Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.

Genet Med. 2018 06;20(6):655-663

Authors: Orlando LA, Sperber NR, Voils C, Nichols M, Myers RA, Wu RR, Rakhra-Burris T, Levy KD, Levy M, Pollin TI, Guan Y, Horowitz CR, Ramos M, Kimmel SE, McDonough CW, Madden EB, Damschroder LJ

Abstract
PurposeImplementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network's efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.MethodsTo facilitate this goal, the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide its approach to identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross-network analyses.ResultsCMG identified 10 high-priority CFIR constructs as important for genomic medicine. Of those, eight did not have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model.ConclusionWe developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field.

PMID: 28914267 [PubMed - indexed for MEDLINE]

[Genetic aspects of binge eating disorder Part 2. Molecular genetics and pharmacogenetic approaches].

Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(8):102-108

Authors: Kibitov АО, Мazo GE

Abstract
Genetic risk of binge eating disorder (ВЕD) is a consequence of joint participation of many genes, the contribution of each one is small, but the total (additive) effect is significant and greatly influences the age at onset, clinical dynamics and the level of treatment resistance. It is assumed that the carriers of different polymorphic variants of genes and their combinations have different levels of genetic risk. No Genom Wide Association studies of ВЕD has been performed and the analysis of the results of candidate genes studies gives reason to believe that pathogenetically substantiated panel of genes, including serotonin system, BDNF and, especially dopamine and endogenous opioid system, would be most useful, taking into account the mechanism of action of drugs for the ВЕD treatment. Genetic studies with this panel if using evidence-based design, detailed and quantitative analysis of the family history of binge eating can give good results for: 1) assessment of the genetic risk of ВЕD for primary prevention programs; 2) identification of the specific clinical forms of development and course of ВЕD with significant genetic influence; 3) identification of the specific genetic variants that increase the effectiveness of personalized pharmacotherapy of ВЕD within pharmacogenetic approach.

PMID: 28635745 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

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13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

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Genetic variability among Mexican Mestizo and Amerindian populations based on three ABCB1 polymorphisms.

Mol Biol Rep. 2018 Oct 13;:

Authors: Favela-Mendoza AF, Rangel-Villalobos H, Fricke-Galindo I, Ortega-Vázquez A, Martínez-Cortés G, López-López M

Abstract
The most widely studied polymorphisms of the ABCB1 gene are rs1128503 (c.1236C>T), rs2032582 (c.2677G>T/A), and rs1045642 (c.3435C>T). Although variation in ABCB1 allele frequencies among Mexican Mestizos (admixed) from different regions has been observed, Mexican Amerindians have been poorly studied. We aimed to describe the genetic variability of these three ABCB1 polymorphisms in a total sample of 273 Mexican volunteers that included Mestizos from the state of Yucatán, and Amerindians from seven populations (Tarahumara, Mayo, Huichol, Purépecha, Nahua, Tojolabal, and Maya). Genotypes were determined by means of Taq Man probes (qPCR). Genotype distribution was in Hardy-Weinberg equilibrium for all three ABCB1polymorphisms in the eight Mexican populations analyzed. For c.1236C>T and c.3435C>T, the heterozygous C/T was the most frequent genotype in the majority of the studied Mexican populations (range 30.8-65.4%), while heterozygous G/T was the most common genotype for c.2677G>T/A (range 25.9-51.2%), mainly followed by G/G (range 3.2-47.1%) and T/T (range 7.0-35.5%). 12 haplotypes were estimated from the three ABCB1 polymorphisms analyzed, with TTT the most frequent haplotype (mean, 37.0%). Genetic differentiation was demonstrated among the studied Mexican populations (Fst p value < 0.0001), which could imply a diverse drug response or a risk for adverse drug reactions to ABCB1 substrates. Although differences among Amerindians are probably due to genetic drift effects, for Mestizos this could imply variation in admixture composition. In conclusion, interpopulation variability in the observed frequencies of ABCB1 polymorphisms among Mexican Mestizos and Amerindians allow predicting diverse drug responses to ABCB1 substrates in these populations.

