Double-blind, 12 month follow-up, placebo-controlled trial of mifepristone on cognition in alcoholics: the MIFCOG trial protocol

Background: Increased levels of cortisol during acute alcohol withdrawal have been linked to cognitive deficits and depression. Preclinical research found that the glucocorticoid Type II receptor antagonist, mifepristone, prevented some of the neurotoxic effects of withdrawal and memory loss. Clinical trials have shown mifepristone effective in the treatment of depression. This study aims to examine the extent to which the glucocorticoid Type II receptor antagonist, mifepristone, when given to alcohol dependent males during the acute phase of alcohol withdrawal, will protect against the subsequent memory loss and depressive symptoms during abstinence from alcohol. Methods/Design: The study is a Phase 4 therapeutic use, “Proof of Concept” trial. The trial is a double-blind randomised controlled clinical trial of mifepristone versus inactive placebo. The trial aims to recruit 120 participants referred for an inpatient alcohol detoxification from community alcohol teams, who meet the inclusion criteria; 1) Male, 2) Aged 18–60 inclusive, 3) alcohol dependent for 5 or more years. A screening appointment will take place prior to admission to inpatient alcohol treatment units to ensure that the individual is suitable for inclusion in the trial in accordance with the inclusion and exclusion criteria. On admission participants are randomised to receive 600 mg a day of mifepristone (200 mg morning, afternoon and evening) for 7 days and 400 mg for the subsequent 7 days (200 mg morning and evening) or the equivalent number of placebo tablets for 14 days. Participants will remain in the trial for 4 weeks (at least 2 weeks as an inpatient) and will be followed up at 3, 6 and 12 months post randomisation. Primary outcome measures are cognitive function at week 3 and 4 after cessation of drinking and symptoms of depression over the 4 weeks after cession of drinking, measured using the Cambridge Neuropsychological Test Automated battery and Beck Depression Inventory, respectively. Secondary outcome measures are severity of the acute phase of alcohol withdrawal, alcohol craving, symptoms of protracted withdrawal and maintenance of abstinence and levels of relapse drinking at follow-up. Discussion: The current trial will provide evidence concerning the role of glucocorticoid Type II receptor activation in cognitive function and depression during acute alcohol withdrawal and the efficacy of treatment with mifepristone

Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology

Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot

© 2018 While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings