Glenn S Gerhard

Publications (51)256.76 Total impact

• Article: Genome-wide Association of Single-Nucleotide Polymorphisms With Weight Loss Outcomes After Roux-en-Y Gastric Bypass Surgery.

  Erica S Rinella, Christopher Still, Yongzhao Shao, G Craig Wood, Xin Chu, Brenda Salerno, Glenn S Gerhard, Harry Ostrer
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  ABSTRACT: 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/m(2)) 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 χ(2) 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.
  The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
• Article: Genetic Variation at NCAN Locus Is Associated with Inflammation and Fibrosis in Non-Alcoholic Fatty Liver Disease in Morbid Obesity.

  Alexis Gorden, Rongze Yang, Laura M Yerges-Armstrong, Kathleen A Ryan, Elizabeth Speliotes, Ingrid B Borecki, Tamara B Harris, Xin Chu, G Craig Wood, Christopher D Still, Alan R Shuldiner, Glenn S Gerhard
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  ABSTRACT: Objective: Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. Methods: In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. Results: We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. Conclusion: NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.
  Human Heredity 04/2013; 75(1):34-43. · 1.79 Impact Factor
• Article: Risk Factors Associated With Mortality After Roux-en-Y Gastric Bypass Surgery.

  Peter Benotti, G Craig Wood, Deborah A Winegar, Anthony T Petrick, Christopher D Still, George Argyropoulos, Glenn S Gerhard
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  ABSTRACT: 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.
  Annals of surgery 03/2013; · 7.90 Impact Factor
• Article: Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance.

  Naoki Kumashiro, Sara A Beddow, Daniel F Vatner, Sachin K Majumdar, Jennifer L Cantley, Fitsum Guebre-Egziabher, Ioana Fat, Blas Guigni, Michael J Jurczak, Andreas L Birkenfeld, [......], Bryce K Perler, Michelle A Puchowicz, Vara Prasad Manchem, Sanjay Bhanot, Christopher D Still, Glenn S Gerhard, Kitt F Petersen, Gary W Cline, Gerald I Shulman, Varman T Samuel
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  ABSTRACT: We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsies, and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high-fat-fed (HFF) rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in ZDF rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance and type 2 diabetes.
  Diabetes 02/2013; · 8.29 Impact Factor
• Article: Impact of β(1)- and β(2)-Adrenergic Receptor Gene Single Nucleotide Polymorphisms on Heart Rate Response to Metoprolol Prior to Coronary Computed Tomographic Angiography.

  Vlad Cotarlan, Alessandra Brofferio, Glenn S Gerhard, Xin Chu, Jamshid Shirani
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  ABSTRACT: A slow, steady heart rate (HR) is necessary for optimal image quality during coronary computed tomographic angiography. Beta blockers are often used, but the goal HR is not achieved in some patients. The aim of this study was to examine the influence of single-nucleotide polymorphisms (SNPs) of the β(1) (codons 49 and 389) and β(2) (codons 16, 27, and 164) adrenergic receptor (AR) genes on HR response to metoprolol in 200 adults (mean age 56 ± 11 years) referred for coronary computed tomographic angiography (using a 64-slice scanner). Oral and intravenous (IV) metoprolol was given to achieve a goal HR of <60 beats/min. Overall, 37 patients (18.5%) did not reach the goal HR despite the administration of oral (181 ± 116 mg) and IV (4.2 ± 9.4 mg) metoprolol. Patients with the β(1)-AR Ser49Gly or Gly49Gly genotype (n = 49) more often failed to reach an optimal HR compared to those with the Ser49Ser genotype (n = 151) (29% vs 15%, p = 0.04), despite receiving higher doses of oral (210 ± 115 vs 172 ± 115 mg, p = 0.048) and IV (7 ± 13 vs 3 ± 8 mg, p = 0.02) metoprolol. Similarly, patients with the β(1)-AR Gly389Gly genotype (n = 11) more often failed to reach an optimal HR compared to those with the Arg389Arg and Arg389Gly genotypes (n = 189) (45% vs 17%, p = 0.02), despite receiving higher doses of IV (13 ± 15 vs 4 ± 9 mg, p = 0.002) but not oral (162 ± 105 vs 182 ± 117 mg, p = 0.50) metoprolol. Multivariate analysis identified β(1)-AR SNPs at codons 49 and 389 and β(2)-AR SNP at codon 27 as independent predictors of suboptimal HR response. In conclusion, these data indicate that the selected SNPs of β(1)-AR and β(2)-AR genes influence HR response to metoprolol in patients who undergo coronary computed tomographic angiography.
  The American journal of cardiology 12/2012; · 3.58 Impact Factor
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  Available from: Xin Chu

