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"systems biology"

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Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.

Clin Pharmacol Ther. 2017 Apr 05;:

Authors: Sundelin EI, Gormsen LC, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen MM, Brøsen K, Frøkiaer J, Jessen N

Abstract
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. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans. This article is protected by copyright. All rights reserved.

PMID: 28380657 [PubMed - as supplied by publisher]

Worldwide distribution of cytochrome P450 alleles: A meta-analysis of population-scale sequencing projects.

Clin Pharmacol Ther. 2017 Apr 05;:

Authors: Zhou Y, Ingelman-Sundberg M, Lauschke VM

Abstract
Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity towards a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole-genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this data set with population-specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this data set into spectra of predicted functional variability in the respective populations and discuss the implications for population-adjusted pharmacological treatment strategies. This article is protected by copyright. All rights reserved.

PMID: 28378927 [PubMed - as supplied by publisher]

Vitamin Pharmacogenomics: New Insight into Individual Differences in Diseases and Drug Responses.

Genomics Proteomics Bioinformatics. 2017 Apr 01;:

Authors: He HY, Liu MZ, Zhang YL, Zhang W

Abstract
Vitamins are vital to sustain normal physiological function, metabolism, and growth for all living organisms. Being an integral component of coenzyme, vitamins can affect the catalytic activities of many enzymes and the expression of drug transporters. Genetic variations in metabolism and/or transporter genes of drugs can influence the exposure of the human body to drugs and/or their active metabolites, thus contributing to the variations in drug responses and toxicities. Nonetheless, pharmacogenomics studies on nutrients have been rarely summarized. In this article, we reviewed recent progress on vitamin pharmacogenomics, for a better understanding on the influence of vitamin-related gene polymorphisms on inter-individual differences in diseases and drug efficacy and safety.

PMID: 28377107 [PubMed - as supplied by publisher]

Exome-based genome-wide association study and risk assessment using genetic risk score to prostate cancer in the Korean population.

Oncotarget. 2017 Mar 24;:

Authors: Oh JJ, Lee SJ, Hwang JY, Kim D, Lee SE, Hong SK, Ho JN, Yoon S, Sung J, Kim WJ, Byun SS

Abstract
PURPOSE: To investigate exome-wide genetic variants associated with prostate cancer (PCa) in Koreans and evaluate the discriminative ability by the genetic risk score (GRS).
PATIENTS AND METHODS: We prospectively recruited 1,001 PCa cases from a tertiary hospital and conducted a case-control study including 2,641 healthy men (Stage I). Participants were analyzed using HumanExome BeadChip. For the external validation, additionally enrolled 514 PCa cases and 548 controls (independent cohort) were analyzed for the identified single nucleotide polymorphisms (SNPs) of Stage I (Stage II). The GRS was calculated as a non-weighted sum of the risk allele counts and investigated for accuracy of prediction of PCa.
RESULTS: the mean age was 66.3 years, and the median level of prostate specific antigen (PSA) was 9.19 ng/ml in PCa cases. In Stage I, 4 loci containing 5 variants (rs1512268 on 8p21.2; rs1016343 and rs7837688 on 8q24.21; rs7501939 on 17q12, and rs2735839 on 19q13.33) were confirmed to reach exome-wide significance (p<8.3x10-7). In Stage II, the mean GRS was 4.23 ± 1.44 for the controls and 4.78 ± 1.43 for the cases. As a reference to GRS 4, GRS 6, 7 and 8 showed a statistically significant risk of PCa (OR=1.85, 2.11 and 3.34, respectively).
CONCLUSIONS: The five variants were validated to associate with PCa in firstly performed exome-wide study in Koreans. The addition of individualized calculated GRS effectively enhanced the accuracy of prediction. These results need to be validated in future studies.

PMID: 28380453 [PubMed - as supplied by publisher]

Identification of STXBP2 as a novel susceptibility locus for myocardial infarction in Japanese individuals by an exome-wide association study.

Oncotarget. 2017 Mar 23;:

Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M

Abstract
We performed exome-wide association studies to identify genetic variants-in particular, low-frequency variants with a large effect size-that confer susceptibility to coronary artery disease or myocardial infarction in Japanese. The exome-wide association studies were performed with 12,698 individuals (3488 subjects with coronary artery disease including 2438 with myocardial infarction, 9210 controls) and with the use of the Illumina HumanExome-12 DNA Analysis or Infinium Exome-24 BeadChip. The relation of allele frequencies for 41,339 single nucleotide polymorphisms that passed quality control to coronary artery disease or myocardial infarction was examined with Fisher's exact test. The exome-wide association study for coronary artery disease revealed that 126 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia showed that six of these polymorphisms were related (P < 0.01) to coronary artery disease, but none was significantly (P < 9.92 × 10-5) associated with this condition. The exome-wide association study for myocardial infarction revealed that 114 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for covariates revealed that nine of these polymorphisms were related (P < 0.01) to myocardial infarction. Among these nine polymorphisms, rs188212047 [G/T (L212F)] of STXBP2 was significantly (dominant model; P = 4.84 × 10-8; odds ratio, 2.94) associated with myocardial infarction. STXBP2 may thus be a novel susceptibility locus for myocardial infarction in Japanese.

