Cytokine signal suppressor (SOCS) 1-1478 CA/del gene polymorphism in Turkish patients with polycystic ovary syndrome.

J Obstet Gynaecol. 2017 Jun 01;:1-6

Authors: Oz Gul O, Cander S, Gul CB, Budak F, Oral B, Ersoy C

Abstract
Eighty-four subjects, premenopausal female patients (n = 42, mean (SD) age: 26.4 (4.2) years) diagnosed with polycystic ovary syndrome (PCOS) and age-matched healthy volunteers (n = 42, mean (SD) age: 27.6(3.4) years), were included in this study. Data on physical examination, anthropometric measurements and blood biochemistry analysis were recorded for each subject along with analysis for SOCS1-1478 CA/del polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The relation of SOCS1-1478 CA/del polymorphism to PCOS status and insulin resistance was analysed via logistic regression analysis. Mean (SD) levels for BMI (28.5(6.5) vs.22.5 (4.9) kg/m(2), p < .001), HOMA-IR (3.1(1.8) vs.1.5 (1.0), p < .001), LDL-cholesterol (115.9(32.7) vs.100.7 (27.3)mg/dL, p = .03) and triglyceride (113.8(64.9) vs.83.3(36.3)mg/dL, p = .017) were significantly higher in patients. Groups were similar in terms of SOCS1-1478 CA/del polymorphism. No significant relation of this polymorphism was noted to PCOS and HOMA-IR. Our findings revealed no difference between groups in terms of the rate of SOCS1-1478 CA/del polymorphism, and no significant relation of this polymorphism to insulin resistance and PCOS status. Impact statement Polycystic ovary syndrome (PCOS), the most common cause of anovulation and the most commonly encountered form of female endocrine disease. SOCS proteins have been suggested to play a fundamental role in the negative feedback regulation of the JAK-STAT pathway, which is the major signalling pathway involved in a wide range of physiologic and pathologic processes, including inflammatory diseases, malignancies and immune disorders. Pathways involving the induction of suppression of SOCS proteins were also shown likely to be involved in mediating cytokine-induced insulin resistance. The present study was designed to determine the frequency of SOCS1-1478 CA/del gene polymorphism in patients with PCOS in relation to healthy controls and insulin resistance. Our findings revealed significantly higher rates of insulin resistance, obesity and dyslipidaemia in Turkish patients with PCOS compared with age-matched healthy controls, while no difference between study groups in terms of the rate of SOCS1-1478 CA/del polymorphism along with no significant relation of SOCS1-1478 CA/del polymorphism to insulin resistance and PCOS status. Future larger scale studies with the application of standardised diagnostic methods and criteria, and of state-of-the-art modern techniques including genomics, proteomics and pharmacogenetics would provide better understanding of the association between PCOS and genomic variants.

PMID: 28569589 [PubMed - as supplied by publisher]

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis.

Genome Med. 2017 May 31;9(1):50

Authors: Ross CJ, Towfic F, Shankar J, Laifenfeld D, Thoma M, Davis M, Weiner B, Kusko R, Zeskind B, Knappertz V, Grossman I, Hayden MR

Abstract
BACKGROUND: Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials.
METHODS: Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials.
RESULTS: A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA).
CONCLUSIONS: This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.

PMID: 28569182 [PubMed - in process]

Mitochondrial DNA analysis of ancient sheep from Altai.

Anim Genet. 2017 May 31;:

Authors: Dymova MA, Zadorozhny AV, Mishukova OV, Khrapov EA, Druzhkova AS, Trifonov VA, Kichigin IG, Tishkin AA, Grushin SP, Filipenko ML