  Dataset: Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

  Naoki Kumashiro, Derek M Erion, Dongyan Zhang, Mario Kahn, Sara A Beddow, Xin Chu, Christopher D Still, Glenn S Gerhard, Xianlin Han, James Dziura, Kitt Falk Petersen, Varman T Samuel, Gerald I Shulman
• Article: The role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats.

  Naoki Kumashiro, Toru Yoshimura, Jennifer L Cantley, Sachin K Majumdar, Fitsum Guebre-Egziabher, Romy Kursawe, Daniel F Vatner, Ioana Fat, Mario Kahn, Derek M Erion, Xian-Man Zhang, Dongyan Zhang, Vara Prasad Manchem, Sanjay Bhanot, Glenn S Gerhard, Kitt F Petersen, Gary W Cline, Varman T Samuel, Gerald I Shulman
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  ABSTRACT: Genome wide array studies have associated the Patatin-like Phospholipase Domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-(13) C]-palmitate into hepatic triglyceride. While the precursors for phosphatidic acid (PA) [long-chain fatty acyl-CoAs and lysophosphatidic acid (LPA)] were not decreased, we did observe an ∼20% reduction in the hepatic PA content, ∼35% reduction in PA / LPA ratio, and ∼60-70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ∼50% reduction in hepatic diacylglycerol (DAG) content, an ∼80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a twofold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 mRNA expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans. Taken together these data suggest that PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of NAFLD associated hepatic insulin resistance.(HEPATOLOGY 2012.).
  Hepatology 11/2012; · 11.66 Impact Factor
• Article: Weight-Independent Effects of Roux-en-Y Gastric Bypass on Glucose Homeostasis via Melanocortin-4 Receptors in Mice and Humans.

  Juliet F Zechner, Uyenlinh L Mirshahi, Santhosh Satapati, Eric D Berglund, Jari Rossi, Michael M Scott, Christopher D Still, Glenn S Gerhard, Shawn C Burgess, Tooraj Mirshahi, Vincent Aguirre
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  ABSTRACT: BACKGROUND & AIMS:: Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis independently of changes in body weight by unknown mechanisms. Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeostasis, via autonomic neurons, and might also contribute to weight loss after RYGB. We investigated whether MC4Rs mediate effects of RYGB, such as its weight-independent effects on glucose homeostasis, in mice and humans. METHODS:: We studied C57BL/6 mice with diet-induced obesity, MC4R-deficient mice, and mice that re-express MC4R specifically in autonomic neurons after RYGB or Sham operations. We also sequenced the MC4R locus in patients undergoing RYGB, to investigate diabetes resolution in carriers of rare MC4R variants. RESULTS:: MC4Rs in autonomic brainstem neurons (including the parasympathetic dorsal motor vagus) mediated improved glucose homeostasis independent of changes in body weight. In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympathetic and parasympathetic) mediated RYGB-induced increased energy expenditure and weight loss. Increased energy expenditure after RYGB is the predominant mechanism of weight loss and confers resistance to weight gain from a high-fat diet, effects of which are MC4R-dependent. MC4R-dependent effects of RYGB still occurred in mice with Mc4r haplosufficiency, and early-stage diabetes resolved at a similar rate in patients with rare variants of MC4R and non-carriers. However, carriers of MC4R (I251L), a rare variant associated with increased weight loss after RYGB and increased basal activity in vitro, were more likely to have early and weight-independent resolution of diabetes than non-carriers, indicating a role for MC4Rs in the effects of RYGB. CONCLUSIONS:: MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans.
  Gastroenterology 11/2012; · 11.68 Impact Factor
• Article: An electronic health record-enabled obesity database.