PMID: 30317428 [PubMed - as supplied by publisher]

Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder.

J Clin Pharm Ther. 2018 Oct 12;:

Authors: Abdolhosseinzadeh S, Sina M, Ahmadiani A, Asadi S, Shams J

Abstract
WHAT IS KNOWN AND OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first line of medication for OCD treatment; however, 40%-60% of patients with OCD do not respond to SSRIs adequately. There are growing pieces of evidence which suggest a significant role for the glutamatergic system in the genesis of OCD and its consequent treatment. In the present study, we aimed to assess the association of SLC1A1 polymorphisms (rs301430, rs2228622 and rs3780413) with OCD and its clinical characteristics, as well as the importance of these SNPs in the response of OCD patients to SSRI pharmacotherapy.
METHODS: Sample study consisted of 243 OCD cases and 221 control subjects. Patients were treated 12 weeks with fluvoxamine (daily dose: 150-300 mg). Based on the reduction in obsessive and compulsive severity scores using Y-BOCS severity scale, patients were classified as responders, non-responders and refractory. A total of 239, 228 and 215 patients were genotyped for rs301430, rs2228622 and rs3780413, respectively, by the means of PCR-RFLP.
RESULTS AND DISCUSSION: No association was detected between SLC1A1 SNPs and OCD, except an association between the familial form of the disease in males with rs2228622 (P = 0.033). The results of pharmacogenetic studies revealed the associations of two SLC1A1 SNPs, rs2228622 (P = 0.031) and rs3780413 (P = 0.008), with treatment response.
WHAT IS NEW AND CONCLUSION: Results of the current study suggest a role for the glutamate transporter in OCD treatment response with SSRIs which should encourage researchers to further investigate the importance of glutamate transporter in OCD pharmacogenetics.

PMID: 30315580 [PubMed - as supplied by publisher]

Interprofessional education through a telehealth team based learning exercise focused on pharmacogenomics.

Curr Pharm Teach Learn. 2018 Aug;10(8):1062-1069

Authors: Quesnelle KM, Bright DR, Salvati LA

Abstract
BACKGROUND: Traditional interprofessional educational (IPE) exercises are those where learning exists "about, from, and with" trainees in two or more professions in order to prepare health sciences professionals to work on interprofessional teams. One emerging difficulty with IPE is the paucity of health profession students at single institutions, and the geographic and financial constraints of multi-institutional collaboration.
INTERPROFESSIONAL EDUCATION ACTIVITY: To circumvent these barriers, we developed a multi-institution telehealth team-based learning (TBL) event between medical and pharmacy students on the topic of pharmacogenomics (PGx). Using a validated pre-post survey design, student attitudes and perceptions were measured before and after an educational intervention designed to simulate interprofessional telehealth collaboration. The survey results showed significant improvement across all areas of student attitudes toward interprofessional collaboration. Also, medical student PGx confidence increased substantially during the exercise even though the only PGx instruction they received was from pharmacy students.
DISCUSSION: These data demonstrate that learning exists "about, from, and with" trainees in other professions, even if they do not physically train in the same location. Free tools are available to create virtual interactions between students on different campuses, and telehealth exercises using these tools are a valid way to conduct IPE across different campuses. The instructional experience does not need to be identical for all participants in the IPE event; rather, tailoring the educational experience to each group of students provides opportunities for inter-student teaching.

PMID: 30314542 [PubMed - in process]

Personalized medicines - are pharmacists ready for the challenge?