Abstract
A comparative analysis of the genetic diversity of ancient and modern sheep can shed light on the origin of these animals and their distribution as well as help to evaluate the role of humans at each formation stage of different sheep breeds. Here we isolated ancient DNA and performed sequencing of the mitochondrial DNA D-loop from 17 sheep bone remains (~4000-1000 years old) found in the archaeological complexes in the south of Altai (Western Siberia). The length of the sequences obtained ranged between 318 and 586 bp. The haplotype diversity and nucleotide diversity were 0.801 ± 0.081 and 0.0096 ± 0.0014 respectively. The average number of nucleotide differences was ~3.1. Nucleotide sequence analysis revealed that 15 specimens were nested within previously described A,B,C,D and E lineages and that two specimens had a basal position relative to the rest of the analyzed samples. A relatively high diversity of sheep haplotypes, including the presence of two basal haplotypes, indicates that the Altai region may have been a transport route of human migration. Further ancient DNA analysis of other specimens and deeper genome sequencing of samples with novel haplotypes is needed to better understand the demographic history of sheep in Southern Siberia.

PMID: 28568904 [PubMed - as supplied by publisher]

From the Viewpoint of Drug Metabolism Research.

Yakugaku Zasshi. 2017;137(6):697-705

Authors: Nakajima M

Abstract
 Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.

PMID: 28566576 [PubMed - in process]

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Diabetes. 2017 May 31;:

Authors: Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M, Pervjakova N, Pers TH, Johnson AD, Eicher JD, Jackson AU, Ferreira T, Lee Y, Ma C, Steinthorsdottir V, Thorleifsson G, Qi L, Van Zuydam NR, Mahajan A, Chen H, Almgren P, Voight BF, Grallert H, Müller-Nurasyid M, Ried JS, Rayner WN, Robertson N, Karssen LC, van Leeuwen EM, Willems SM, Fuchsberger C, Kwan P, Teslovich TM, Chanda P, Li M, Lu Y, Dina C, Thuillier D, Yengo L, Jiang L, Sparso T, Kestler HA, Chheda H, Eisele L, Gustafsson S, Frånberg M, Strawbridge RJ, Benediktsson R, Hreidarsson AB, Kong A, Sigurðsson G, Kerrison ND, Luan J, Liang L, Meitinger T, Roden M, Thorand B, Esko T, Mihailov E, Fox C, Liu CT, Rybin D, Isomaa B, Lyssenko V, Tuomi T, Couper DJ, Pankow JS, Grarup N, Have CT, Jørgensen ME, Jørgensen T, Linneberg A, Cornelis MC, van Dam RM, Hunter DJ, Kraft P, Sun Q, Edkins S, Owen KR, Perry JR, Wood AR, Zeggini E, Tajes-Fernandes J, Abecasis GR, Bonnycastle LL, Chines PS, Stringham HM, Koistinen HA, Kinnunen L, Sennblad B, Mühleisen TW, Nöthen MM, Pechlivanis S, Baldassarre D, Gertow K, Humphries SE, Tremoli E, Klopp N, Meyer J, Steinbach G, Wennauer R, Eriksson JG, Mӓnnistö S, Peltonen L, Tikkanen E, Charpentier G, Eury E, Lobbens S, Gigante B, Leander K, McLeod O, Bottinger EP, Gottesman O, Ruderfer D, Blüher M, Kovacs P, Tonjes A, Maruthur NM, Scapoli C, Erbel R, Jöckel KH, Moebus S, de Faire U, Hamsten A, Stumvoll M, Deloukas P, Donnelly PJ, Frayling TM, Hattersley AT, Ripatti S, Salomaa V, Pedersen NL, Boehm BO, Bergman RN, Collins FS, Mohlke KL, Tuomilehto J, Hansen T, Pedersen O, Barroso I, Lannfelt L, Ingelsson E, Lind L, Lindgren CM, Cauchi S, Froguel P, Loos RJ, Balkau B, Boeing H, Franks PW, Gurrea AB, Palli D, van der Schouw YT, Altshuler D, Groop LC, Langenberg C, Wareham NJ, Sijbrands E, van Duijn CM, Florez JC, Meigs JB, Boerwinkle E, Gieger C, Strauch K, Metspalu A, Morris AD, Palmer CN, Hu FB, Thorsteinsdottir U, Stefansson K, Dupuis J, Morris AP, Boehnke M, McCarthy MI, Prokopenko I, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

