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PubMed | University of Connecticut, Genomas Inc. and Hartford Hospital
Type: Comparative Study | Journal: Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery | Year: 2016

Surgical weight loss response is variable, with suboptimal outcomes in some patients. We hypothesized that genetic biomarkers may be related to weight change.We tested 330 single nucleotide polymorphisms (SNPs) in genes relevant to metabolic regulation in 161 patients whose decrease in body mass index (BMI), 1 year after laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB), was small (lowest quartile response) or large (highest quartile response). LAGB patients whose BMI decreased4.7 or10.2 units comprised groups I (n = 43) and II (n = 40), respectively. RYGB patients whose BMI decreased13.6 or19.8 units comprised groups III (n = 39) and IV (n = 39), respectively. Within each surgery, SNPs with large differences in reference allele frequency (z score>2, corresponding to values displaced 2 standard deviations [SD] from the mean for all SNPs) in low versus high quartiles, were identified. We compared reference allele frequencies, within surgical procedure, using the (2) test (using Bonferroni correction for multiple testing).The mean percent excess weight losses (SD) corresponding to groups I, II, III, and IV were: 16 (12), 64 (30), 55 (16), and 75 (17), respectively. SNPs with z score>2 were identified in genes involved in LAGB response, lipid metabolic regulation (APOE, rs439401; APOC4, rs2288911), neural processes (DRD3, rs167771; HTR3 B, rs3758987), and xeno- or endobiotic metabolism (CYP3 A4, rs12333983); and for RYGB response, in lipid transport (SCARB1, rs10846744), folate metabolism (MTHFR, rs2066470), regulation of glycolysis in immune cells (HIF1 A, rs1951795), vitamin K cycling (VKORC1, rs2359612), and xeno- or endobiotic metabolism (CYP3 A4, rs2242480). For LAGB response, APOE SNP frequencies were significantly different.With further validation, information derived from patient DNA may be useful to predict surgical weight loss outcomes and guide selection of surgical approach.

PubMed | Genzyme, Cyclica Inc., Genomas Inc., San Francisco General Hospital and Hartford Hospital
Type: Journal Article | Journal: Clinics in laboratory medicine | Year: 2016

Statin responsiveness is an area of great research interest given the success of the drug class in the treatment of hypercholesterolemia and in primary and secondary prevention of cardiovascular disease. Interrogation of the patients genome for gene variants will eventually guide anti-hyperlipidemic intervention. In this review, we discuss methodological approaches to discover genetic markers predictive of class-wide and drug-specific statin efficacy and safety. Notable pharmacogenetic findings are summarized from hypothesis-free genome wide and hypothesis-led candidate gene association studies. Physiogenomic models and clinical decision support systems will be required for DNA-guided statin therapy to reach practical use in medicine.

Seip R.L.,Genomas Inc. | Seip R.L.,Hartford Hospital | Duconge J.,University of Puerto Rico at San Juan | Ruano G.,Genomas Inc. | Ruano G.,Hartford Hospital
Future Cardiology | Year: 2010

Genotyping has the potential to improve the efficacy and safety of major antithrombotic drugs. For warfarin, the stable maintenance dose varies from 1-10 mg/day. The VKORC1 -1639G>A allele and the CYP2C9*2 and *3 alleles (cumulative frequency: 90% in Asians, 65% in Europeans and 20% in Africans), explain 45% of response variability in European and 30% in African populations. The large clinical trials COAG and EU-PACT will define the extent to which pharmacogenetic dosing affects the safety and efficacy of warfarin and coumarin derivatives. The platelet inhibitor clopidogrel requires activation by the CYP2C19 enzyme. CYP2C19*2 and *3 alleles (cumulative frequency: 20-50%) produce null enzyme activity, and their presence attenuates platelet inhibition and increases cardiovascular events. The US FDA-mandated drug labeling recognizes the relevance of genotyping in the selection and dosing of both warfarin and clopidogrel. © 2010 Future Medicine Ltd.

