Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight. 2020 Apr 23;5(8):

Authors: Portelli MA, Dijk FN, Ketelaar ME, Shrine N, Hankinson J, Bhaker S, Grotenboer NS, Obeidat M, Henry AP, Billington CK, Shaw D, Johnson SR, Pogson ZE, Fogarty A, McKeever TM, Nickle DC, Bossé Y, van den Berge M, Faiz A, Brouwer S, Vonk JM, de Vos P, Brandsma CA, Vermeulen CJ, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Niven R, Simpson A, Blakey JD, Tobin MD, Postma DS, Hall IP, Wain LV, Nawijn MC, Brightling CE, Koppelman GH, Sayers I

Abstract
The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

PMID: 32324168 [PubMed - as supplied by publisher]

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines.

Front Cell Infect Microbiol. 2020;10:139

Authors: Azad AK, Lloyd C, Sadee W, Schlesinger LS

Abstract
Universal approaches to the prevention and treatment of human diseases fail to take into account profound immune diversity resulting from genetic variations across populations. Personalized or precision medicine takes into account individual lifestyle, environment, and biology (genetics and immune status) and is being adopted in several disease intervention strategies such as cancer and heart disease. However, its application in infectious diseases, particularly global diseases such as tuberculosis (TB), is far more complex and in a state of infancy. Here, we discuss the impact of human genetic variations on immune responses and how they relate to failures seen in current TB diagnostic, therapy, and vaccine approaches across populations. We offer our perspective on the challenges and potential for more refined approaches going forward.

PMID: 32322562 [PubMed - in process]

Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A.

Scientifica (Cairo). 2020;2020:8329286

Authors: Mustafa MI, Murshed NS, Abdelmoneim AH, Abdelmageed MI, Elfadol NM, Makhawi AM

Abstract
Background: Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging SNPs in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools.
Methods: The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.
Results: Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115).
Conclusions: In this study, the impact of nsSNPs in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

PMID: 32322428 [PubMed]

Genetic Editing and Pharmacogenetics in Current And Future Therapy Of Neurocognitive Disorders.

Curr Alzheimer Res. 2020 Apr 22;:

Authors: Prendecki M, Kowalska M, Toton E, Kozubski W

Abstract
Dementia is an important issue in western societies, and in the following years, this problem will also rise in the developing regions, such as Africa and Asia. The most common types of dementia in adults are Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and vascular dementia (VaD), of which, AD accounts for more than half of the cases. The most prominent symptom of AD is cognitive impairment, currently treated with four drugs: donepezil, rivastigmine, and galantamine, enhancing cholinergic transmission; as well as memantine, protecting neurons against glutamate excitotoxicity. Despite ongoing efforts, no new drugs in the treatment of AD have been registered for the last ten years, thus multiple studies have been conducted on genetic factors affecting the efficacy of antidementia pharmacotherapy. The researchers investigate the effects of variants in multiple genes, such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22A1/2/5, SLC47A1, UGT1A6, UGT1A9 and UGT2B7, associated with numerous pathways: the development of pathological proteins, formation and metabolism of acetylcholine, transport, metabolism and excretion of antidementia drugs and transcription factors regulating the expression of genes responsible for metabolism and transport of drugs. The most promising results have been demonstrated for APOE E4, dementia risk variant, BCHE-K, reduced butyrylcholinesterase activity variant, and CYP2D6 UM, ultrarapid hepatic metabolism. Further studies investigate the possibilities of the development of emerging drugs or genetic editing by CRISPR/Cas9 for causative treatment. In conclusion, the pharmacogenetic studies on dementia diseases may improve the efficacy of pharmacotherapy in some patients with beneficial genetic variants, at the same time, identifying the carriers of unfavorable alleles, the potential group of novel approaches to the treatment and prevention of dementia.

PMID: 32321403 [PubMed - as supplied by publisher]

[Genetics of Posttraumatic Stress Disorder (PTSD)].

Psychother Psychosom Med Psychol. 2019 Jul;69(7):266-274

Authors: Weiss EM, Parson W, Niederstätter H, Marksteiner J, Lampe A

Abstract
Post-traumatic stress disorder (PTSD) is a mental disorder following a severe traumatic experience and is characterized by high rates of comorbidity with related psychiatric disorders. However, even for individuals experiencing the same trauma, there is considerable inter-individual variability in the risk of PTSD, and this is largely thought to be determined by biological processes, such as genetic predisposition and epigenetic mechanism. In this review we will summarize recent research on genetics of PTSD, primarily focusing on candidate gene-association studies, targeting on functional genetic variants in the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis. In addition, results from recent genome-wide association studies (GWAS) will be reported and we will highlight the interplay of genetic factors with environmental factors, based on evidence from gene-environment interaction analysis and studies on the epigenetic regulation of PTSD. Finally, we will provide a brief outlook towards the potential and perspectives of pharmaco-genetic studies.

PMID: 30025422 [PubMed - indexed for MEDLINE]

Different Plasmodium falciparum clearance times in two Malian villages following artesunate monotherapy.

Int J Infect Dis. 2020 Apr 19;:

Authors: Kone A, Sissoko S, Fofana B, Sangare CO, Dembele D, Haidara AS, Diallo N, Coulibaly A, Traore A, Toure S, Haidara K, Sanogo K, Sagara I, Beshir KB, Gil JP, Doumbo OK, Djimde AA

Abstract
BACKGROUND: Artemisinin resistance described as increased parasite clearance time (PCT) is rare in Africa. More sensitive methods such as qPCR might better characterize the clearance phenotype in sub-Saharan Africa.
METHODS: PCT is explored in Mali using light microscopy and qPCR after artesunate for uncomplicated malaria. In two villages, patients were followed for 28 days. Blood smears and spots were collected respectively for microscopy and qPCR. Parasitemia slope half-life was calculated after microscopy. Patient residual parasitemia were measured by qPCR.
RESULTS: Uncorrected adequate clinical and parasitological responses (ACPR) observed in Faladje and Bougoula-Hameau were 78% and 92%, respectively (p=0.01). This reached 100% for both after molecular correction. Proportions of 24H microscopy positive patients in Faladje and Bougoula-Hameau were 97.2% and 72%, respectively (p<0.0001). Slope half-life was 2.8h in Faladje vs 2h in Bougoula-Hameau (p<0.001) and Proportions of 72h patients with residual parasitemia were 68.5% and 40% in Faladje and Bougoula-Hameau, respectively (p=0.003). The mean residual parasitemia was 2.9 in Faladje vs. 0.008 in Bougoula-Hameau (p=0.002). Although artesunate is efficacious in Mali, the longer parasite clearance time with submicroscopic parasitemia observed may represent early signs of developing P. falciparum resistance to artemisinins.

PMID: 32320811 [PubMed - as supplied by publisher]

Clinically relevant CYP3A4 induction mechanisms and drug screening in 3D spheroid cultures of primary human hepatocytes.

Clin Pharmacol Ther. 2020 Apr 22;:

Authors: Hendriks DFG, Vorrink SU, Smutny T, Sim SC, Nordling Å, Ullah S, Kumondai M, Jones BC, Johansson I, Andersson TB, Lauschke VM, Ingelman-Sundberg M

Abstract
CYP3A4 induction is an important cause of drug-drug interactions, making early identification of drug candidates with CYP3A4 induction liability in drug development a prerequisite. Here, we present 3D spheroid cultures of primary human hepatocytes (PHH) as a novel CYP3A4 induction screening model. Screening of 25 drugs (12 known CYP3A4 inducers in vivo and 13 negative controls) at physiologically relevant concentrations revealed a 100% sensitivity and 100% specificity of the system. Three of the in vivo CYP3A4 inducers displayed much higher CYP3A4 induction capacity in 3D spheroid cultures as compared to in 2D monolayer cultures. Among those, we identified AZD1208, a PIM kinase inhibitor terminated in phase I of development due to unexpected CYP3A4 autoinduction, as a CYP3A4 inducer only active in 3D spheroids but not in 2D monolayer cultures. Gene knockdown experiments revealed that AZD1208 requires PXR to induce CYP3A4. Rifampicin requires solely PXR to induce CYP3A4 and CYP2B6, while phenobarbital-mediated induction of these CYPs did not show absolute dependency on either PXR or CAR suggesting its ability to switch nuclear receptor activation. Mechanistic studies into AZD1208 uncovered an involvement of the MAPK/ERK pathway in CYP3A4 induction that is sensitive to the culture format used, as revealed by its inhibition of ERK1/2 Tyr204 phosphorylation and sensitivity to EGF pressure. In line, we also identified lapatinib, a dual EGFR/HER2 inhibitor, as another CYP3A4 inducer only active in 3D spheroid culture. Our findings offer insights into the pathways involved in CYP3A4 induction and suggest PHH spheroids for preclinical CYP3A4 induction screening.

PMID: 32320483 [PubMed - as supplied by publisher]

Pharmacogenetic associations and evidence-based pharmacogenomics guidelines: supporting label and off-label use of drug-gene interaction data.

Pharmacogenomics. 2020 Apr 22;:

Authors: Kisor DF, Monte AA, Müller DJ

PMID: 32319356 [PubMed - as supplied by publisher]

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

Pharmacogenet Genomics. 2020 Apr 20;:

Authors: van der Wouden CH, Böhringer S, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VHM, Dolžan V, Ingelman-Sundberg M, Jönsson S, Karlsson MO, Kriek M, Mitropoulou C, Patrinos GP, Pirmohamed M, Rial-Sebbag E, Samwald M, Schwab M, Steinberger D, Stingl J, Sunder-Plassmann G, Toffoli G, Turner RM, van Rhenen MH, van Zwet E, Swen JJ, Guchelaar HJ, Ubiquitous Pharmacogenomics Consortium

Abstract
OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design.
METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses.
RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis.
CONCLUSIONS: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

PMID: 32317559 [PubMed - as supplied by publisher]

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Int J Mol Sci. 2020 Apr 16;21(8):

Authors: Jessurun NT, Wijnen PA, Bast A, van Puijenbroek EP, Bekers O, Drent M

Abstract
Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

PMID: 32316326 [PubMed - in process]

Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures.

Epilepsia. 2020 Apr 21;:

Authors: Leontariti M, Avgeris M, Katsarou MS, Drakoulis N, Siatouni A, Verentzioti A, Alexoudi A, Fytraki A, Patrikelis P, Vassilacopoulou D, Gatzonis S, Sideris DC

Abstract
OBJECTIVE: Epilepsy is one of the most prevalent neurologic disorders, causing serious psychological problems and reducing quality of life. Although 20 different antiepileptic drugs (AEDs) have been approved by the US Food and Drug Administration (FDA), 30% of patients have drug-resistant epilepsy (DRE). Considering the role of miR-146a and miR-134 in neuroinflammation and dendritic functionality, respectively, the aim of this study was the clinical evaluation of circulating miR-146a and miR-134 as novel noninvasive molecular markers for the prognosis of refractory epilepsy.
METHODS: The study included 162 patients with focal impaired awareness seizures. Total RNA was extracted from serum samples spiked with synthetic cel-miR-39-3p for normalization purposes. First-strand complementary DNA (cDNA) synthesis was performed using microRNA-specific stem-loop primers, and hsa-miR-134/146a levels were quantified by quantitative polymerase chain reaction (qPCR). DRE was used as clinical end point event. Internal validation was performed by bootstrap analysis, and decision curve analysis was used to evaluate the clinical benefit on disease prognosis.
RESULTS: The circulating levels of both miR-134 and miR-146a were elevated in patients with drug-resistant seizures. The receiver-operating characteristic (ROC) curve and logistic regression analysis demonstrated that patients with increased circulating miR-134/146a levels are at significantly higher risk for developing DRE, independently of temporal lobe sclerosis, epilepsy duration, familial history, age at first seizure, age, body mass index (BMI), smoking behavior, and gender. Finally, decision curve analysis highlighted that the evaluation of circulating miR-134/146a led to superior clinical benefit for DRE prognosis and patients' risk stratification.
SIGNIFICANCE: Elevated serum miR-134/146a levels are associated with a higher risk for AED-resistant epilepsy and could constitute novel noninvasive molecular markers to improve disease early prognosis and support precision medicine.

PMID: 32314378 [PubMed - as supplied by publisher]

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice.

J Clin Invest. 2019 04 15;129(5):2133-2144

Authors: Cohen TS, Takahashi V, Bonnell J, Tovchigrechko A, Chaerkady R, Yu W, Jones-Nelson O, Lee Y, Raja R, Hess S, Stover CK, Worthington JJ, Travis MA, Sellman BR

Abstract
Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β-activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

PMID: 30985291 [PubMed - indexed for MEDLINE]

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Pharmacologic treatment of transplant recipients infected with SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions.

Ther Drug Monit. 2020 Apr 15;:

Authors: Elens L, Langman LJ, Hesselink DA, Bergan S, Moes DJAR, Molinaro M, Venkataramanan R, Lemaitre F

Abstract
BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-corona virus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs. It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals.
METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of immunosuppressive drugs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature.
RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining immunosuppressive drug concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight.
CONCLUSIONS: With the present manuscript, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with immunosuppressive drugs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

PMID: 32304488 [PubMed - as supplied by publisher]

Clinically relevant pharmacogenetic markers in Tatars and Balkars.

Mol Biol Rep. 2020 Apr 17;:

Authors: Abdullaev SP, Mirzaev KB, Burashnikova IS, Shikaleva AA, Kachanova AA, Abdullaev SP, Akmalova KA, Sozaeva ZA, Grishina EA, Sozaeva MS, Rytkin EI, Sychev DA

Abstract
This study was aimed to investigate the prevalence of CYP2C9*2 (p.430C > T, rs1799853), CYP2C9*3 (p.1075A > C, rs1057910), CYP4F2*3 (p.1297G > A, rs2108622), CYP2C19*2 (p.681G > A, rs4244285), CYP2C19*3 (p.636G > A, rs4986893), CYP2C19*17 (p.1260C > A, rs12248560), ABCB1 (p.3435C > T, rs1045642), CYP2D6*4 (p.1846G > A, rs3892097), SLCO1B1*5 (p.521T > C, rs4149056) and CES1 (p.1168-33A > C, rs2244613) among Tatars and Balkars ethnic groups living in Russia to provide a basis for future clinical studies concerning on understanding of population-level differences in drug response. The study involved 341 apparently healthy, unrelated, and chronic medication-free volunteers of both sexes of ethnic groups of Tatars and Balkars living in Volga and Caucasus regions of Russia. Genotyping was performed using real-time polymerase chain reaction-based methods. The allelic prevalence of studied markers in ethnic groups were compared with Russians as a largest ethnic group in Russia. Statistically significant differences for the following gene polymorphisms were found between both ethnic groups in respect of different markers and with Russians. Our study shows differences in prevalence of the main relevant pharmacogenetic markers in Tatars and Balkars. These findings should be taken into consideration for personalization algorithms development and pharmacogenetics implementation in regions with ethnic minorities as Russia has.

PMID: 32303955 [PubMed - as supplied by publisher]

Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD.

Am J Hum Genet. 2020 Apr 14;:

Authors: Chasman DI, Giulianini F, Demler OV, Udler MS

Abstract
Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. The component GRSs' weights are derived from the singular value decomposition (SVD) of the matrix of appropriately scaled genetic effects, i.e., beta coefficients, of the disease variants across a panel of the disease-related phenotypes. The SVD-based formalism also associates combinations of disease-related phenotypes with inferred disease pathways. Applied to incident type 2 diabetes (T2D) in the Women's Genome Health Study (N = 23,294), component GRSs discriminate glycemic control and lipid-based genetic risk, while revealing significant interactions between specific components and BMI or physical activity, the latter not observed with a GRS for overall T2D genetic liability. Applied to coronary artery disease (CAD) in both the WGHS and in JUPITER (N = 8,749), a randomized trial of rosuvastatin for primary prevention of CVD, component GRSs discriminate genetic risk associated with LDL-C from risk associated with reciprocal genetic effects on triglycerides and HDL-C. They also inform the pharmacogenetics of statin treatment by demonstrating that benefit from rosuvastatin is as strongly related to genetic risk from triglycerides and HDL-C as from LDL-C.

PMID: 32302534 [PubMed - as supplied by publisher]

Cis-acting regulatory elements regulating CYP3A4 transcription in human liver.

Pharmacogenet Genomics. 2020 Apr 14;:

Authors: Collins JM, Wang D

Abstract
The CYP3A4 enzyme is the most abundant drug-metabolizing enzyme in the liver, metabolizing ~50% of commonly used medications. CYP3A4 displays large interperson variability in expression and enzyme activity with unknown causes. This study aims to identify cis-acting regulatory elements controlling the transcription of CYP3A4, using chromatin conformation capture (4C and 3C assays), chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), clustered regularly interspaced short palindromic repeats (CRISPR)-mediated deletions of genomic regions and reporter gene assays in primary culture human hepatocytes and hepatic cell lines. 4C assays identified four regions (R1-R4) interacting with the CYP3A4 promoter, one of which overlaps with the previously identified upstream enhancers CLEM4/XREM (R2) while the other three are novel. ChIP-qPCR, reporter gene assays and CRISPR-mediated deletion experiments indicate regulatory roles for both R2 and R4. Interestingly, the deletion of R4 increased CYP3A4 while decreasing CYP3A43 expression, possibly due to competitive domain-domain interactions within the CYP3A cluster, supported by deletion of R4 increasing interaction between the CYP3A4 promoter and R2. We also identified a single nucleotide polymorphism rs62471956 within R4, with the variant allele A having increased transcriptional activity in a reporter gene assay. The rs62471956 A allele is associated with higher CYP3A43 expression and lower CYP3A4 expression in a cohort of 136 liver samples, further supporting the opposing effects of R4 on CYP3A4 and CYP3A43. rs62471956 is in complete linkage disequilibrium with CYP3A4*22, potentially contributing to reduced expression of CYP3A4*22. These results validate previously identified enhancers (CLEM4 and XREM) of CYP3A4 and demonstrate additional regulatory mechanisms underlying CYP3A4 transcriptional control via competitive domain-domain interactions within the CYP3A cluster.