Abstract
To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common SNVs. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion, and in adipocytes, monocytes and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

PMID: 28566273 [PubMed - as supplied by publisher]

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

Lancet Diabetes Endocrinol. 2017 May 26;:

Authors: Zewinger S, Kleber ME, Tragante V, McCubrey RO, Schmidt AF, Direk K, Laufs U, Werner C, Koenig W, Rothenbacher D, Mons U, Breitling LP, Brenner H, Jennings RT, Petrakis I, Triem S, Klug M, Filips A, Blankenberg S, Waldeyer C, Sinning C, Schnabel RB, Lackner KJ, Vlachopoulou E, Nygård O, Svingen GFT, Pedersen ER, Tell GS, Sinisalo J, Nieminen MS, Laaksonen R, Trompet S, Smit RAJ, Sattar N, Jukema JW, Groesdonk HV, Delgado G, Stojakovic T, Pilbrow AP, Cameron VA, Richards AM, Doughty RN, Gong Y, Cooper-DeHoff R, Johnson J, Scholz M, Beutner F, Thiery J, Smith JG, Vilmundarson RO, McPherson R, Stewart AFR, Cresci S, Lenzini PA, Spertus JA, Olivieri O, Girelli D, Martinelli NI, Leiherer A, Saely CH, Drexel H, Mündlein A, Braund PS, Nelson CP, Samani NJ, Kofink D, Hoefer IE, Pasterkamp G, Quyyumi AA, Ko YA, Hartiala JA, Allayee H, Tang WHW, Hazen SL, Eriksson N, Held C, Hagström E, Wallentin L, Åkerblom A, Siegbahn A, Karp I, Labos C, Pilote L, Engert JC, Brophy JM, Thanassoulis G, Bogaty P, Szczeklik W, Kaczor M, Sanak M, Virani SS, Ballantyne CM, Lee VV, Boerwinkle E, Holmes MV, Horne BD, Hingorani A, Asselbergs FW, Patel RS, GENIUS-CHD consortium, Krämer BK, Scharnagl H, Fliser D, März W, Speer T

Abstract
BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.
METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.
FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies.
INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

PMID: 28566218 [PubMed - as supplied by publisher]

The genetics of gout: towards personalised medicine?

BMC Med. 2017 May 31;15(1):108

Authors: Dalbeth N, Stamp LK, Merriman TR

Abstract
Over the last decade, there have been major advances in the understanding of the genetic basis of hyperuricaemia and gout as well as of the pharmacogenetics of urate-lowering therapy. Key findings include the reporting of 28 urate-associated loci, the discovery that ABCG2 plays a central role on extra-renal uric acid excretion, the identification of genes associated with development of gout in the context of hyperuricaemia, recognition that ABCG2 variants influence allopurinol response, and the impact of HLA-B*5801 testing in reducing the prevalence of allopurinol hypersensitivity in high-risk populations. These advances, together with the reducing cost of whole genome sequencing, mean that integrated personalised medicine approaches may soon be possible in clinical practice. Genetic data may inform assessment of disease prognosis in individuals with hyperuricaemia or established gout, personalised lifestyle advice, selection and dosing of urate-lowering therapy, and prevention of serious medication adverse effects. In this article, we summarise the discoveries from genome-wide association studies and discuss the potential for translation of these findings into clinical practice.

PMID: 28566086 [PubMed - in process]

Pharmacological management of non-alcoholic fatty liver disease: Atorvastatin versus pentoxifylline.