PMID: 28380445 [PubMed - as supplied by publisher]

Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.

Eur J Hum Genet. 2017 Apr 05;:

Authors: Brien A, Marshall CR, Blaser S, Ray PN, Yoon G

Abstract
Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.European Journal of Human Genetics advance online publication, 5 April 2017; doi:10.1038/ejhg.2017.39.

PMID: 28378817 [PubMed - as supplied by publisher]

A genome-wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study.

Genet Epidemiol. 2017 Apr 05;:

Authors: Gao C, Hsu FC, Dimitrov LM, Okut H, Chen YI, Taylor KD, Rotter JI, Langefeld CD, Bowden DW, Palmer ND

Abstract
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10(-12) ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10(-7) , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10(-4) , LOD = 3.67), apolipoprotein B (P = 1.39 × 10(-3) , LOD = 4.64), and total cholesterol (P = 1.35 × 10(-2) , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.

PMID: 28378447 [PubMed - as supplied by publisher]

Detecting PKD1 variants in polycystic kidney disease patients by single-molecule long-read sequencing.

Hum Mutat. 2017 Apr 04;:

Authors: Borràs DM, Vossen R, Liem M, Buermans HP, Dauwerse H, van Heusden D, Gansevoort RT, den Dunnen JT, Janssen B, Peters DJ, Losekoot M, Anvar SY

Abstract
A genetic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is challenging due to allelic heterogeneity, high GC-content, and homology of the PKD1 gene with six pseudogenes. Short-read next-generation sequencing (NGS) approaches, such as whole genome (WGS) and whole exome sequencing (WES), often fail at reliably characterizing complex regions such as PKD1. However, long-read single-molecule sequencing has been shown to be an alternative strategy that could overcome PKD1 complexities and discriminate between homologous regions of PKD1 and its pseudogenes. In this study, we present the increased power of resolution for complex regions using long-read sequencing to characterize a cohort of 19 patients with ADPKD. Our approach provided high sensitivity in identifying PKD1 pathogenic variants, diagnosing 94.7% of the patients. We show that reliable screening of ADPKD patients in a single test without interference of PKD1 homologous sequences, commonly introduced by residual amplification of PKD1 pseudogenes, by direct long-read sequencing is now possible. This strategy can be implemented in diagnostics and is highly suitable to sequence and resolve complex genomic regions that are of clinical relevance. This article is protected by copyright. All rights reserved.

PMID: 28378423 [PubMed - as supplied by publisher]

[Genetic methods for analysis of autoinflammatory diseases].

Z Rheumatol. 2017 Apr 04;:

Authors: Bienias M, König N, Wolf C, Kretschmer S, Rösen-Wolff A, Berner R, Tüngler V, Lee-Kirsch MA

Abstract
Over the past years the phenotypic and genetic spectrum of autoinflammatory diseases has continuously increased. Moreover, several monogenic autoinflammatory disorders have now been identified where febrile episodes are not among the leading symptoms and which can be accompanied by autoimmune phenomena and susceptibility to infections. Autoinflammatory conditions that are characterized by uncontrolled activity of cytokines, such as interleukin-1 beta (IL1β), tumor necrosis factor alpha (TNF-α) and type 1 interferons (1-IFN), are amenable to specific therapeutic interventions. Thus, identification of the underlying genetic cause is important. During diagnostic work-up, genetic testing of a patient with autoinflammation should be carried out depending on the clinical presentation. If a distinct disorder is suspected, sequencing of the causative gene should be performed. Genetic tests using next generation sequencing (NGS), such as panel sequencing, exome sequencing and array comparative genomic hybridization (CGH) can be carried out if symptoms cannot be assigned to a specific disease entity.

PMID: 28378116 [PubMed - as supplied by publisher]

A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family.

Ann Saudi Med. 2017 Mar-Apr;37(2):148-153

Authors: Naseer MI, Rasool M, Sogaty S, Chaudhary RA, Mansour HM, Chaudhary AG, Abuzenadah AM, Al-Qahtani MH

Abstract
BACKGROUND: Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease.
OBJECTIVE: To study the genetic defect in a consanguineous Saudi family with primary microcephaly.
DESIGN: Cross-sectional clinical genetics study of a Saudi family.
SETTING: Medical genomics research center.
PATIENTS AND METHODS: Blood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impedi-ments and seizures.
MAIN OUTCOME MEASURE(S): Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly.
RESULTS: The exome variant analysis identified a novel missense mutation (c.3878C > A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic.
CONCLUSIONS: Functional impairment of the WDR62 gene can lead to severe neurodevelopmental de-fects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype.
LIMITATIONS: Mutation was identified in a single family.

PMID: 28377545 [PubMed - in process]

Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder.

Eur J Med Genet. 2017 Apr 01;:

Authors: Dai Z, Whitt Z, Mighion LC, Pontoglio A, Bean LJ, Colombo R, Hegde M

Abstract
To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.

