Crit Rev Oncol Hematol. 2021 May 26:103366. doi: 10.1016/j.critrevonc.2021.103366. Online ahead of print.

ABSTRACT

Lenvatinib is a non-selective tyrosine kinase inhibitor with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight <60 kg or severe hepatic failure. No significant change in lenvatinib pharmacokinetics has been observed with other patient-related factors and very few data are available on lenvatinib pharmacogenetics. Lenvatinib can be administered orally regardless of food and no clinically relevant drug-drug interactions have been reported.

PMID:34051303 | DOI:10.1016/j.critrevonc.2021.103366

J Immunother Cancer. 2021 May;9(5):e002521. doi: 10.1136/jitc-2021-002521.

ABSTRACT

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance-elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

PMID:34049931 | DOI:10.1136/jitc-2021-002521

Schizophr Res. 2021 May 25;232:112-124. doi: 10.1016/j.schres.2021.05.010. Online ahead of print.

ABSTRACT

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.

PMID:34049235 | DOI:10.1016/j.schres.2021.05.010

Drug Alcohol Depend. 2021 May 21;225:108762. doi: 10.1016/j.drugalcdep.2021.108762. Online ahead of print.

ABSTRACT

BACKGROUND: In an initial study, we reported that topiramate reduced heavy drinking among individuals who sought to reduce their drinking and that the effect was moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al., 2014). In a subsequent study that prospectively randomized patients to medication group based on their rs2832407 genotype, we replicated the main effect of topiramate but not the moderating effect of the SNP (Kranzler et al., 2021). Given the similar design of the two studies, here we combined the findings to provide greater statistical power to test the pharmacogenetic effect.

MATERIAL AND METHODS: This secondary analysis of two 12-week, randomized controlled trials of topiramate included a total of 292 European-ancestry individuals (67.1 % male; topiramate: 48.3 %, placebo: 51.7 %) with problematic alcohol use. Using MANOVA, we examined changes in self-reported alcohol consumption, problems resulting from alcohol use, and quality of life, and the biomarker γ-glutamyltransferase. To test the pharmacogenetic hypothesis, all patients were genotyped for rs2832407.

RESULTS: There was a significant overall effect of topiramate on the alcohol-related outcomes (partial η2 = 0.134, p < 0.001), with follow-up analyses showing significant reductions in percent heavy drinking days (Cohen's d = 0.49), percent days abstinent (d = 0.23), drinks/day (d = 0.29) and alcohol-related problems (d = 0.45). Overall, the moderating effect of the SNP was non-significant (partial η² = 0.026, p = 0.37).

CONCLUSIONS: Although topiramate is an efficacious medication for reducing drinking and alcohol-related problems among patients with problematic alcohol use, rs2832407 does not appear to moderate its therapeutic effects. www.clinicaltrials.gov registrations: NCT00626925 and NCT02371889.

PMID:34049101 | DOI:10.1016/j.drugalcdep.2021.108762

Clin Pharmacol Ther. 2021 May 28. doi: 10.1002/cpt.2315. Online ahead of print.

ABSTRACT

Depression is a leading cause of disability worldwide and despite the availability of numerous antidepressants, the lack of standardised criteria to apply personalised prescription is still a major issue. Pharmacogenetic (PGx) markers in cytochrome P450 (CYP450) genes are already usable to guide antidepressant choice/titration according to clinical guidelines; they are an important step towards personalised psychiatry as they can reduce the time to identify an effective and tolerated treatment. Clinical application is still limited due to the financial and organisational challenges, but the number of services providing genotyping of pharmaco-genes is increasing, with encouraging projections of cost-effectiveness. Critical aspects that emerged from the available studies are the importance of integration of genotyping results in electronic medical records, standardisation and regular updates of decision support systems, training and collaboration of different professionals, need of longer follow-ups to estimate cost-effectiveness, importance of avoiding inequalities in access to genotyping. Diversities exist among the groups of patients to whom genotyping is offered (pre-emptive or reactive testing) and the type of clinical services (e.g., hospitals, primary care), currently without a consensus on which is the best approach. Future studies should aim to clarify these issues, as well as consider and compare PGx applications among different countries and health care systems. Finally, the extension of genotyping outside pharmacokinetic genes should be considered as a key step to improve the clinical impact of PGx, as this could significantly increase the variance explained in treatment outcomes.

PMID:34047355 | DOI:10.1002/cpt.2315

Front Endocrinol (Lausanne). 2021 May 11;12:628169. doi: 10.3389/fendo.2021.628169. eCollection 2021.