  G Craig Wood, Xin Chu, Christina Manney, William Strodel, Anthony Petrick, Jon Gabrielsen, Jamie Seiler, David Carey, George Argyropoulos, Peter Benotti, Christopher D Still, Glenn S Gerhard
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  ABSTRACT: BACKGROUND: The effectiveness of weight loss therapies is commonly measured using body mass index and other obesity-related variables. Although these data are often stored in electronic health records (EHRs) and potentially very accessible, few studies on obesity and weight loss have used data derived from EHRs. We developed processes for obtaining data from the EHR in order to construct a database on patients undergoing Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Clinical data obtained as part of standard of care in a bariatric surgery program at an integrated health delivery system were extracted from the EHR and deposited into a data warehouse. Data files were extracted, cleaned, and stored in research datasets. To illustrate the utility of the data, Kaplan-Meier analysis was used to estimate length of post-operative follow-up. RESULTS: Demographic, laboratory, medication, co-morbidity, and survey data were obtained from 2028 patients who had undergone RYGB at the same institution since 2004. Pre-and postoperative diagnostic and prescribing information were available on all patients, while survey laboratory data were available on a majority of patients. The number of patients with postoperative laboratory test results varied by test. Based on Kaplan-Meier estimates, over 74% of patients had post-operative weight data available at 4 years. CONCLUSION: A variety of EHR-derived data related to obesity can be efficiently obtained and used to study important outcomes following RYGB.
  BMC Medical Informatics and Decision Making 05/2012; 12(1):45. · 1.48 Impact Factor
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  Available from: Xin Chu

  Article: Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients.

  Arijeet K Gattu, Andreas L Birkenfeld, Francois Jornayvaz, James Dziura, Fangyong Li, Susan E Crawford, Xin Chu, Christopher D Still, Glenn S Gerhard, Chuhan Chung, Varman Samuel
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  ABSTRACT: Obesity is a significant risk factor for developing diabetes. Pigment epithelium-derived factor (PEDF) has been identified by experimental and clinical studies as both a causative and counter-regulatory factor in the metabolic syndrome. We set out to determine whether serum PEDF levels correlated with the degree of insulin resistance in morbidly obese patients. Sera from 53 patients who were evaluated prior to gastric bypass surgery were analyzed for PEDF levels using a commercial ELISA. None of the patients were on diabetes medications prior to enrollment. Baseline data included BMI, serum glucose and insulin, and homeostasis model assessment (HOMA) scores. Patients were stratified based on HOMA score and glucose levels into three groups: insulin sensitive (IS): HOMA <2 and glucose <126; insulin resistant (IR): HOMA >2 and glucose ≤126; and diabetes mellitus (DM): HOMA >2 and glucose >126. Pre- and post-gastric bypass sera from 12 patients were obtained for serial assessment of metabolic parameters and PEDF levels. PEDF secretion was assessed in primary human hepatocytes, HCC cells, and cultured adipocytes in the absence and presence of high glucose media. No significant differences in age, gender, and BMI were found among the three groups. PEDF levels were similar between IR patients and the other groups, but were significantly higher in DM compared to IS patients (p = 0.01). Serum PEDF in individual patients declined significantly after gastric bypass (p = 0.006). High glucose media led to significantly higher PEDF release by human hepatocytes in vitro (p = 0.016). These data demonstrate that serum PEDF concentrations better relate to insulin resistance than to adiposity and suggest that PEDF expression is closely linked to the development of insulin resistance.
  Acta Diabetologica 05/2012; · 2.78 Impact Factor
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  Available from: Xin Chu

  Article: Association of ghrelin receptor promoter polymorphisms with weight loss following Roux-en-Y gastric bypass surgery.

  Michelle E Matzko, George Argyropoulos, G Craig Wood, Xin Chu, Roger J M McCarter, Christopher D Still, Glenn S Gerhard
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  ABSTRACT: Ghrelin plays a role in appetite and has been hypothesized to play a role in the mechanism of Roux-en-Y gastric bypass (RYGB) surgery. Single nucleotide polymorphisms (SNPs) in the promoter region of its receptor gene (growth hormone secretagogue receptor type 1a--GHSR) have also been associated with weight loss outcomes following long-term dietary intervention in adults with impaired glucose tolerance. Our objectives were to evaluate changes in serum ghrelin levels and determine the effect of GHSR promoter polymorphisms on post-RYGB surgery weight loss. Preoperative and 6-month postoperative serum ghrelin levels were measured in 37 patients with extreme obesity undergoing RYGB surgery. Total ghrelin was also measured in liver tissue collected intraoperatively. Association analysis between genotypes for SNPs rs9819506 and rs490683 in the promoter region of the GHSR gene and weight loss outcomes in the 30 months following surgery was performed in over 650 RYGB patients. Serum ghrelin levels increased after RYGB surgery. Weight loss trajectories were significantly different using an additive model for both ghrelin SNPs, with patients homozygous for the rs490683 CC genotype exhibiting the most weight loss. Weight loss trajectories were also different using a dominant model. The rs490683 risk allele demonstrated decreased promoter activity in vitro. The role of increased ghrelin levels in weight loss outcomes following RYGB surgery may be influenced by variation in the GHSR gene.
  Obesity Surgery 03/2012; 22(5):783-90. · 3.29 Impact Factor
• Article: The MC4R(I251L) allele is associated with better metabolic status and more weight loss after gastric bypass surgery.

