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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.

Hayes S.,Keiser University | Stoeckel N.,Geisinger Medical Center Psychiatry | Napolitano M.A.,George Washington University | Collins C.,Geisinger Medical Center Psychiatry | And 5 more authors.
Obesity Surgery | Year: 2015

Background: The Beck Depression Inventory-II (BDI-II) is frequently used to evaluate bariatric patients in clinical and research settings; yet, there are limited data regarding the factor structure of the BDI-II with a bariatric surgery population. Methods: Exploratory factor analysis (EFA) using principal axis factoring with oblimin rotation was employed with data from 1228 consecutive presurgical bariatric candidates. Independent t tests were used to examine potential differences between sexes. Confirmatory factor analysis (CFA) was conducted with the next 383 consecutive presurgical patients to evaluate the proposed model based on EFA results. Results: EFA revealed three factors: negative perceptions, diminished vigor, and cognitive dysregulation, each with adequate internal consistency. Six BDI-II items did not load significantly on any of the three factors. CFA results largely supported the proposed model. Conclusions: Results suggest that dimensions of depression for presurgical bariatric candidates vary from other populations and raise important caveats regarding the utility of the BDI-II in bariatric research. © 2014, Springer Science+Business Media New York.

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.

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.

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