ABSTRACT

Infertility is a major concern for couples wanting to have progeny. Despite recent advances in the field of IVF, success rates still need improvement. Understanding the patient's variability and addressing it with personalized interventions may improve the success rate of fertilization and live births. This study examined the impact of a personalized pharmacogenomic approach on LH supplementation on the pregnancy and live birth rate outcomes in comparison with the traditional approaches. 193 patients undergoing a second IVF cycle in Krishna IVF Clinic received LH supplementation either as per the conventional methods or based on N312S (rs2293275) LHCGR gene polymorphism. Results showed a significant increase in pregnancy rate (P-value: 0.049) and a trend showing improvement in live birth rates (P-value: 0.082) when r-hLH supplementation protocol was decided as per the genotypes A/A, A/G, and G/G of the N312S variant in the respective patients. This stimulation regimen helped in providing optimum levels of r-hLH supplementation to patients with impaired hormone-receptor interacting activity, to achieve higher success in pregnancy and live birth rates.

PMID:34046009 | PMC:PMC8147863 | DOI:10.3389/fendo.2021.628169

Pharmacogenomics J. 2021 May 27. doi: 10.1038/s41397-021-00237-5. Online ahead of print.

ABSTRACT

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.

PMID:34045667 | DOI:10.1038/s41397-021-00237-5

Pharmacogenomics. 2021 May 28. doi: 10.2217/pgs-2020-0160. Online ahead of print.

ABSTRACT

Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.

PMID:34044623 | DOI:10.2217/pgs-2020-0160

Pharmacogenomics. 2021 May 28. doi: 10.2217/pgs-2020-0165. Online ahead of print.

ABSTRACT

Bladder cancer (BC) is the most common cancer involving the urinary system and the ninth most common cancer worldwide. Tobacco smoking is the most important environmental risk factor of BC. Several single nucleotide polymorphisms have been validated by genome-wide association studies as genetic risk factors for BC. However, the identification of DNA mismatch-repair genes, including MSH2 in Lynch syndrome and MUTYH in MUTYH-associated polyposis, raises the possibility of monogenic hereditary forms of BC. Moreover, other genetic mutations may play a key role in familial and hereditary transmissions of BC. Therefore, the aim of this review is to focus on the major hereditary syndromes involved in the development of BC and to report BC genetic susceptibilities established with genome-wide significance level.

PMID:34044612 | DOI:10.2217/pgs-2020-0165

Cell. 2021 May 22:S0092-8674(21)00585-7. doi: 10.1016/j.cell.2021.05.002. Online ahead of print.

ABSTRACT

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

PMID:34043940 | DOI:10.1016/j.cell.2021.05.002

Clin Pharmacol Ther. 2021 May 27. doi: 10.1002/cpt.2312. Online ahead of print.

ABSTRACT

Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on pharmacokinetics (PK), due to our relatively advanced understanding of the genes involved in PK and the causative effects of variants in those genes. Genetic variants can also affect pharmacodynamics (PD), but relatively few PGx-PD associations have been identified. This is partially due to a more limited understanding of the relevant genes and the consequences of genetic variation, but is also due in part to the potential confounding of PK variability in assessments of clinical outcomes that have a contribution from both PK and PD. For example, it is challenging to confirm the effect of mu opioid receptor (OPRM1) genetic variation on opioid response due to the contribution of CYP2D6 genotype to bioactivation of some opioid drugs (i.e., codeine and tramadol). The objectives of this mini-review are to describe several recent efforts to discover and validate PGx-PD that disentangle the influence of PK variability and propose potential approaches that could be used in future PGx-PD analyses. We use the effect of OPRM1 genetics on opioid response to illustrate how these analyses could be conducted and conclude by discussing how PGx-PD could be translated into clinical practice to improve therapeutic outcomes.

PMID:34043820 | DOI:10.1002/cpt.2312

Clin Pharmacol Ther. 2021 May 27. doi: 10.1002/cpt.2316. Online ahead of print.

ABSTRACT

This study aimed to analyse associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1 and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and non-carriers of the SNVs or haplotypes. In total 1,806 patients on apixaban, dabigatran or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (HR 0.42, 95% CI 0.18-0.98, p=0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI 0.20-0.95, p=0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI 1.03-6.36, p=0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI 2.35-14.72, p<0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI 0.16-0.89, p=0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.

PMID:34043814 | DOI:10.1002/cpt.2316

IEEE/ACM Trans Comput Biol Bioinform. 2021 May 27;PP. doi: 10.1109/TCBB.2021.3084562. Online ahead of print.

