Obesity, commonly defined as a body mass index (BMI) greater than 30 kg/m2, is associated with an increased risk for a number of metabolic derangements including type 2 diabetes mellitus (T2D), hypertension (HTN), dyslipidemia including hypertriglyceridemia (hiTRI) and low HDL levels (loHDL), as well as cardiovascular disease and overall mortality. Morbid obesity (BMI>40 kg/m2), which afflicts over 5% of the U.S. population, further increases disease burden and risk of mortality. Weight loss is effective at decreasing these risks, as well as ameliorating disease severity, thus reducing body weight in the morbidly obese is a major clinical goal. Currently available dietary and pharmacological modalities can produce small to moderate levels of weight loss, which can have significant impact on comorbidities, but are difficult to achieve or sustain in many patients. Bariatric surgery has thus emerged as a highly effective therapy for long-term weight loss in morbidly obese patients, and more recently as a surgical therapy for the potential cure of type 2 diabetes. However, the degree of weight loss and improvement in specific co-morbid conditions is variable. Our long-term objectives are to identify the molecular and genetic determinants of dietary and surgical weight loss in the morbidly obese, as well as the factors related to the resolution of co-morbid conditions. Based upon heritability and linkage studies, as well as genome wide association studies, genetic variation appears to play a strong role in obesity and related co-morbid conditions. Only a few of these genes/loci have been studied in the context of morbid obesity. Our primary hypothesis is that genetic variants confer resistance to weight loss therapies and inhibit weight-loss induced resolution of co-morbid conditions. To date, only small studies of a few candidate genes have been evaluated in diet and surgical weight loss. The specific goals of this proposal are to first identify common genetic variants associated with weight loss outcomes through genotyping """"""""Metabochip"""""""" SNPs in individuals who have undergone a prudent hypocaloric weight loss program and Roux-en-Y gastric bypass surgery. We will then test for association between SNPs and weight loss outcomes. All trait-associated markers will be validated in independent cohorts. We will then identify rare genetic variants associated with weight loss outcomes by direct sequencing of selected candidate genes, as well as prioritized genes associated with Metabochip loci. Finally, we will identify genes whose expression levels are associated with weight loss outcomes through profiling hepatic gene expression in liver RNA and identify both common and rare variants associated with these genes. Completion of these aims will enhance our understanding of the molecular mechanisms underlying heterogeneity in weight loss outcomes following dietary and surgical interventions in the morbidly obese population.

Public Health Relevance

Severely obese people suffer from many medical problems such as diabetes, high blood pressure, and high cholesterol. Losing weight can help these problems in some, but not all, people and those who try to lose weight through either diet or surgery often regain weight. Little is known about why this occurs. This study will determine whether genes affect how people lose weight and whether their medical problems improve. Identifying these factors may help guide which types of weight loss therapies should be performed in the extremely obese population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088231-05
Application #
8700385
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Karp, Robert W
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$514,689
Indirect Cost
$109,914
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Gerhard, Glenn S; Legendre, Christophe; Still, Christopher D et al. (2018) Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes. J Endocr Soc 2:710-726
McCracken, Emily; Wood, G Craig; Prichard, Wesley et al. (2018) Severe anemia after Roux-en-Y gastric bypass: a cause for concern. Surg Obes Relat Dis 14:902-909
Benotti, Peter N; Wood, G Craig; Carey, David J et al. (2017) Gastric Bypass Surgery Produces a Durable Reduction in Cardiovascular Disease Risk Factors and Reduces the Long-Term Risks of Congestive Heart Failure. J Am Heart Assoc 6:
Gerhard, Glenn S; Bann, Darrin V; Broach, James et al. (2017) Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer. NPJ Genom Med 2:
Leti, Fatjon; Legendre, Christophe; Still, Christopher D et al. (2017) Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells. Transl Res 190:25-39.e21
Wang, Hong; Hong, Chan E; Lewis, Joshua P et al. (2016) Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis. G3 (Bethesda) 6:3525-3532
Wood, G Craig; Benotti, Peter N; Lee, Clare J et al. (2016) Evaluation of the Association Between Preoperative Clinical Factors and Long-term Weight Loss After Roux-en-Y Gastric Bypass. JAMA Surg 151:1056-1062
Irving, Brian A; Wood, G Craig; Bennotti, Peter N et al. (2016) Nutrient Transporter Expression in the Jejunum in Relation to Body Mass Index in Patients Undergoing Bariatric Surgery. Nutrients 8:
Noel, Olivier F; Still, Christopher D; Gerhard, Glenn S (2016) Genetics of Bariatric Surgery Outcomes. Endocrinol Metab Clin North Am 45:623-32
Noel, Olivier F; Still, Christopher D; Argyropoulos, George et al. (2016) Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery. J Obes 2016:4390254

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