  Uyenlinh L Mirshahi, Christopher D Still, Kathryn K Masker, Glenn S Gerhard, David J Carey, Tooraj Mirshahi
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  ABSTRACT: 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. The objective of the study was to examine the role of MC4R variants and diabetic status in long-term weight loss after RYGB. 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. 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. 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.
  The Journal of clinical endocrinology and metabolism 12/2011; 96(12):E2088-96. · 6.50 Impact Factor
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  Available from: Xin Chu

  Article: Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease.

  Naoki Kumashiro, Derek M Erion, Dongyan Zhang, Mario Kahn, Sara A Beddow, Xin Chu, Christopher D Still, Glenn S Gerhard, Xianlin Han, James Dziura, Kitt Falk Petersen, Varman T Samuel, Gerald I Shulman
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  ABSTRACT: Insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD) and is a major factor in the pathogenesis of type 2 diabetes. The development of hepatic insulin resistance has been ascribed to multiple causes, including inflammation, endoplasmic reticulum (ER) stress, and accumulation of hepatocellular lipids in animal models of NAFLD. However, it is unknown whether these same cellular mechanisms link insulin resistance to hepatic steatosis in humans. To examine the cellular mechanisms that link hepatic steatosis to insulin resistance, we comprehensively assessed each of these pathways by using flash-frozen liver biopsies obtained from 37 obese, nondiabetic individuals and correlating key hepatic and plasma markers of inflammation, ER stress, and lipids with the homeostatic model assessment of insulin resistance index. We found that hepatic diacylglycerol (DAG) content in cytoplasmic lipid droplets was the best predictor of insulin resistance (R = 0.80, P < 0.001), and it was responsible for 64% of the variability in insulin sensitivity. Hepatic DAG content was also strongly correlated with activation of hepatic PKCε (R = 0.67, P < 0.001), which impairs insulin signaling. In contrast, there was no significant association between insulin resistance and other putative lipid metabolites or plasma or hepatic markers of inflammation. ER stress markers were only partly correlated with insulin resistance. In conclusion, these data show that hepatic DAG content in lipid droplets is the best predictor of insulin resistance in humans, and they support the hypothesis that NAFLD-associated hepatic insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCε.
  Proceedings of the National Academy of Sciences 09/2011; 108(39):16381-5. · 9.68 Impact Factor
• Article: Role of complement cascade in abdominal aortic aneurysms.

  Irene Hinterseher, Robert Erdman, Larry A Donoso, Tamara R Vrabec, Charles M Schworer, John H Lillvis, Amy M Boddy, Kimberly Derr, Alicia Golden, William D Bowen, Zoran Gatalica, Nikos Tapinos, James R Elmore, David P Franklin, John L Gray, Robert P Garvin, Glenn S Gerhard, David J Carey, Gerard Tromp, Helena Kuivaniemi
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  ABSTRACT: The goal of this study was to investigate the role of complement cascade genes in the pathobiology of human abdominal aortic aneurysms (AAAs). Results of a genome-wide microarray expression profiling revealed 3274 differentially expressed genes between aneurysmal and control aortic tissue. Interestingly, 13 genes in the complement cascade were significantly differentially expressed between AAA and the controls. In silico analysis of the promoters of the 13 complement cascade genes showed enrichment for transcription factor binding sites for signal transducer and activator of transcription (STAT)5A. Chromatin-immunoprecipitation experiments demonstrated binding of transcription factor STAT5A to the promoters of the majority of the complement cascade genes. Immunohistochemical analysis showed strong staining for C2 in AAA tissues. These results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.
  Arteriosclerosis Thrombosis and Vascular Biology 07/2011; 31(7):1653-60. · 6.37 Impact Factor
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  Available from: Xin Chu

  Article: High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery.