PMID: 32301865 [PubMed - as supplied by publisher]

The clinical utility of combinatorial pharmacogenomic testing for patients with depression: a meta-analysis.

Pharmacogenomics. 2020 Apr 17;:

Authors: Brown L, Vranjkovic O, Li J, Yu K, Al Habbab T, Johnson H, Brown K, Jablonski MR, Dechairo B

Abstract
Aim: To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions for patients with major depressive disorder (MDD). Patients & methods: The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model. Results: Overall, 1556 patients were included from four studies, with outcomes evaluated at week 8 or week 10. Patient outcomes were significantly improved for patients with MDD whose care was guided by the combinatorial pharmacogenomic test results compared with unguided care (symptom improvement Δ = 10.08%, 95% CI: 1.67-18.50, p = 0.019; response RR = 1.40, 95% CI: 1.17-1.67, p < 0.001; remission RR = 1.49, 95% CI: 1.17-1.89, p = 0.001). Conclusion: GeneSight Psychotropic guided care improves outcomes among patients with MDD.

PMID: 32301649 [PubMed - as supplied by publisher]

Cost-effectiveness of combinatorial pharmacogenomic testing for depression from the Canadian public payer perspective.

Pharmacogenomics. 2020 Apr 17;:

Authors: Tanner JA, Davies PE, Overall CC, Grima D, Nam J, Dechairo BM

Abstract
Aim: Evaluate cost-effectiveness of combinatorial pharmacogenomic (PGx) testing, versus treatment as usual (TAU), to guide treatment for patients with depression, from the Canadian public healthcare system perspective. Materials & methods: Clinical and economic data associated with depression were extracted from published literature. Clinical (quality adjusted life years; QALYs) and economic (incremental cost-effectiveness ratio) outcomes were modeled using combinatorial PGx and TAU treatment strategies across a 5-year time horizon. Results: With the combinatorial PGx strategy to guide treatment, patients were projected to gain 0.14-0.19 QALYs versus TAU. Accounting for test price, combinatorial PGx saved CAD $1,687-$3,056 versus TAU. Incremental cost-effectiveness ratios ranged from -$11,861 to -$16,124/QALY gained. Conclusion: Combinatorial PGx testing was more efficacious and less costly compared with the TAU for depression.

PMID: 32301648 [PubMed - as supplied by publisher]

Comparative Study of Salivary, Duodenal, and Fecal Microbiota Composition Across Adult Celiac Disease.

J Clin Med. 2020 Apr 13;9(4):

Authors: Panelli S, Capelli E, Lupo GFD, Schiepatti A, Betti E, Sauta E, Marini S, Bellazzi R, Vanoli A, Pasi A, Cacciatore R, Bacchi S, Balestra B, Pastoris O, Frulloni L, Corazza GR, Biagi F, Ciccocioppo R

Abstract
BACKGROUND: Growing evidence suggests that an altered microbiota composition contributes to the pathogenesis and clinical features in celiac disease (CD). We performed a comparative analysis of the gut microbiota in adulthood CD to evaluate whether: (i) dysbiosis anticipates mucosal lesions, (ii) gluten-free diet restores eubiosis, (iii) refractory CD has a peculiar microbial signature, and (iv) salivary and fecal communities overlap the mucosal one.
METHODS: This is a cross-sectional study where a total of 52 CD patients, including 13 active CD, 29 treated CD, 4 refractory CD, and 6 potential CD, were enrolled in a tertiary center together with 31 controls. A 16S rRNA-based amplicon metagenomics approach was applied to determine the microbiota structure and composition of salivary, duodenal mucosa, and stool samples, followed by appropriate bioinformatic analyses.
RESULTS: A reduction of both α- and β-diversity in CD, already evident in the potential form and achieving nadir in refractory CD, was evident. Taxonomically, mucosa displayed a significant abundance of Proteobacteria and an expansion of Neisseria, especially in active patients, while treated celiacs showed an intermediate profile between active disease and controls. The saliva community mirrored the mucosal one better than stool.
CONCLUSION: Expansion of pathobiontic species anticipates villous atrophy and achieves the maximal divergence from controls in refractory CD. Gluten-free diet results in incomplete recovery. The overlapping results between mucosal and salivary samples indicate the use of saliva as a diagnostic fluid.

PMID: 32294965 [PubMed]