8 years. The cumulative incidence of hypoglycemia at 1 and 5 years post-RYGB was 2.7% and 13.3%, respectively. Incidence of PGBH was identified in 158 patients and was associated with lower preoperative BMI (P = 0.048), lower preoperative HbA1c (P = 0.012), and higher 6-month percent of excess body weight loss (%EWL) (P = 0.001). A lower preoperative HbA1c (HR = 1.73, P = 0.0034) and higher 6-month %EWL (HR = 1.96, P = 0.0074) remained independently correlated with increased risk for PGBH in multi-regression analysis. Conclusions: The 5-year incidence of PGBH among nondiabetic individuals was 13.3% and was associated with a lower preoperative HbA1c and greater weight loss at 6 months following surgery. © 2016 The Obesity Society

Gerhard G.S.,Geisinger Obesity Research Institute | Gerhard G.S.,Pennsylvania State University | Chu X.,Geisinger Obesity Research Institute | Wood G.C.,Geisinger Obesity Research Institute | And 7 more authors.
Human Heredity | Year: 2013

Objectives: Genome-wide association studies (GWAS) have led to the identification of single nucleotide polymorphisms in or near several loci that are associated with the risk of obesity and nonalcoholic fatty liver disease (NAFLD). We hypothesized that missense variants in GWAS and related candidate genes may underlie cases of extreme obesity and NAFLD-related cirrhosis, an extreme manifestation of NAFLD. Methods: We performed whole-exome sequencing on 6 Caucasian patients with extreme obesity [mean body mass index (BMI) 84.4] and 4 obese Caucasian patients (mean BMI 57.0) with NAFLD-related cirrhosis. Results: Sequence analysis was performed on 24 replicated GWAS and selected candidate obesity genes and 5 loci associated with NAFLD. No missense variants were identified in 19 of the 29 genes analyzed, although all patients carried at least 2 missense variants in the remaining genes without excess homozygosity. One patient with extreme obesity carried 2 novel damaging mutations in BBS1 and was homozygous for benign and damaging MC3R variants. In addition, 1 patient with NAFLD-related cirrhosis was compound heterozygous for rare damaging mutations in PNPLA3. Conclusions: These results indicate that analyzing candidate loci previously identified by GWAS analyses using whole-exome sequencing is an effective strategy to identify potentially causative missense variants underlying extreme obesity and NAFLD-related cirrhosis. © 2013 S. Karger AG, Basel.

Petrick A.,Geisinger Obesity Research Institute | Benotti P.,Geisinger Obesity Research Institute | Wood G.C.,Geisinger Obesity Research Institute | Still C.D.,Geisinger Obesity Research Institute | And 7 more authors.
Obesity Surgery | Year: 2015

Background: Nonalcoholic fatty liver disease (NAFLD) is common in adults with extreme obesity and can impact long-term health and survival. Liver biopsy is the only accurate test for diagnosis and staging, but is invasive and costly. Non-invasive testing offers an attractive alternate, but the overall accuracy remains a significant issue. This study was conducted to determine the accuracy and clinical utility of pre-operative ultrasound and liver transaminase levels, as well as intra-operative hepatic visual inspection, for assessing presence of NAFLD as confirmed by hepatic histology. Methods: Data was collected prospectively from 580 morbidly obese adult patients who underwent Roux-en-Y gastric bypass surgery with intraoperative wedge biopsy between January 2004 and February 2009. Complete data for ultrasound, ALT and AST levels, and documented visual inspection was available for 513 patients. Results: The prevalence of NAFLD was 69 % and that of NASH was 32 %. The individual non-invasive clinical assessments demonstrated low sensitivity, specificity, and accuracy for detecting the presence of steatosis, steatohepatitis, or fibrosis. The combination of normal or abnormal results for all tests improved predictive utility. Abnormal tests with all three assessments had a sensitivity of 95–98 % and a specificity of 28–48 % for major histologic findings in NAFLD/NASH. Normal tests with all three assessments had a sensitivity of 12–22 % and a specificity of 89–97 % for major histologic findings in NAFLD/NASH. Conclusions: Although individual clinical tests for NAFLD have limited accuracy, the use of combined clinical tests may prove useful. © 2015, Springer Science+Business Media New York.

Rinella E.S.,New York University | Still C.,Geisinger Obesity Research Institute | Shao Y.,New York University | Wood G.C.,Geisinger Obesity Research Institute | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss. Objective: Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery. Design: We conducted a genome-wide association study using a 2-stage phenotypic extreme study design. Setting: Patients were recruited from a comprehensive weight loss program at an integrated health system. Patients: Eighty-six obese (body mass index >35 kg/m2) patients who had the least percent excess body weight loss (%EBWL) and 89 patients who had the most% EBWL at 2 years after surgery were genotyped using Affymetrix version 6.0 single-nucleotide polymorphism (SNP) arrays. A second group from the same cohort consisting of 164 patients in the lower quartile of %EBWL and 169 from the upper quartile were selected for evaluation of candidate regions using custom SNP arrays. Intervention: We performed RYGB surgery. Main Outcome Measures: We assessed %EBWL at 2 years after RYGB and SNPs. Results: We identified 111 SNPs in the first-stage analysis whose frequencies were significantly different between 2 phenotypic extremes of weight loss (allelic χ2 test P < .0001). Linear regression of %EBWL at 2 years after surgery revealed 17 SNPs that approach P < .05 in the validation stage and cluster in or near several genes with potential biological relevance including PKHD1, HTR1A, NMBR, and IGF1R. Conclusions: This is the first genome-wide association study of weight loss response to RYGB. Variation in weight loss outcomes after RYGB may be influenced by several common genetic variants. Copyright © 2013 by The Endocrine Society.

PubMed | Geisinger Obesity Research Institute, Carnegie Institution for Science and University of Maryland Baltimore County
Type: | Journal: Hepatology (Baltimore, Md.) | Year: 2016

The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant, rs58542926, is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis, but is paradoxically associated with lower levels of hepatic-derived triglyceride-rich lipoproteins (TRLs). TM6SF2 is expressed predominately in liver and small intestine, sites for triglyceride rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System (GHS) in PA and from 3,556 study participants enrolled in the Amish Complex Disease Research Program (ACDRP). Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high fat challenge, carriers in the ACDRP cohort exhibited significantly lower postprandial serum triglycerides suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2-deficiency resulted in defects in small intestine metabolism in response to dietary lipids including significantly increased lipid accumulation, decreased lipid clearance and increased endoplasmic reticulum stress.These data strongly support a role of TM6SF2 in regulation of postprandial lipemia potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically- and intestinally-derived TRLs. This article is protected by copyright. All rights reserved.

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