Integr Pharm Res Pract. 2018;7:113-123

Authors: Kennedy MJ

Abstract
The field of personalized medicine affords multiple opportunities to pharmacists, and pharmacists have specific knowledge, skills and abilities that make them uniquely suited to advance the use of personalized medicine as a clinical tool. The pharmacy profession as a whole, however, has been slow to embrace the concept of clinical pharmacogenetics and is now facing a critical juncture that can potentially redefine the professional identity of the pharmacist. Before practice transformation can occur, however, it is important for our profession to ask and fully explore the following question: Are pharmacists ready for the challenge of personalized medicine? When assessing the readiness of pharmacy for personalized medicine, one must consider factors that are specific to the individual pharmacist as well as systematic considerations that allow pharmacists to successfully integrate personalized medicine into their individual practice area. These include factors such as education and training, competency, an attitude of engagement and adequate support and guidance. Personnel, information technology and laboratory infrastructure are also critical elements that are required, and financially sustainable practice models must be developed. Successful advancement of clinical pharmacogenetics will also require the profession to clearly define their vision of what success looks like and where it wants to be at the end of the transformational journey. Without a clear destination, we will continue to move as individuals in different directions and fail to progress as a whole. While pharmacists might not be completely ready for the challenge of pharmacogenetics, they are most certainly up to facing the challenge. The time is right and the stage is set for pharmacy to embark on another transformative journey - a journey that will redefine the role of the pharmacist and will secure a place for pharmacy in the era of personalized medicine and beyond.

PMID: 30310772 [PubMed]

Gene expression and single nucleotide polymorphism of ATP7B are associated with platinum-based chemotherapy response in non-small cell lung cancer patients.

J Cancer. 2018;9(19):3532-3539

Authors: Li YQ, Chen J, Yin JY, Liu ZQ, Li XP

Abstract
Objectives: Platinum-based chemotherapy is first-line treatment for non-small cell lung cancer (NSCLC) patients. The efficacy is limited by drug resistance. Recent studies suggest that ATP7B, a copper efflux transporter, may be involved in platinum resistance. However, the clinical significance of ATP7B expression in NSCLC is controversial. Moreover, the effects of single nucleotide polymorphisms (SNPs) in ATP7B gene on the response to platinum-based chemotherapy are scarcely understood. The aim of our study is to evaluate the clinical value of ATP7B in NSCLC patients and explore the interrelationships between ATP7B SNPs and protein expression, and their association with chemotherapy response. Materials and Methods: A total of 247 NSCLC patients were recruited in this study. Among them, 158 patients who received platinum-based chemotherapy were used to explore the interrelationships between ATP7B SNPs, protein expression and chemotherapy response, while 89 patients who underwent surgical resection were used to further investigate the association between ATP7B SNPs and expression level. We genotyped 15 SNPs of ATP7B by Sequenom MassARRAY and determined ATP7B protein levels by immunohistochemistry. Results: Patients with ATP7B-negative tumors had improved chemotherapeutic response (p=0.025) and better overall survival (p=0.044) compared with the patients with ATP7B-positive tumors. The multivariate Cox regression analysis revealed that ATP7B expression was an independent prognostic factor (HR=0.639, 95%CI=0.424-0.962, p=0.032). Moreover, we found that the rs9526814 GG genotype was significantly associated with favorable response to platinum-based chemotherapy when compared with TT+TG genotypes (OR=0.362, 95CI%=0.140-0.935, p=0.036). Mechanistically, rs9526814 GG genotype showed a strong trend towards reduced expression level of ATP7B compared with the TT+TG genotypes (p= 0.048). Conclusion: Our findings indicate that ATP7B rs9526814 may contribute to platinum resistance by influencing ATP7B gene expression and can be used as a potential biomarker to predict the sensitivity of platinum-based chemotherapy in NSCLC patients.

PMID: 30310510 [PubMed]

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity.

Genomics Inform. 2018 Sep;16(3):52-58

Authors: Oh J, Yi S, Gu N, Shin D, Yu KS, Yoon SH, Cho JY, Jang IJ

Abstract
In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p ＜ 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

PMID: 30309203 [PubMed]

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10 - A study on therapeutic drug monitoring data from 1,003 genotyped Scandinavian patients.

Br J Clin Pharmacol. 2018 Oct 12;:

Authors: Haslemo T, Eliasson E, Jukić MM, Ingelman-Sundberg M, Molden E

Abstract
AIM: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population.
METHODS: 1,003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores.
RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P<0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n=269), CYP2D6*9-10/null (n=17), CYP2D6*41/null (n=30) and CYP2D6null/null (n=95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10.
CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 versus CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.