Exp Ther Med. 2017 May;13(5):2375-2381

Authors: Cioboată R, Găman A, Traşcă D, Ungureanu A, Docea AO, Tomescu P, Gherghina F, Arsene AL, Badiu C, Tsatsakis AM, Spandidos DA, Drakoulis N, Călina D

Abstract
In this study, we aimed to evaluate the efficacy of pentoxifylline and atorvastatin in the treatment of non-alcoholic fatty liver disease (NAFLD). The study included 98 patients with histologically confirmed NAFLD divided into 2 groups as follows: group I (57 dyslipidemic patients, receiving atorvastatin 20 mg/day and group II (41 non-dyslipidemic patients, treated with pentoxifylline, 800 mg/day). The present study was conducted for a mean of 32.8±3.4 weeks. For all patients, we determined the body mass index, a liver biopsy was performed, and we measured the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total cholesterol (TC) and triglycerides (TG) at the beginning and at the end of the study period. The NAFLD activity score (NAS) was used to evaluate the liver biopsies for steatosis, fibrosis and necroinflammation. The patients in group I exhibited a considerable reduction in ALT, AST, GGT, TC, AP and TG levels (P<0.0001). Histologically, there were no changes in fibrosis and necroinflammation, although the extent steatosis was reduced. The improvement in the ALT, AST and GGT values (P<0.05) in group II were similar to those in group I; however, no statistically significant decrease was noted in the levels of ALP, TC and TG in this group. Our results thus demonstrated that atorvastatin attenuated steatosis and improved liver function parameters in patients with NAFLD associated with dyslipidemia. Similar results were obtained in the non-dyslipidemic patients administered pentoxifylline.

PMID: 28565851 [PubMed - in process]

High Efficacy of Primaquine Treatment for Plasmodium vivax in Western Thailand.

Am J Trop Med Hyg. 2016 Nov 02;95(5):1086-1089

Authors: Longley RJ, Sripoorote P, Chobson P, Saeseu T, Sukasem C, Phuanukoonnon S, Nguitragool W, Mueller I, Sattabongkot J

Abstract
Primaquine is the only licensed antimalarial drug that is capable of clearing dormant Plasmodium vivax liver stage parasites. To date, there is no clear evidence of resistance of the liver stage parasite against this drug, because of the difficulty in ascertaining the cause of recurrent infection. We followed 52 Thai P. vivax patients for 9 months after directly observed treatment of 15 mg primaquine daily for 14 days. Blood samples taken at 2-4 weekly intervals were assessed by microscopy and polymerase chain reaction (PCR) for the presence of parasites. Only four of 52 (7.7%) volunteers had recurrent P. vivax infections, all at least 8 weeks after treatment. This demonstrates that primaquine retains a high efficacy in this population. Although a risk of new infections could not be ruled out, parasite genotyping at two polymorphic markers suggested a high probability of late relapsing infections in these volunteers. Continued monitoring of primaquine efficacy in this region is advisable.

PMID: 27601524 [PubMed - indexed for MEDLINE]

Gene Set Enrichment Analyses: lessons learned from the heart failure phenotype.

BioData Min. 2017;10:18

Authors: Tragante V, Gho JMIH, Felix JF, Vasan RS, Smith NL, Voight BF, CHARGE Heart Failure Working Group, Palmer C, van der Harst P, Moore JH, Asselbergs FW

Abstract
BACKGROUND: Genetic studies for complex diseases have predominantly discovered main effects at individual loci, but have not focused on genomic and environmental contexts important for a phenotype. Gene Set Enrichment Analysis (GSEA) aims to address this by identifying sets of genes or biological pathways contributing to a phenotype, through gene-gene interactions or other mechanisms, which are not the focus of conventional association methods.
RESULTS: Approaches that utilize GSEA can now take input from array chips, either gene-centric or genome-wide, but are highly sensitive to study design, SNP selection and pruning strategies, SNP-to-gene mapping, and pathway definitions. Here, we present lessons learned from our experience with GSEA of heart failure, a particularly challenging phenotype due to its underlying heterogeneous etiology.
CONCLUSIONS: This case study shows that proper data handling is essential to avoid false-positive results. Well-defined pipelines for quality control are needed to avoid reporting spurious results using GSEA.

PMID: 28559929 [PubMed]

Adverse Drug Reactions in Children: The Double-Edged Sword of Therapeutics.

Clin Pharmacol Ther. 2017 Jun;101(6):725-735

Authors: Elzagallaai AA, Greff M, Rieder MJ

Abstract
Adverse drug reactions (ADRs) represent a major health problem worldwide, with high morbidity and mortality rates. ADRs are classified into Type A (augmented) and Type B (bizarre) ADRs, with the former group being more common and the latter less common but often severe and clinically more problematic due to their unpredictable nature and occurrence at any dose. Pediatric populations are especially vulnerable to ADRs due to the lack of data for this age group from the drug development process and because of the wide use of off-label and unlicensed use of drugs. Children are more prone to specific types of ADRs because of the level of maturity of body systems involved in absorption, metabolism, transportation, and elimination of drugs. This state-of-the-art review provides an overview of definitions, classifications, epidemiology, and pathophysiology of ADRs and discusses the available evidence for related risk factors and causes of ADRs in the pediatric population.

PMID: 28295234 [PubMed - indexed for MEDLINE]

The Influence of Genotype Information on Psychiatrists' Treatment Recommendations: More Experienced Clinicians Know Better What to Ignore.

Value Health. 2017 Jan;20(1):126-131

Authors: McMichael AJ, Boeri M, Rolison JJ, Kane J, O'Neill FA, Scarpa R, Kee F

Abstract
BACKGROUND: This study applies attribute nonattendance to medical decision making. We aimed to demonstrate how this type of analysis can be used in medical decision making to assess whether psychiatrists were influenced in their treatment recommendations by information on the genotype of a patient, despite knowing the patient's response to treatment as measured by the Positive and Negative Syndrome Scale. A patient's genetic information may be used to predict their response to therapy; such information, however, becomes redundant, and should not influence decisions, once a clinician knows the patient's actual response to treatment.
METHODS: Sixty-seven psychiatrists were presented with patients' pre- or post-treatment scores on the Positive and Negative Syndrome Scale for two hypothetical treatments for schizophrenia. Psychiatrists were also informed whether the patient possessed a genotype linked to hyper-responsiveness to one of the treatments, and were asked to recommend one of these two treatments. Attribute nonattendance assessed whether the information on genotype influenced psychiatrists' treatment recommendations.
RESULTS: Years of experience predicted whether psychiatrists were influenced by the genetic information. Psychiatrists with 1 year or less of experience had a 46% probability of considering genetic information, whereas psychiatrists with at least 15 years of experience had a lower probability (7%).
CONCLUSIONS: Psychiatrists and other clinicians should be cautious about allowing a patient's genetic information to carry unnecessary weight in their clinical decision making.

PMID: 28212953 [PubMed - indexed for MEDLINE]

Spatial regulation of the KH domain RNA-binding protein Rnc1 mediated by a Crm1-independent nuclear export system in Schizosaccharomyces pombe.

Mol Microbiol. 2017 May;104(3):428-448

Authors: Satoh R, Matsumura Y, Tanaka A, Takada M, Ito Y, Hagihara K, Inari M, Kita A, Fukao A, Fujiwara T, Hirai S, Tani T, Sugiura R

Abstract
RNA-binding proteins (RBPs) play important roles in the posttranscriptional regulation of gene expression, including mRNA stability, transport and translation. Fission yeast rnc1(+) encodes a K Homology (KH)-type RBP, which binds and stabilizes the Pmp1 MAPK phosphatase mRNA thereby suppressing the Cl(-) hypersensitivity of calcineurin deletion and MAPK signaling mutants. Here, we analyzed the spatial regulation of Rnc1 and discovered a putative nuclear export signal (NES)Rnc1 , which dictates the cytoplasmic localization of Rnc1 in a Crm1-independent manner. Notably, mutations in the NESRnc1 altered nucleocytoplasmic distribution of Rnc1 and abolished its function to suppress calcineurin deletion, although the Rnc1 NES mutant maintains the ability to bind Pmp1 mRNA. Intriguingly, the Rnc1 NES mutant destabilized Pmp1 mRNA, suggesting the functional importance of the Rnc1 cytoplasmic localization. Mutation in Rae1, but not Mex67 deletion or overproduction, induced Rnc1 accumulation in the nucleus, suggesting that Rnc1 is exported from the nucleus to the cytoplasm via the mRNA export pathway involving Rae1. Importantly, mutations in the Rnc1 KH-domains abolished the mRNA-binding ability and induced nuclear localization, suggesting that Rnc1 may be exported from the nucleus together with its target mRNAs. Collectively, the functional Rae1-dependent mRNA export system may influence the cytoplasmic localization and function of Rnc1.

PMID: 28142187 [PubMed - indexed for MEDLINE]

Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits.

Genetics. 2017 Feb;205(2):979-992

Authors: Traglia M, Bseiso D, Gusev A, Adviento B, Park DS, Mefford JA, Zaitlen N, Weiss LA

Abstract
Common diseases often show sex differences in prevalence, onset, symptomology, treatment, or prognosis. Although studies have been performed to evaluate sex differences at specific SNP associations, this work aims to comprehensively survey a number of complex heritable diseases and anthropometric traits. Potential genetically encoded sex differences we investigated include differential genetic liability thresholds or distributions, gene-sex interaction at autosomal loci, major contribution of the X-chromosome, or gene-environment interactions reflected in genes responsive to androgens or estrogens. Finally, we tested the overlap between sex-differential association with anthropometric traits and disease risk. We utilized complementary approaches of assessing GWAS association enrichment and SNP-based heritability estimation to explore explicit sex differences, as well as enrichment in sex-implicated functional categories. We do not find consistent increased genetic load in the lower-prevalence sex, or a disproportionate role for the X-chromosome in disease risk, despite sex-heterogeneity on the X for several traits. We find that all anthropometric traits show less than complete correlation between the genetic contribution to males and females, and find a convincing example of autosome-wide genome-sex interaction in multiple sclerosis (P = 1 × 10(-9)). We also find some evidence for hormone-responsive gene enrichment, and striking evidence of the contribution of sex-differential anthropometric associations to common disease risk, implying that general mechanisms of sexual dimorphism determining secondary sex characteristics have shared effects on disease risk.

PMID: 27974502 [PubMed - indexed for MEDLINE]

Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2.

Exp Hematol. 2016 Nov;44(11):1072-1084

Authors: Buscarlet M, Tessier A, Provost S, Mollica L, Busque L

Abstract
Epigenetic alteration may play a role in age-associated dysfunction of stem cells and predispose to the development of hematological cancers. We analyzed global levels of hematopoietic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in a cross-sectional study comprising 198 unrelated individuals from four age categories (neonates, 25-30, 70-75, and >90 years old) by liquid chromatography-electrospray ionization-tandem mass spectrometry with multiple reaction monitoring. X-chromosome inactivation (XCI) ratios and telomere length (TL) were measured in all individuals by polymerase chain reaction. Sequencing of epigenetic regulator genes (including TET2, DNMT3A, ASXL1, IDH1, IDH2, and WT1) was performed in the two older subcohorts. We found that global 5hmC levels declined with age in human blood cells (27.5% reduction from birth to old age, p < 0.0005). The levels of 5mC underwent a more modest reduction (2.4% drop) between newborns and the elderly (p < 0.0005). Low 5hmC was associated with increased skewing of XCI (age-adjusted p = 0.0304) and reduced TL (age-adjusted p = 0.0354), both surrogate markers of clonal dominance. Of the 100 individuals over the age of 70, 16 had somatic mutations in TET2, 14 in DNMT3A, and none in IDH1, IDH2, or WT1. Individuals with TET2 mutations had significantly lower 5hmC (relative to unmutated individuals), whereas DNMT3A-mutated subjects did not. However, mutations in TET2 cannot account solely for the decline in 5hmC levels observed with aging because unmutated older individuals also had lower 5hmC levels compared with younger individuals. This suggests that the age-associated decline in 5hmC is multifactorial. Larger prospective studies are needed to determine whether 5hmC reduction is a biomarker of hematological cancer development.