  Christopher D Still, G Craig Wood, Xin Chu, Robert Erdman, Christina H Manney, Peter N Benotti, Anthony T Petrick, William E Strodel, Uyenlinh L Mirshahi, Tooraj Mirshahi, David J Carey, Glenn S Gerhard
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  ABSTRACT: 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 >35 kg/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 <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/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.
  Obesity 02/2011; 19(8):1676-83. · 4.28 Impact Factor
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  Available from: PubMed Central

  Article: The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients.

  Glenn S Gerhard, Ravi Chokshi, Christopher D Still, Peter Benotti, G Craig Wood, Mollie Freedman-Weiss, Cody Rider, Anthony T Petrick
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  ABSTRACT: Gastric bypass surgery is a highly effective therapy for long-term weight loss in severely obese patients, but carries significant perioperative risks including infection, wound dehiscence, and leaks from staple breakdown. Iron status can affect immune function and wound healing, thus may influence peri-operative complications. Common mutations in the HFE gene, the gene responsible for the iron overload disorder hereditary hemochromatosis, may impact iron status. We analyzed 1064 extremely obese Caucasian individuals who underwent open and laparoscopic Roux-n-Y gastric bypass surgery at the Geisinger Clinic. Serum iron, ferritin, transferrin, and iron binding capacity were measured pre-operatively. All patients had intra-operative liver biopsies and were genotyped for the C282Y and H63D mutations in the HFE gene. Associations between surgical complications and serum iron measures, HFE gene status, and liver iron histology were determined. We found that increased serum iron and transferrin saturation were present in patients with any post-operative complication, and that increased serum ferritin was also increased in patients with major complications. Increased serum transferrin saturation was also associated with wound complications in open RYGB, and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without. Serum iron status and HFE genotype may be associated with complications following RYGB surgery in the extremely obese.
  Patient Safety in Surgery 01/2011; 5(1):1.
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  Available from: Xin Chu

  Article: Nicotinic acetylcholine receptor genes on chromosome 15q25.1 are associated with nicotine and opioid dependence severity.

  Porat M Erlich, Stuart N Hoffman, Margaret Rukstalis, John J Han, Xin Chu, W H Linda Kao, Glenn S Gerhard, Walter F Stewart, Joseph A Boscarino
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  ABSTRACT: A locus on chromosome 15q25.1 previously implicated in nicotine, alcohol, and cocaine dependence, smoking, and lung cancer encodes subunits of the nicotinic acetylcholine receptor (nAChR) expressed in the mesolimbic system and thought to mediate substance dependence. Opioid dependence severity (ODS), nicotine dependence severity (NDS), smoking status and quantity, and the number of attempts to quit were assessed using questionnaire instruments in 505 subjects who were prescribed opioid medications for chronic pain in outpatient practice sites. Multivariate regression was used to test for genetic association of these phenotypes with 5 SNPs in the nAChR gene cluster on chromosome 15q25.1, adjusting for background variables. A coding variant in CHRNA5 (rs16969968[A]) was significantly associated with 1.4-unit higher ODS (p < 0.00017). A variant in the 3' untranslated region of CHRNA3 (rs660652[G]) was significantly associated with 1.7-fold higher odds of lifetime smoking (p < 0.0092), 1.1-unit higher NDS (p < 0.0007), 0.7 more pack-years of cigarette smoking (p < 0.0038), and 0.8 more lifetime attempts to quit (p < 0.0084). Our data suggest an association of DNA variants in the nAChR gene cluster on chromosome 15q25.1 with ODS, as well as NDS and related smoking phenotypes. While the association of this locus with NDS and smoking phenotypes is well known, the association with ODS, a dimension of opioid substance dependence, is novel and requires verification in independent studies.
  Human Genetics 11/2010; 128(5):491-9. · 5.07 Impact Factor
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  Available from: proovebio.com

  Article: Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system.