ABSTRACT

It is infeasible to test many different chemotherapy drugs on actual patients in large clinical trials, which motivates computational methods with the ability to learn and exploit associations between drug effectiveness and patient characteristics. This work proposes a machine learning approach to infer robust predictors of drug responses from patient genomic information. Rather than predicting the exact drug response on a given cell line, we introduce an elastic-net regression methodology to compare a drug-cell line pair against an alternative pair. Using predicted pairwise comparisons we rank the effectiveness of different drugs on the same cell line. A total of 173 cell lines and 100 drug responses were used in various settings for training and testing the proposed models. By comparing our approach against twelve baseline methods, we demonstrate that it outperforms the state-of-the-art methods in the literature. In contrast to most other methods, the algorithm is able to maintain its high performance even when we use a large number of drugs and few cell lines.

PMID:34043512 | DOI:10.1109/TCBB.2021.3084562

Phytother Res. 2021 May 27. doi: 10.1002/ptr.7134. Online ahead of print.

ABSTRACT

Depression is one of the most common mental disorders worldwide. The genetic factors are linked to depression and anti-depressant outcomes. Traditional Persian medicine (TPM) manuscripts have provided various anti-depressant remedies, which may be useful in depression management. This review has studied the bioactive compounds, underlying mechanisms, and treatment outcomes of the medicinal plants traditionally mentioned effective for depression from "The storehouse of medicament" (a famous pharmacopeia of TPM) to merge those with the novel genetics science and serve new scope in depression prevention and management. This review paper has been conducted in two sections: (1) Collecting medicinal plants and their bioactive components from "The storehouse of medicament," "Physician's Desk Reference (PDR) for Herbal Medicines," and "Google scholar" database. (2) The critical key factors and genes in depression pathophysiology, prevention, and treatment were clarified. Subsequently, the association between bioactive components' underlying mechanism and depression treatment outcomes via considering polymorphisms in related genes was derived. Taken together, α-Mangostin, β-carotene, β-pinene, apigenin, caffeic acid, catechin, chlorogenic acid, citral, ellagic acid, esculetin, ferulic acid, gallic acid, gentiopicroside, hyperoside, kaempferol, limonene, linalool, lycopene, naringin, protocatechuic acid, quercetin, resveratrol, rosmarinic acid, and umbelliferone are suitable for future pharmacogenetics-based studies in the management of depression.

PMID:34041799 | DOI:10.1002/ptr.7134

Clin Pharmacokinet. 2021 May 27. doi: 10.1007/s40262-021-01033-x. Online ahead of print.

ABSTRACT

BACKGROUND: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data.

OBJECTIVE: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates.

METHODS: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods.

RESULTS: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods.

CONCLUSION: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.

PMID:34041714 | DOI:10.1007/s40262-021-01033-x

Front Psychiatry. 2021 May 10;12:664228. doi: 10.3389/fpsyt.2021.664228. eCollection 2021.

ABSTRACT

Recent studies suggest that the endocannabinoid system could play an important role in the physiopathology of obsessive-compulsive disorder (OCD). There are reports of effective treatment with derivatives of tetrahydrocannabinol (THC). The study of the genetic factor associated with psychiatric disorders has made possible an exploration of its contribution to the pharmacological response. However, very little is known about the genetic factor or the prevalence of cannabis use in the Mexican population with OCD. The objective of this study is to compare the prevalence of use and dependence on cannabis in individuals with obsessive-compulsive symptomatology (OCS) with that of individuals with other psychiatric symptoms (psychosis, depression, and anxiety), and to explore the association between genetic risk and use. The study includes a total of 13,130 individuals evaluated in the second stage of the 2016 National Survey of Drug, Alcohol, and Tobacco Use (Encodat 2016), with genetic analysis (polygenic risk scoring) of a subsample of 3,521 individuals. Obsessive symptomatology had a prevalence of 7.2% and compulsive symptomatology a prevalence of 8.6%. The proportion of individuals with OCS who had ever used cannabis was 23.4%, and of those with cannabis dependency was 2.7%, the latter figure higher than that in individuals with other psychiatric symptoms (hypomania, 2.6%; anxiety, 2.8%; depression, 2.3%), except psychosis (5.9%). Individuals with OCS who reported using cannabis had an increased genetic risk for cannabis dependence but not for OCD. We thus cannot know how the increased genetic risk of cannabis dependence in people with OCD is influenced by their pharmacological response to derivatives of THC. The results, however, suggest paths for future studies.