PMID: 27475703 [PubMed - indexed for MEDLINE]

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

Cancer Epidemiol. 2017 May 26;49:46-52

Authors: Rivu SF, Apu MNH, Shabnaz S, Nahid NA, Islam MR, Al-Mamun MMA, Nahar Z, Rabbi SNI, Ahmed MU, Islam MS, Hasnat A

Abstract
Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR=2.58, 95% CI=1.77-3.77, p<0.05) and Pro/Pro mutant homozygosity (adjusted OR=2.92, 95% CI=1.78-4.78, p<0.05) along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR=2.70, 95% CI=1.90-3.82, p<0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p<0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR=2.02, 95% CI=1.42-2.87, p<0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.

PMID: 28554075 [PubMed - as supplied by publisher]

MicroRNA Hsa-miR-370-3p Suppresses the Expression and Induction of CYP2D6 by Facilitating mRNA Degradation.

Biochem Pharmacol. 2017 May 25;:

Authors: Zeng L, Chen Y, Wang Y, Yu LR, Knox B, Chen J, Shi T, Chen S, Ren Z, Guo L, Wu Y, Liu D, Huang K, Tong W, Yu D, Ning B

Abstract
Cytochrome P450 2D6 (CYP2D6) participates in the metabolism of approximately 20-25% of prescribed drugs. Genetic polymorphisms influence the expression and/or activity of CYP2D6, and inter-individual differences in drug activation and elimination caused by CYP2D6 genetic variants were reported. However, little is known about the potential modulation of CYP2D6 expression by microRNAs (miRNAs). In the current study, by using in silico prediction of the stabilities of miRNA/mRNA complexes, we screened 38 miRNA candidates that may interact with the transcript of CYP2D6. An inverse correlation between the expression of miRNA hsa-miR-370-3p and the expression of CYP2D6 was observed in human liver tissue samples. Electrophoretic mobility shift assays confirmed that hsa-miR-370-3p was able to directly bind to its cognate target within the coding region of the CYP2D6 transcript. The transfection of hsa-miR-370-3p mimics into the HepG2(CYP2D6) cell line, a genetically modified cell line that overexpresses exogenous CYP2D6, was able to suppress the expression of CYP2D6 significantly at both mRNA and protein levels. The transfection of hsa-miR-370-3p mimics was also able to inhibit endogenous mRNA expression and/or protein production of CYP2D6 in HepaRG cells. Furthermore, in HepaRG, HepG2, and Huh7 cells, dexamethasone-induced expression of CYP2D6 was inhibited by hsa-miR-370-3p mimics. To investigate whether the miRNA mediated suppression is caused by inhibiting protein translation or promoting mRNA degradation, an actinomycin D assay was used to measure the stability of CYP2D6 transcripts. The results indicated that hsa-miR-370-3p mimics facilitated significantly the degradation of CYP2D6 mRNA. In addition, proteomics analyses of proteins isolated from the miRNA/mRNA/protein complex suggested that a group of multifunctional proteins facilitated the interaction between hsa-miR-370-3p and CYP2D6, thereby promoting mRNA degradation.

PMID: 28552654 [PubMed - as supplied by publisher]

Thiopurine S-Methyltransferase as a Pharmacogenetic Biomarker: Significance of Testing and Review of Major Methods.

Cardiovasc Hematol Agents Med Chem. 2017 May 28;:

Authors: Asadov C, Aliyeva G, Mustafayeva K

Abstract
Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at the high risk of severe adverse drug reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity. However, TPMT-deficient patients can successfully be treated with decreased thiopurine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience in an application of a pharmacogenetic testing in clinical settings. 4 TPMT (*2,*3A, *3B, *3C) alleles are known to account for 80-95% of a decreased enzyme activity, and therefore, identifying the presence of these alleles supported by phenotypic measurement of the enzyme activity can reveal patient's TPMT status. Evaluation of the levels of thiopurine metabolites further supports the practice of appropriate dose adjustment by providing the efficient monitoring of drug cytotoxicity. We hereby review the thiopurine pharmacogenetics and the methods applied in common practice to evaluate patient's TPMT status.