  Joseph A Boscarino, Margaret Rukstalis, Stuart N Hoffman, John J Han, Porat M Erlich, Glenn S Gerhard, Walter F Stewart
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  ABSTRACT: Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0-29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts.
  Addiction 10/2010; 105(10):1776-82. · 4.31 Impact Factor
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  Available from: Xin Chu

  Article: Association of an INSIG2 obesity allele with cardiovascular phenotypes is gender and age dependent.

  Kimberly A Skelding, Glenn S Gerhard, Helen Vlachos, Faith Selzer, Sheryl F Kelsey, Xin Chu, Robert Erdman, David O Williams, Kevin E Kip
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  ABSTRACT: The INSIG2 gene has been implicated in cholesterol metabolism and a single nucleotide polymorphism (SNP) near INSIG2 has been shown to be associated with obesity. We sought to determine the relationship of the INSIG2 SNP to cardiovascular disease (CVD) related phenotypes. Nine hundred forty six patients undergoing percutaneous coronary intervention (PCI) in wave 5 of the multicenter NHLBI Dynamic Registry were genotyped using RT-PCR/TaqMan/allelic discrimination for the rs7566605 SNP near the INSIG2 gene. Clinical variables analyzed include demographics, medical history, and procedural details. The prevalence of peripheral vascular disease (PVD) was significantly higher in older men (≥65 years) who were either homozygous or carriers of the obesity/lipid risk allele ("C") compared to non-carriers (odds ratio 3.4, p = 0.013) using a logistic regression model incorporating history of hypercholesterolemia, history of hypertension, cerebrovascular disease, history of diabetes, and BMI. A similar relationship with cerebrovascular disease was found in older (>65) women (odds ratio 3.4, p = 0.013). The INSIG2 SNP was not associated with BMI, nor with other clinical variables. Age and gender may influence the association of the INSIG2 obesity SNP with PVD and cerebrovascular disease in patients with pre-existing CVD.
  BMC Cardiovascular Disorders 09/2010; 10:46. · 1.52 Impact Factor
• Article: C-B3-02: Association of FTO, INSIG2, MC4R, and PCSK1 Obesity SNPs With Binge Eating in Morbidly Obese Patients.

  Glenn S Gerhard, Christopher D Still, G Craig Wood, Xin Chu, Robert Erdman, Meghan Susek, Heather Gerst, Kim Derr, Mouna Alagha, Christina Hartman, David Carey, Peter Benotti
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  ABSTRACT: Background/Aims: Obesity has a strong genetic component. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in or near over a dozen genes that are related to body mass index (BMI). Despite the association of these SNPs with BMI, the mechanism by which they influence the determination of body weight is not yet known. Recently, the fat- mass and obesity-associated (FTO) obesity SNP was related to energy intake and preference for foods of high caloric density in children. FTO genotype was not associated with resting energy expenditure. We have extended this type of analysis to eating behaviors in the morbidly obese. Methods: DNA was obtained from approximately 900 morbidly obese (BMI>40 kg/m(2)) patients and used to genotype obesity SNPs in or near the FTO, INSIG2, MC4R, and PCSK1 genes. Binge eating status (normal, episodic overeating, or any binge eating) was determined using the validated Questionnaire on Eating and Weight Patterns (QEWP). Binge eating status was correlated with each individual genotype, the combined obesity allele burden, and the combined homozygous obesity gene burden. Results: Binge eating data was obtained from 640 patients who had completed the QEWP. Of these 640, 116 (18%) were classified as manifesting binge eating behavior. No association was present between heterozygous or homozygous FTO (P=0.59), MC4R (P=0.30), or PSK1 (P=0.77) obesity SNPs. However, 29% of those who were homozygous for the INSIG2 obesity SNP were classified as binge eaters, versus 17% of heterozygous or homozygous normal patients (P=0.006). Association was also found with binge eating status and the presence of 2 or more homozygous obesity genotypes (28% versus 17%, P=0.041), likely due to the INSIG2 gene. Cumulative obesity allele burden (0-8 alleles for the 4 genes) was not associated with binge eating status (P=0.42). Conclusions: The INSIG2 obesity SNP appears to influence binge eating behavior in morbidly obese adults. The FTO obesity SNP appears to influence eating behavior in children suggesting that different genes may influence obesity at different ages. For both genes, excess caloric intake appears to be the major mechanism influencing BMI. How other obesity genes influence body weight regulation has not yet been determined.
  Clinical Medicine &amp Research 03/2010; 8(1):50.