PMID: 28377322 [PubMed - as supplied by publisher]

Novel Presentation of Rosai-Dorfman Histiocytosis With a Prolonged Course of Cranial and Peripheral Neuropathies.

Pediatr Neurol. 2017 Mar 08;:

Authors: Tripathi R, Serajee F, Jiang H, Huq AH

Abstract
BACKGROUND: Rosai-Dorfman disease is a form of histiocytosis affecting the systemic lymph nodes. Intracranial Rosai-Dorfman disease is rare and presents with extra-parenchymal or intraparenchymal proliferative mass lesions. Cranial neuropathy has not been reported in Rosai-Dorfman disease except when caused by mass effect by an adjacent lesion.
PATIENT DESCRIPTION: We describe a girl with Rosai-Dorfman disease who presented with peripheral and multiple cranial neuropathies. Detailed clinical, immunologic, neurophysiology, imaging, and genetic studies were performed. She had a prolonged course but recovered fully after immune therapies. She had increased titers of striated muscle and smooth muscle antibodies. Imaging studies revealed contrast enhancement of cranial nerves and striated muscles. Demyelination was evident in the nerve twigs from muscle biopsy. Exome sequencing did not reveal a genetic mutation.
CONCLUSIONS: Most patients with Rosai-Dorfman disease have a benign course, but severe neurological dysfunction due to bulbar involvement and cranial and peripheral neuropathies may occur. Treatment with immunoglobulin and steroids may be of benefit.

PMID: 28377039 [PubMed - as supplied by publisher]

Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis.

Clin Microbiol Infect. 2017 Apr 01;:

Authors: Horita N, Shibata Y, Watanabe H, Namkoong H, Kaneko T

Abstract
OBJECTIVES: Compare the effectiveness and safety of antipseudomonal beta-lactam empiric monotherapy for febrile neutropenia by network meta-analysis.
METHODS: The searches using Pubmed, Cochrane CENTRAL, EMBASE, and Web of Science Core Collection were carried out in June 2016. English articles, non-English articles, full-length articles, short articles, and conference abstracts were allowed. Eligible trial design was a parallel-group individual randomization. We included febrile neutropenia adult and pediatric patients undergoing chemotherapy for either solid tumors or hematological malignanciesand treated with intravenous antipseudomonal beta-lactams for initial empiric therapy. Protocol was registered with PROSPERO ID 42016043377.
RESULTS: Of 1275 articles detected by the search, 50 studies with 10872 patients were finally included. Among guideline-recommended Cefepime, Meropenem, Imipenem/Cilastatin, Piperacillin/Tazobactam, and Ceftazidime; Imipenem/Cilastatin showed the highest odds of treatment success without modification, which was the primary endpoint, based on the random-effect model network analysis. Ceftazidime was related to lower treatment success rate without modification compared to Imipenem/Cilastatin with odds ratio (OR) of 0.71 (95%CI 0.57-0.89, P = 0.006). Imipenem/Cilastatin showed the lowest odds of all-cause death. Patients treated by Cefepime had higher risk for all-cause death compared to those treated by Imipenem/Cilastatin (OR 2.05, 95%CI 1.11-3.78, P = 0.029). Any adverse event was significantly more prevalent in Imipenem/Cilastatin arm; however, there was no difference concerning adverse event leading to discontinuation.
CONCLUSIONS: Imipenem/Cilastatin, Piperacillin/Tazobactam, and Meropenem may be reasonable first-choice medications for empiric therapy of febrile neutropenia.

PMID: 28377312 [PubMed - as supplied by publisher]

Adverse drug reactions among patients admitted with infectious diseases at a Brazilian hospital.

Rev Soc Bras Med Trop. 2016 Nov-Dec;49(6):763-767

Authors: Saavedra PA, Meiners MM, Lopes LC, Silva EV, Silva DL, Noronha EF, Toledo MI

Abstract
INTRODUCTION: : Despite the therapeutic benefits of drugs, adverse drug reactions (ADRs) occur. Method: We assessed a series of suspected ADRs identified from notifications and intensive monitoring of inpatients from March 2013 to March 2014.
RESULTS:: Skin reactions predominated (31%). Systemic anti-infective agents were implicated in 16 (72%) reactions. Fifteen (68%) ADRs were classified as possible. The implicated drug was not correctly identified by the healthcare team in 12 cases.
CONCLUSIONS: : Some reactions were not correctly attributed to the causative drug(s), suggesting that the use of a validated evaluation method can promote successful identification of causal links between ADRs and drugs.

PMID: 28001225 [PubMed - indexed for MEDLINE]

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

Assay Drug Dev Technol. 2017 Apr 05;:

Authors: Pulley JM, Shirey-Rice JK, Lavieri RR, Jerome RN, Zaleski NM, Aronoff DM, Bastarache L, Niu X, Holroyd KJ, Roden DM, Skaar EP, Niswender CM, Marnett LJ, Lindsley CW, Ekstrom LB, Bentley AR, Bernard GR, Hong CC, Denny JC

Abstract
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.

PMID: 28379727 [PubMed - as supplied by publisher]