Ruano G.,Hartford Hospital | Ruano G.,Genomas Inc. | Szarek B.L.,Hartford Hospital | Villagra D.,Genomas Inc. | And 5 more authors.
Biomarkers in Medicine | Year: 2013

Aim: This study aimed to determine the effect of the CYP2D6 genotype on the length of hospitalization stay for patients treated for major depressive disorder. Methods: A total of 149 inpatients with a diagnosis of major depressive disorder at the Institute of Living, Hartford Hospital (CT, USA), were genotyped to detect altered alleles in the CYP2D6 gene. Prospectively defined drug metabolism indices (metabolic reserve, metabolic alteration and allele alteration) were determined quantitatively and assessed for their relationship to length of hospitalization stay. Results: Hospital stay was significantly longer in deficient CYP2D6 metabolizers (metabolic reserve <2) compared with functional or suprafunctional metabolizers (metabolic reserve ≥2; 7.8 vs 5.7 days, respectively; p = 0.002). Conclusion: CYP2D6 enzymatic functional status significantly affected length of hospital stay, perhaps due to reduced efficacy or increased side effects of the medications metabolized by the CYP2D6 isoenzyme. Functional scoring of CYP2D6 alleles may have a substantial impact on the quality of care, patient satisfaction and the economics of psychiatric treatment. © 2013 Future Medicine Ltd.

PubMed | Yale University, Genomas Inc. and Hartford Hospital
Type: | Journal: Clinica chimica acta; international journal of clinical chemistry | Year: 2016

We describe a population genetic approach to compare samples interpreted with expert calling (EC) versus automated calling (AC) for CYP2D6 haplotyping. The analysis represents 4812 haplotype calls based on signal data generated by the Luminex xMap analyzers from 2406 patients referred to a high-complexity molecular diagnostics laboratory for CYP450 testing. DNA was extracted from buccal swabs. We compared the results of expert calls (EC) and automated calls (AC) with regard to haplotype number and frequency. The ratio of EC to AC was 1:3. Haplotype frequencies from EC and AC samples were convergent across haplotypes, and their distribution was not statistically different between the groups. Most duplications required EC, as only expansions with homozygous or hemizygous haplotypes could be automatedly called. High-complexity laboratories can offer equivalent interpretation to automated calling for non-expanded CYP2D6 loci, and superior interpretation for duplications. We have validated scientific expert calling specified by scoring rules as standard operating procedure integrated with an automated calling algorithm. The integration of EC with AC is a practical strategy for CYP2D6 clinical haplotyping.

The invention is generally directed to a physiogenomic method for predicting diabetes and metabolic syndromes induced by psychotropic drugs. In one embodiment, the invention relates to the use of genetic variants of marker genes to predict the likelihood that an individual will experience undesirable metabolic side effects as a result of the use of a drug including, but not limited to, psychotropic drugs. The invention also relates to methods predicting the likelihood of diabetes and metabolic syndromes induced by the use of drugs with undesirable metabolic side effects.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.25M | Year: 2011