PMID: 30312494 [PubMed - as supplied by publisher]

Sodium Valproate Ameliorates Neuronal Apoptosis in a Kainic Acid Model of Epilepsy via Enhancing PKC-Dependent GABAAR γ2 Serine 327 Phosphorylation.

Neurochem Res. 2018 Oct 11;:

Authors: Li Q, Li QQ, Jia JN, Cao S, Wang ZB, Wang X, Luo C, Zhou HH, Liu ZQ, Mao XY

Abstract
GABA is a dominant inhibitory neurotransmitter in the brain and A type GABA receptor (GABAAR) phosphorylation is critical for GABA-mediated inhibitory effect. However, its role in the neuroprotective effect of sodium valproate (VPA), a prevalent drug for treating patients with epilepsy, remains elusive. The present study was conducted to explore the role of GABAAR phosphorylation in the neuroprotection of VPA against a kainic acid-induced epileptic rat model and the potential molecular mechanisms. Neuronal apoptosis was evaluated by TUNEL assay, PI/Annexin V double staining, caspase-3 activity detection and Bax and Bcl-2 proteins expression via Western blot analysis. The primary rat hippocampal neurons were cultivated and cell viability was measured by CCK8 detection following KA- or free Mg2+-induced neuronal impairment. Our results found that VPA treatment significantly reduced neuronal apoptosis in the KA-induced rat model (including reductions of TUNEL-positive cells, caspase-3 activity and Bax protein expression, and increase of Bcl-2 protein level). In the in vitro experiments, VPA at the concentration of 1 mM for 24 h also increased cell survival and suppressed cell apoptosis in KA- or no Mg2+-induced models via CCK8 assay and PI/Annexin V double staining, respectively. What is more important, the phosphorylation of γ2 subunit at serine 327 residue for GABAAR was found to be robustly enhanced both in the KA-induced epileptic rat model and neuronal cultures following KA exposure after VPA treatment, while no evident alteration was found in terms of GABAAR β3 phosphorylation (408 or 409 serine residue). Additionally, pharmacological inhibition of protein kinase C (PKC) clearly abrogated the neuroprotective potential of VPA against KA- or free Mg2+-associated neuronal injury, indicating a critical role of PKC in the effect of GABAAR γ2 serine 327 phosphorylation in VPA's protection. In summary, our work reveals that VPA mitigates neuronal apoptosis in KA-triggered epileptic seizures, at least, via augmenting PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue.

PMID: 30311181 [PubMed - as supplied by publisher]

Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target.

Int J Mol Sci. 2018 Oct 10;19(10):

Authors: Hung CS, Wang SC, Yen YT, Lee TH, Wen WC, Lin RK

Abstract
Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients. As compared with paired normal tissues and healthy individuals, CCND2 promoter hypermethylation was detected in 40.9% of breast tumors and 44.4% of plasma circulating cell-free DNA of patients. The western cohort of The Cancer Genome Atlas also demonstrated CCND2 promoter hypermethylation in female lung cancer, lung adenocarcinoma, and breast cancer patients and that CCND2 promoter hypermethylation is an independent poor prognostic factor. The cell model assay indicated that CCND2 expression inhibited cancer cell growth and migration ability. The demethylating agent antroquinonol D upregulated CCND2 expression, caused cell cycle arrest, and inhibited cancer cell growth and migration ability. In conclusion, hypermethylation of CCND2 is a potential diagnostic, prognostic marker and drug target, and it is induced by antroquinonol D.

PMID: 30308939 [PubMed - in process]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenomics Testing for Postoperative Pain Optimization Before Total Knee and Total Hip Arthroplasty.

JBJS Rev. 2018 Oct 09;:

Authors: Awad ME, Padela MT, Sayeed Z, Abaab L, El-Othmani MM, Saleh KJ

PMID: 30300249 [PubMed - as supplied by publisher]

Towards the integration of pharmacogenetics in psychiatry: a minimum, evidence-based genetic testing panel.