PMID:34040556 | PMC:PMC8141625 | DOI:10.3389/fpsyt.2021.664228

Front Pharmacol. 2021 May 10;12:668843. doi: 10.3389/fphar.2021.668843. eCollection 2021.

ABSTRACT

Reduced or absent compliance to anti-hypertensive treatment is a major obstacle to the achievement of blood pressure target in patients with arterial hypertension. Current available methods for therapeutic adherence assessment display low accuracy, limited applicability in clinical practice and/or high costs. We designed a prospective study to evaluate the accuracy of serial measurement of ARR to assess the therapeutic compliance to RAAS inhibitors. We prospectively enrolled 80 subjects: 40 patients with arterial hypertension and 40 normotensive controls. The ARR was evaluated at baseline and 2 and 8 week after initiation of a RAAS inhibitor in patients with hypertension, and at baseline and 2 weeks for the control group. Adherence to the prescribed therapy was confirmed by therapeutic drug monitoring. We observed a significant increase of renin levels and reduction of aldosterone levels after RAAS inhibitors initiation, with consequent reduction of ARR. Delta ARR (ΔARR), defined as relative change in ARR before and after treatment initiation, provided high accuracy for determination of therapeutic compliance, with an AUC of 0.900 at 2 weeks and 0.886 at 8 weeks. A cut-off of -48% of ΔARR provided 90% sensitivity and 75% specificity, at 2 and 8 weeks. In conclusion, the measurement of ΔARR is a powerful test, cheap and widely available to accurately identify the non-adherence to RAAS inhibitors treatment. Herein we propose the implementation of ΔARR in clinical practice through a multi-step flow-chart for the management of patients with uncontrolled blood pressure, with identification of those suspected of non-adherence, reserving therapeutic drug monitoring for non-adherence confirmation.

PMID:34040531 | PMC:PMC8141919 | DOI:10.3389/fphar.2021.668843

Pharmgenomics Pers Med. 2021 May 18;14:569-577. doi: 10.2147/PGPM.S224894. eCollection 2021.

ABSTRACT

Pharmacogenomics (PGx) is expanding across health-care practice settings, including the community pharmacy. In the United States, models of implementation of PGx in the community pharmacy have described independent services and those layered on to medication therapy management. The drug-gene pair of clopidogrel-CYP2C19 has been a focus of implementation of PGx in community pharmacy and serves as an example of the evolution of the application of drug-gene interaction information to help optimize drug therapy. Expanded information related to this drug-gene pair has been provided by the US Food and Drug Administration and clinical PGx guidelines have and continue to be updated to support clinical decision-making. Most recently direct-to-consumer (DTC) PGx has resulted in patient generated sample collection and submission to a genetic testing-related company for analysis, with reporting of genotype and related phenotype information directly to the patient without a health-care professional guiding or even being involved in the process. The DTC testing approach needs to be considered in the development or modification of PGx service models in the community pharmacy setting. The example of clopidogrel-CYP2C19 is discussed and current models of PGx implementation in the community pharmacy in the United States are presented. New approaches to PGx services are offered as implementation continues to evolve and may now include DTC information.

PMID:34040417 | PMC:PMC8140945 | DOI:10.2147/PGPM.S224894

Curr Opin Allergy Clin Immunol. 2021 May 25. doi: 10.1097/ACI.0000000000000754. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions.

RECENT FINDINGS: Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B*13:01 with co-trimoxazole-induced SCAR, and HLA-A*32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B*57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B*15:02-restricted carbamazepine-induced SJS/TEN. More recent strategies for the use of HLA and other risk factors may include risk-stratification, early diagnosis, and diagnosis in addition to screening.

SUMMARY: HLA is necessary but insufficient as a risk factor for the development of most T-cell-mediated reactions. Newly emerged genetic and ecological risk factors, combined with HLA-restricted response, align with underlying immunopathogenesis and drive towards enhanced strategies to improve positive-predictive and negative-predictive values. With large population-matched cohorts, genetic studies typically focus on populations that have been readily accessible to research studies, but it is now imperative to address similar risk in globally relevant and understudied populations.

PMID:34039850 | DOI:10.1097/ACI.0000000000000754

Am J Hum Genet. 2021 May 20:S0002-9297(21)00185-3. doi: 10.1016/j.ajhg.2021.05.001. Online ahead of print.

ABSTRACT

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.

PMID:34038741 | DOI:10.1016/j.ajhg.2021.05.001