DESCRIPTION (provided by applicant): Currently 30 million Americans with elevated cholesterol receive statin therapy, making statins the most prescribed drug class in the U.S. Statin Induction and Neuro-Myopathy (SINM), the balance of potency and safety, is the main clinical management challenge of these drugs, particularly when treatment targets are aggressive requiring LDL cholesterol levels below 100 mg/dl. In medical practice, Neuro-Myopathy presents as a constellation of neuromuscular side effects, including myalgia (muscle aches, cramps, weakness) and myopathy (muscular injury monitored by serum creatine kinase (CK) elevation). Neuro-myopathy is more frequent at the higher doses required for treating advanced cardiovascular disease and varies in extentbetween individual statins and from patient to patient. Statin usage is ultimately limited by toxicity. Clearly there is an urgent need to simultaneously avert side effects and optimize lipid lowering at the outset of treatment to bolster success in lowering cardiovascular disease risk in literally millions of patients. Recognizing that clinicians balance safety with efficacy when prescribing statins, our research group and others have established genetic markers that are valid candidates for a panel of safety and efficacy markers. The SINM PhyzioType System is the first diagnostic tool to integrate statin safety and efficacy markers for clinical use. The SINM PhyzioType system can predict the safety and efficacy of the pre-eminent statin drugs (namely, atorvastatin [Lipitor(R)], simvastatin [Zocor(R)], and rosuvastatin [Crestor(R)]-which together account for 85% of the U.S. market share8) according to the genome of each patient, enabling selection of the optimal drug for each patient. Alternatively if a patient's genomic profile proves to be incompatible with statins, the clinician can opt to prescribe another drug class. This Phase II Renewal Program is entitled SYSTEM FOR DNA-GUIDED OPTIMIZATION AND PERSONALIZATION OF STATIN THERAPY. Our previous Fast-Track SBIR Program enabled the discovery of gene markers and configuration of predictive bioclinical algorithms, and it advanced the clinical development of the SINM PhyzioType product closer to commercialization. The proposed Phase II Renewal Program will validate the performance of the SINM PhyzioType product in a prospective study of an independent population of 400 patients naove to statin therapy or who had not received statins for at least 3 months. Allocated funds will be used to validate the product forpersonalized clinical management of statins, to develop a medical informatics interface enabling use of the product by clinicians (Personalized Health Portal) and to prepare the SINM PhyzioType for commercialization. With this project, Genomas will continue to enlist some of the most highly qualified lipid clinical specialists in the world, including Paul D. Thompson, M.D., of Hartford Hospital's Division of Cardiology, John P. Kane, M.D., of the Cardiovascular Research Institute at University of California at San Francisco, and Bruce Gordon, M.D., of the Rogosin Institute at New York Presbyterian Medical Center for this Program. Theodore Holford, Ph.D., of the Yale School of Medicine will serve as a consultant in biostatistics. The expected outcome is final development of the Genomas product SINM PhyzioTypeTM System, that predicts the variable lipid-altering efficacy and the risk of drug-induced neuromuscular side effects that arise in the substantial segment of patients receiving statins. With data collected Phase II Renewal funding, Genomas will be able to serve confirmatory proof that the PhyzioType product is a reliable, reproducible and cost-effective product enabling physicians to optimize treatment strategies in lipid disorders while avoiding neuromyopathy. The goal is to enable clinicians to deploy a genetic decision support system to manage statins, prescribe these drugs on a DNA-guided, personalized basis and effectively lower the risk of cardiovascular disease for each patient. PUBLIC HEALTHRELEVANCE: In the proposed Phase II Renewal Program, the SINM PhyzioTypeTM System for optimization and personalization of statin therapy will be validated through a prospective study to finalize the product ahead of commercialization. This validation study will serve confirmatory proof that the SINM PhyzioTypeTM System is a reliable, reproducible and cost-effect product enabling physicians to optimize treatment strategies in lipid disorders and minimize detrimental neuromuscular side effects. This pioneering product, which represents the first tool to integrate statin safety and efficacy markers for clinical use, will advance the practice of personalized medicine and reduce side effects while elevating therapeutic benefits of the country's most popular drugs that are already on the market.

The present invention relates to the use of genetic variants of associated marker genes to predict an individuals susceptibility to muscular injury and muscular side effects in response to statin therapy. The present invention further relates to analytical assays and computational methods using the novel marker gene set. The present invention has utility for personalized medical treatment, drug safety, statin compliance, and prophylaxis of muscle side effect.

Disclosed herein are compositions and methods relevant to a novel Drug Metabolism Reserve Physiotype to determine the metabolic capacity of a human individual. The Drug Metabolism Reserve Physiotype allows the determination of the innate metabolic capacity of the patient relevant to antidepressant and stimulant treatment and can be predicted and diagnosed simply from a blood sample. In the disclosed method, an individual is genotyped for a plurality of polymorphisms in a gene encoding CYP2C9, a gene encoding CYP2C19 and a gene encoding CYP2D6, and the genotypes are used to produce four novel indices, which relate to the metabolic capacity of the human individual.

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