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Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final \"maintenance\" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the α-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Key Points Until recently, pharmacogenetic studies focused attention on only a few candidate genes. Developments in genomic technologies now allow a drastic expansion in the scope of pharmacogenetic studies. The genetic bases of inter-individual variation in drug response are likely to be simpler in many cases than the genetic bases of common diseases, which indicates that progress in pharmacogenetics might move faster than disease genetics. Forty-two polymorphisms that have been significantly associated with drug response in at least two studies show that obvious candidate genes, such as drug-metabolizing enzymes and drug targets, often carry important pharmacogenetic polymorphisms, and that such polymorphisms are often owing to common alleles. Most pharmacogenetics studies so far have been limited, both in terms of sample sizes and the genetic data analysed, and provide insufficient information for assessing clinical usefulness. Progress in pharmacogenetics will require notable increases in study size and the quality of the genetic analyses, including the efficient use of haplotype mapping. The translation of pharmacogenetic results into improved therapies will usually require the identification of the causal variants that underlie associations between genotypes and phenotypes. Effective translation will also require prospective clinical evaluation of how to use the polymorphism. Realizing the benefits of pharmacogenetics will be facilitated by research environments that combine a clinical diagnostic activity with basic pharmacogenetic research. Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up. It seems increasingly likely that investment in this field might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours.

Throughout much of the world, 'race' and 'ethnicity' are key determinants of health. For example, African Americans have, by some estimates, a twofold higher incidence of fatal heart attacks and a 10% higher incidence of cancer than European Americans, and South Asian- or Caribbean-born British are approximately 3.5 times as likely to die as a direct result of diabetes than are British of European ancestry. The health care that people receive also depends on 'race' and 'ethnicity'. African Americans are less likely to receive cancer-screening services and more likely to have late-stage cancer when diagnosed than European Americans. Health disparities such as these are one of the greatest social injustices in the developed world and one of the most important scientific and political challenges.

The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

The field of pharmacogenetics has grown rapidly over the last few years yet, with a couple of exceptions, pharmacogenetic diagnostics are not yet used in a clinical setting. Progress in the field is discussed and the current state of pharmacogenetic research is assessed in a literature review. This thesis describes studies to investigate the pharmacogenetics of the anti-epileptic drugs phenytoin, carbamazepine and levetiracetam, using data obtained from the routine clinical use of these drugs, and the pharmacogenetics of the beta-blocker bucindolol in a clinical trial setting. Evidence is presented of a common polymorphism in the SCN1A gene that is associated with the clinical use (dosing) of both phenytoin and carbamazepine. Preliminary results are also presented concerning genetic variation in the SV2A and SV2C genes which may influence response to levetiracetam. For this study genetic variation was represented using the tagging SNP method applied to HapMap data. Genetic variation in ADRB2 may influence response to bucindolol yet the results are not conclusive. More importantly however, they do provide an illustration of how differences in polymorphism frequencies among populations could account for average differences in drug response among populations. It is also shown that there are substantial genetic differences within self-identified racial groups within the context of a clinical trial. The implications of pharmacogenetics for different racial or ethnic groups are discussed in a separate chapter. In conclusion, common variation in obvious candidate genes does influence drug response, however, rigorous clinical study is required before the use of pharmacogenetic variants to guide choice or dose of drugs becomes part of clinical practice.

Macrophage migration inhibitory factor (MIF) exerts multiple effects on immune cells, as well as having functions outside the immune system. MIF can promote inflammation through the induction of other cytokines, including TNF, IL-6, and IL-1 family cytokines. Here, we show that inhibition of MIF regulates the release of IL-1α, IL-1β, and IL-18, not by affecting transcription or translation of these cytokines, but via activation of the NLRP3 inflammasome. MIF is required for the interaction between NLRP3 and the intermediate filament protein vimentin, which is critical for NLRP3 activation. Further, we demonstrate that MIF interacts with NLRP3, indicating a role for MIF in inflammasome activation independent of its role as a cytokine. These data advance our understanding of how MIF regulates inflammation and identify it as a factor critical for NLRP3 inflammasome activation. MIF is a cytokine best known for its modulatory effect on expression of proinflammatory cytokines. Here the authors show that MIF facilitates the NLRP3–vimentin interaction, resulting in Nlrp3 inflammasome activation.

We evaluated the performance of self-collected anterior nasal swab (ANS) and saliva samples compared with healthcare worker–collected nasopharyngeal swab specimens used to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used the same PCR diagnostic panel to test all self-collected and healthcare worker–collected samples from participants at a public hospital in Atlanta, Georgia, USA. Among 1,076 participants, 51.9% were men, 57.1% were >50 years of age, 81.2% were Black (non-Hispanic), and 74.9% reported >1 chronic medical condition. In total, 8.0% tested positive for SARS-CoV-2. Compared with nasopharyngeal swab samples, ANS samples had a sensitivity of 59% and saliva samples a sensitivity of 68%. Among participants tested 3–7 days after symptom onset, ANS samples had a sensitivity of 80% and saliva samples a sensitivity of 85%. Sensitivity varied by specimen type and patient characteristics. These findings can help physicians interpret PCR results for SARS-CoV-2.

To improve recognition of coronavirus disease (COVID-19) and inform clinical and public health guidance, we randomly selected 600 COVID-19 case-patients in Colorado. A telephone questionnaire captured symptoms experienced, when symptoms occurred, and how long each lasted. Among 128 hospitalized patients, commonly reported symptoms included fever (84%), fatigue (83%), cough (73%), and dyspnea (72%). Among 236 nonhospitalized patients, commonly reported symptoms included fatigue (90%), fever (83%), cough (83%), and myalgia (74%). The most commonly reported initial symptoms were cough (21%-25%) and fever (20%-25%). In multivariable analysis, vomiting, dyspnea, altered mental status, dehydration, and wheezing were significantly associated with hospitalization, whereas rhinorrhea, headache, sore throat, and anosmia or ageusia were significantly associated with nonhospitalization. General symptoms and upper respiratory symptoms occurred earlier in disease, and anosmia, ageusia, lower respiratory symptoms, and gastrointestinal symptoms occurred later. Symptoms should be considered alongside other epidemiologic factors in clinical and public health decisions regarding potential COVID-19 cases.