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Diabetes pharmacogenetics

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https://www.readbyqxmd.com/read/28871186/analysis-of-population-specific-pharmacogenomic-variants-using-next-generation-sequencing-data
#1
Eunyong Ahn, Taesung Park
Functional rare variants in drug-related genes are believed to be highly differentiated between ethnic- or racial populations. However, knowledge of population differentiation (PD) of rare single-nucleotide variants (SNVs), remains widely lacking, with the highest fixation indices, (Fst values), from both rare and common variants annotated to specific genes, having only been marginally used to understand PD at the gene level. In this study, we suggest a new, gene-based PD method, PD of Rare and Common variants (PDRC), for analyzing rare variants, as inspired by Generalized Cochran-Mantel-Haenszel (GCMH) statistics, to identify highly population-differentiated drug response-related genes ("pharmacogenes")...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805572/personalized-medicine-and-nonmotor-symptoms-in-parkinson-s-disease
#2
Nataliya Titova, K Ray Chaudhuri
Parkinson's disease (PD) is a multineurotransmitter dysfunction related disorder resulting in a range of motor and nonmotor symptoms. Phenotypic heterogeneity is pronounced in PD and nonmotor symptoms dominant subtypes have been described. These endophenotypes may be underpinned by considerable nondopaminergic dysfunction; however, conventional treatment of PD continues to be mostly reliant on dopamine replacement strategy or manipulation of brain dopaminergic pathways. Consequently, treatment of many nondopaminergic nonmotor and some motor symptoms remains a key unmet need...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28770331/the-pharmacogenetics-of-metformin
#3
REVIEW
Jose C Florez
Despite its widespread use as the first-line agent for the treatment of type 2 diabetes, it has become clear that metformin does not work optimally for everyone. Elucidating who are the likely metformin responders and non-responders is hampered by our limited knowledge of its precise molecular mechanism of action. One approach to achieve the related goals of stratifying patients into response subgroups and identifying the molecular targets of metformin involves the deployment of agnostic genome-wide approaches in cohorts of appropriate size to attain sufficient statistical power...
August 3, 2017: Diabetologia
https://www.readbyqxmd.com/read/28696414/pharmacogenetics-of-oral-antidiabetes-drugs-evidence-for-diverse-signals-at-the-irs1-locus
#4
S Prudente, R Di Paola, S Pezzilli, M Garofolo, O Lamacchia, T Filardi, G C Mannino, L Mercuri, F Alberico, M G Scarale, G Sesti, S Morano, G Penno, M Cignarelli, M Copetti, V Trischitta
To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1...
July 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28685055/identification-of-genetic-variants-in-pharmacogenetic-genes-associated-with-type-2-diabetes-in-a-mexican-mestizo-population
#5
Nidia Samara Rodríguez-Rivera, Patricia Cuautle-Rodríguez, Fernando Castillo-Nájera, Juan Arcadio Molina-Guarneros
Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic pathologies in the world. In developing countries, such as Mexico, its prevalence represents an important public health and research issue. Determining factors triggering T2DM are environmental and genetic. While diet, exercise and proper weight control are the first measures recommended to improve the quality of life and life expectancy of patients, pharmacological treatment is usually the next step. Within every population there are variations in interindividual drug response, which may be due to genetic background...
July 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28664816/cyp2c19-17-protects-against-metabolic-complications-of-clozapine-treatment
#6
Irina Piatkov, Dorgival Caetano, Yolinda Assur, Sue Lynn Lau, Micheline Coelho, Trudi Jones, Tristan Nguyen, Steven Boyages, Mark McLean
OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes...
July 18, 2017: World Journal of Biological Psychiatry
https://www.readbyqxmd.com/read/28654165/using-personalized-medicine-in-the-management-of-diabetes-mellitus
#7
REVIEW
Nina Elk, Otito F Iwuchukwu
Diabetes mellitus is a worldwide problem with an immense pharmacoeconomic burden. The multifactorial and complex nature of the disease lends itself to personalized pharmacotherapeutic approaches to treatment. Variability in individual risk and subsequent development of diabetes has been reported in addition to differences in response to the many oral glucose lowering therapies currently available for diabetes pharmacotherapy. Pharmacogenomic studies have attempted to uncover the heritable components of individual variability in risk susceptibility and response to pharmacotherapy...
September 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28587604/kcnj11-abcc8-and-tcf7l2-polymorphisms-and-the-response-to-sulfonylurea-treatment-in-patients-with-type-2-diabetes-a-bioinformatics-assessment
#8
Jingwen Song, Yunzhong Yang, Franck Mauvais-Jarvis, Yu-Ping Wang, Tianhua Niu
BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing...
June 6, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28380657/genetic-polymorphisms-in-organic-cation-transporter-1-attenuates-hepatic-metformin-exposure-in-humans
#9
Elias Immanuel Ordell Sundelin, Lars Christian Gormsen, Jonas Brorson Jensen, Mikkel Holm Vendelbo, Steen Jakobsen, Ole Lajord Munk, Mette Marie Hougaard Christensen, Kim Brøsen, Jørgen Frøkiaer, Niels Jessen
Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed non-invasive (11) C-metformin PET/CT to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1...
April 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28349930/pharmacogenetics-of-posttransplant-diabetes-mellitus
#10
REVIEW
P Lancia, T Adam de Beaumais, E Jacqz-Aigrain
Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'...
June 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28283684/pharmacogenetics-in-type-2-diabetes-precision-medicine-or-discovery-tool
#11
REVIEW
Jose C Florez
In recent years, technological and analytical advances have led to an explosion in the discovery of genetic loci associated with type 2 diabetes. However, their ability to improve prediction of disease outcomes beyond standard clinical risk factors has been limited. On the other hand, genetic effects on drug response may be stronger than those commonly seen for disease incidence. Pharmacogenetic findings may aid in identifying new drug targets, elucidate pathophysiology, unravel disease heterogeneity, help prioritise specific genes in regions of genetic association, and contribute to personalised or precision treatment...
May 2017: Diabetologia
https://www.readbyqxmd.com/read/28160554/pharmacogenetics-of-dipeptidyl-peptidase-4-inhibitors-in-a-taiwanese-population-with-type-2-diabetes
#12
Wen-Ling Liao, Wen-Jane Lee, Ching-Chu Chen, Chieh Hsiang Lu, Chien-Hsiun Chen, Yi-Chun Chou, I-Te Lee, Wayne H-H Sheu, Jer-Yuarn Wu, Chi-Fan Yang, Chung-Hsing Wang, Fuu-Jen Tsai
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral anti-hyperglycemic drugs enabling effective glycemic control in type 2 diabetes (T2D). Despite DPP-4 inhibitors' advantages, the patients' therapeutic response varies. In this retrospective cohort study, 171 Taiwanese patients with T2D were classified as sensitive or resistant to treatment based on the mean change in HbA1c levels. Using an assumption-free genome-wide association study, 45 single nucleotide polymorphisms (SNPs) involved in the therapeutic response to DPP-4 inhibitors (P < 1 × 10-4) were identified at or near PRKD1, CNTN3, ASK, and LOC10537792...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28134748/influence-of-common-polymorphisms-in-the-slc5a2-gene-on-metabolic-traits-in-subjects-at-increased-risk-of-diabetes-and-on-response-to-empagliflozin-treatment-in-patients-with-diabetes
#13
Heike Zimdahl, Axel Haupt, Michael Brendel, Louis Bour, Fausto Machicao, Afshin Salsali, Uli C Broedl, Hans-Juergen Woerle, Hans-Ulrich Häring, Harald Staiger
OBJECTIVE: Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. PATIENTS AND METHODS: Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus...
April 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/27859023/variants-in-pharmacokinetic-transporters-and-glycemic-response-to-metformin-a-metgen-meta-analysis
#14
T Dujic, K Zhou, S W Yee, N van Leeuwen, C E de Keyser, M Javorský, S Goswami, L Zaharenko, M M Hougaard Christensen, M Out, R Tavendale, M Kubo, M M Hedderson, A A van der Heijden, L Klimčáková, V Pirags, A Kooy, K Brøsen, J Klovins, S Semiz, I Tkáč, B H Stricker, Cna Palmer, L M 't Hart, K M Giacomini, E R Pearson
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals...
June 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27701696/-severe-hypoglycemia-following-tramadol-intake-in-a-79-year-old-non-diabetic-patient
#15
Cornelius Kürten, Mladen Tzvetkov, Volker Ellenrieder, Harald Schwörer
History and clinical findings | We report about a 79 year old non-diabetic patient who was admitted to the emergency room with severe hypoglycemia (blood glucose level: 36 mg / dl and Glasgow Coma Scale Score: 3). After the infusion of G40 % her blood glucose level stabilised. The patient reported to have taken 50 mg of Tramadol during the night to treat her headache. Investigations and diagnosis | No other differential diagnosis for hypoglycemia (i.e. diabetes, insulinoma, severe liver or kidney disease) could be established...
September 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27681143/genetic-determinants-of-clozapine-induced-metabolic-side-effects
#16
Kamini Vasudev, Yun-Hee Choi, Ross Norman, Richard B Kim, Ute I Schwarz
OBJECTIVE: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. METHOD: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR)...
February 2017: Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
https://www.readbyqxmd.com/read/27662521/patterns-of-antiplatelet-drug-use-after-a-first-myocardial-infarction-during-a-10-year-period
#17
Alfi Yasmina, Anthonius de Boer, Vera H M Deneer, Patrick C Souverein, Olaf H Klungel
AIMS: The aims of the present study were to assess antiplatelet drug use patterns after a first myocardial infarction (MI) and to evaluate the determinants of antiplatelet nonpersistence. METHODS: The present study was conducted in 4690 patients from the Utrecht Cardiovascular Pharmacogenetics cohort with a first MI between 1986 and 2010, who were followed for a maximum of 10 years. Medication use and event diagnosis were obtained from the Dutch PHARMO Record Linkage System...
March 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27555891/pharmacogenetic-studies-update-in-type-2-diabetes-mellitus
#18
REVIEW
Shalini Singh, Kauser Usman, Monisha Banerjee
Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control...
August 10, 2016: World Journal of Diabetes
https://www.readbyqxmd.com/read/27503844/the-risk-of-hepatotoxicity-new-onset-diabetes-and-rhabdomyolysis-in-the-era-of-high-intensity-statin-therapy-does-statin-type-matter
#19
REVIEW
Lane B Benes, Nikhil S Bassi, Michael H Davidson
The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects...
September 2016: Progress in Cardiovascular Diseases
https://www.readbyqxmd.com/read/27432166/evaluation-of-differential-effects-of-metformin-treatment-in-obese-children-according-to-pubertal-stage-and-genetic-variations-study-protocol-for-a-randomized-controlled-trial
#20
Belén Pastor-Villaescusa, Javier Caballero-Villarraso, M Dolores Cañete, Raúl Hoyos, José Maldonado, Gloria Bueno, Rosaura Leis, Ángel Gil, Ramón Cañete, Concepción M Aguilera
BACKGROUND: Overweight and obesity are considered to be serious public health problems. In pediatric populations, insulin resistance, dyslipidemia, and hypertension associated with obesity occur with increased frequencies. Metformin is an oral anti-hyperglycemic agent that has been demonstrated to be efficacious in the treatment of diabetic and non-diabetic obese adults. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response...
2016: Trials
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