Curr Opin Psychiatry. 2018 Oct 05;:

Authors: Bousman C, Maruf AA, Müller DJ

Abstract
PURPOSE OF REVIEW: The implementation of pharmacogenetic testing in psychiatry is underway but is not yet standard protocol. Barriers to pharmacogenetics becoming standard practice are the lack of translation of evidence-based recommendations and standardization of genetic testing panels. As for the latter, there are currently no regulatory standards related to the gene and allele content of testing panels used to derive medication selection and dosing advice. To address these barriers, we summarize the current gene-drug interaction knowledgebase and proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry.
RECENT FINDINGS: The Pharmacogenomics Knowledgebase has cataloged 448 gene-drug interactions relevant to psychiatry based on the current scientific literature, drug labels, and pharmacogenetic-based implementation guidelines. A majority of these interactions involved two cytochrome P450 enzymes (CYP2D6 and CYP2C19) and antidepressant medications, however, CYP2C9, HLA-A, and HLA-B are relevant to mood stabilizers/anticonvulsants.
SUMMARY: On the basis of evidence base, we proposed a minimum gene and allele set for pharmacogenetic testing in psychiatry that includes 16 variant alleles within five genes (CYP2C9, CYP2C19, CYP2D6, HLA-A, HLA-B). The intent is to assist clinicians in judging the gene and allele content of pharmacogenetic tests and to facilitate pharmacogenetic testing as a standard protocol and companion tool for psychotropic medication selection and dosing.

PMID: 30299306 [PubMed - as supplied by publisher]

Principles of precision medicine and its application in toxicology.

J Toxicol Sci. 2018;43(10):565-577

Authors: Cook JC, Wu H, Aleo MD, Adkins K

Abstract
Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug's mode-of-action. Nonclinical models such as the mouse and non-human primate can be used to understand genetic variation and its potential translation to humans, and are available for toxicologists to employ in advance of drugs moving into clinical development. Understanding interindividual differences in response to drugs and how these differences can influence the drug's risk-benefit profile and lead to the identification of biomarkers that enhance patient efficacy and safety is of critical importance for toxicologists today, and in the future, as the fields of pharmacogenomics and genetics continue to advance.

PMID: 30298845 [PubMed - in process]

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Nat Genet. 2018 Oct 08;:

Authors: Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, Payne AJ, Steinthorsdottir V, Scott RA, Grarup N, Cook JP, Schmidt EM, Wuttke M, Sarnowski C, Mägi R, Nano J, Gieger C, Trompet S, Lecoeur C, Preuss MH, Prins BP, Guo X, Bielak LF, Below JE, Bowden DW, Chambers JC, Kim YJ, Ng MCY, Petty LE, Sim X, Zhang W, Bennett AJ, Bork-Jensen J, Brummett CM, Canouil M, Ec Kardt KU, Fischer K, Kardia SLR, Kronenberg F, Läll K, Liu CT, Locke AE, Luan J, Ntalla I, Nylander V, Schönherr S, Schurmann C, Yengo L, Bottinger EP, Brandslund I, Christensen C, Dedoussis G, Florez JC, Ford I, Franco OH, Frayling TM, Giedraitis V, Hackinger S, Hattersley AT, Herder C, Ikram MA, Ingelsson M, Jørgensen ME, Jørgensen T, Kriebel J, Kuusisto J, Ligthart S, Lindgren CM, Linneberg A, Lyssenko V, Mamakou V, Meitinger T, Mohlke KL, Morris AD, Nadkarni G, Pankow JS, Peters A, Sattar N, Stančáková A, Strauch K, Taylor KD, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tuomilehto J, Witte DR, Dupuis J, Peyser PA, Zeggini E, Loos RJF, Froguel P, Ingelsson E, Lind L, Groop L, Laakso M, Collins FS, Jukema JW, Palmer CNA, Grallert H, Metspalu A, Dehghan A, Köttgen A, Abecasis GR, Meigs JB, Rotter JI, Marchini J, Pedersen O, Hansen T, Langenberg C, Wareham NJ, Stefansson K, Gloyn AL, Morris AP, Boehnke M, McCarthy MI

Abstract
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

PMID: 30297969 [PubMed - as supplied by publisher]