Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

ObjectiveTo characterize, among European and Han Chinese populations, the genetic predictors ofmaculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepilepticdrugs.MethodsWe conducted a case-control genome-wide association study of autosomal genotypes, in-cluding Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent.Results from each cohort were meta-analyzed.ResultsWe report an association between a rare variant in the complement factor H–related 4(CFHR4) gene and phenytoin-induced MPE in Europeans (p= 4.5 × 10–11; odds ratio [95%confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium witha missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our resultsreinforce the association betweenHLA-A*31:01and carbamazepine hypersensitivity. We didnot identify significant genetic associations with MPE among Han Chinese patients.ConclusionsThe identification of genetic predictors of MPE in CFHR4 and CFH, members of thecomplement factor H–related protein family, suggest a new link between regulation of thecomplement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury.

Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the "one-treatment fits all" approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex "-omics" data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can be a daunting task for the treating clinician. Within this review, we highlight the current status of such multi-modal omics data sets in moderate/severe TBI, current limitations to the utilization of such data, and a potential path forward through employing integrative neuroinformatic approaches, which are applied in other neuropathologies. Such advances are positioned to facilitate the transition to precision prognostication and inform a top-down approach to the development of personalized therapeutics in moderate/severe TBI

Ethical and legal implications of whole genome and whole exome sequencing in African populations

BACKGROUND: Rapid advances in high throughput genomic technologies and next generation sequencing are making medical genomic research more readily accessible and affordable, including the sequencing of patient and control whole genomes and exomes in order to elucidate genetic factors underlying disease. Over the next five years, the Human Heredity and Health in Africa (H3Africa) Initiative, funded by the Wellcome Trust (United Kingdom) and the National Institutes of Health (United States of America), will contribute greatly towards sequencing of numerous African samples for biomedical research. DISCUSSION: Funding agencies and journals often require submission of genomic data from research participants to databases that allow open or controlled data access for all investigators. Access to such genotype-phenotype and pedigree data, however, needs careful control in order to prevent identification of individuals or families. This is particularly the case in Africa, where many researchers and their patients are inexperienced in the ethical issues accompanying whole genome and exome research; and where an historical unidirectional flow of samples and data out of Africa has created a sense of exploitation and distrust. In the current study, we analysed the implications of the anticipated surge of next generation sequencing data in Africa and the subsequent data sharing concepts on the protection of privacy of research subjects. We performed a retrospective analysis of the informed consent process for the continent and the rest-of-the-world and examined relevant legislation, both current and proposed. We investigated the following issues: (i) informed consent, including guidelines for performing culturally-sensitive next generation sequencing research in Africa and availability of suitable informed consent documents; (ii) data security and subject privacy whilst practicing data sharing; (iii) conveying the implications of such concepts to research participants in resource limited settings. SUMMARY: We conclude that, in order to meet the unique requirements of performing next generation sequencing-related research in African populations, novel approaches to the informed consent process are required. This will help to avoid infringement of privacy of individual subjects as well as to ensure that informed consent adheres to acceptable data protection levels with regard to use and transfer of such information

Genome-wide Scan Identifies Association Between an Interferon Regulatory Factor Variant and Interferon-beta Induced Liver Injury in Multiple Sclerosis Patients

10.1016/j.vascn.2017.09.01988173-17

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

10.1002/cpt.1179CLINICAL PHARMACOLOGY & THERAPEUTICS1052402-41