PMID: 28552060 [PubMed - as supplied by publisher]

ABCB1 Polymorphisms and Cold Pressor Pain Responses: Opioid-Dependent Patients on Methadone Maintenance Therapy.

Nurs Res. 2017 Mar/Apr;66(2):134-144

Authors: Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, Tan SC, Mohamad N, Ismail R

Abstract
BACKGROUND: Methadone is a substrate of the P-glycoprotein efflux transporter, which is encoded by ABCB1 (MDR1), and thus, ABCB1 polymorphisms may influence the transport of methadone at the blood-brain barrier, affecting its adverse effects.
OBJECTIVES: This study investigated the association between ABCB1 polymorphisms and cold pressor pain responses among opioid-dependent patients on methadone maintenance therapy (MMT).
METHODS: Malay male opioid-dependent patients receiving MMT (n = 148) were recruited. Cold pressor pain responses (pain threshold, pain tolerance, and pain intensity) were measured at 0, 2, 4, 8, 12, and 24 hours post-methadone dose. DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms including 1236C>T (rs1128503), 2677G>T/A (rs2032582), and 3435C>T (rs1045642) using the allelic discrimination real-time polymerase chain reaction. Repeated-measure analysis of variance between-group analysis was used to compare the three cold pressor pain responses and ABCB1 polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) according to genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes.
RESULTS: Patients with 2677 GG or 2677G allele had the lowest pain threshold compared with 2677G>T/A genotypes or alleles (p = .007 and .002, respectively). Haplotype analysis showed a significant association between ABCB1 haplotypes and pain threshold (p = .02). Patients with 2677G allele had the lowest pain tolerance compared to those with 2677T and 2677A alleles (2677G < 2677T < 2677A allele carriers; p = .05). In terms of pain intensity scores, patients with 2677 GG or 2677G allele had the highest scores compared to other 2677G>T/A genotypes or alleles (p = .04 and .008, respectively). Haplotype analysis revealed a significant difference between patients with CGC haplotype and those without this haplotype (p = .02).
DISCUSSION: To the best of our knowledge, this study provides the first evidence that ABCB1 polymorphisms are associated with cold pressor pain responses among Malay male patients with opioid dependence on MMT. The results may provide an initial prediction on heightened pain sensitivity or hyperalgesia for individuals who are carriers of the ABCB1 polymorphisms.

PMID: 28252574 [PubMed - indexed for MEDLINE]

Designer Drugs 2.0.

Clin Pharmacol Ther. 2017 Feb;101(2):152-157

Authors: Huestis MA, Tyndale RF

Abstract
This "Designer Drugs 2.0" issue of Clinical Pharmacology & Therapeutics focuses on novel psychoactive substances, primarily cannabinoids and cathinones, and the repurposing of established psychoactive compounds (e.g., modafinil, psilocybin, lysergic acid diethylamide, and 3,4-methylenedioxymethamphetamine) that simultaneously offer new pharmacotherapies and pose serious health problems. Novel psychoactive substances were initially used as potent tools to investigate endogenous neurotransmitter systems; for example, synthetic cannabinoids have much higher potency than Δ9-tetrahydrocannabinol at the cannabinoid receptors. However, they are now being used illicitly as well as being tested for their efficacy in numerous clinical indications. Likewise, previously established psychoactive drugs are being repurposed as treatments for a wide variety of indications where currently approved medications are ineffective. This set of papers examines the arising problems associated with designer drugs (e.g., adverse events, psychosis, rapid new synthesis, abuse liability testing, internet sales, scheduling) as well as the potential therapeutic promises in areas as diverse as cognition enhancement, exercise-mimetics, epilepsy, multiple sclerosis, and posttraumatic stress disorder.

PMID: 28084644 [PubMed - indexed for MEDLINE]