A Polygenic Score for Type 2 Diabetes Improves Risk Stratification Beyond Current Clinical Screening Factors in an Ancestrally Diverse Sample.

A substantial proportion of the adult United States population with type 2 diabetes (T2D) are undiagnosed, calling into question the comprehensiveness of current screening practices, which primarily rely on age, family history, and body mass index (BMI). We hypothesized that a polygenic score (PGS) may serve as a complementary tool to identify high-risk individuals. The T2D polygenic score maintained predictive utility after adjusting for family history and combining genetics with family history led to even more improved disease risk prediction. We observed that the PGS was meaningfully related to age of onset with implications for screening practices: there was a linear and statistically significant relationship between the PGS and T2D onset (-1.3 years per standard deviation of the PGS). Evaluation of U.S. Preventive Task Force and a simplified version of American Diabetes Association screening guidelines showed that addition of a screening criterion for those above the 90th percentile of the PGS provided a small increase the sensitivity of the screening algorithm. Among T2D-negative individuals, the T2D PGS was associated with prediabetes, where each standard deviation increase of the PGS was associated with a 23% increase in the odds of prediabetes diagnosis. Additionally, each standard deviation increase in the PGS corresponded to a 43% increase in the odds of incident T2D at one-year follow-up. Using complications and forms of clinical intervention (i.e., lifestyle modification, metformin treatment, or insulin treatment) as proxies for advanced illness we also found statistically significant associations between the T2D PGS and insulin treatment and diabetic neuropathy. Importantly, we were able to replicate many findings in a Hispanic/Latino cohort from our database, highlighting the value of the T2D PGS as a clinical tool for individuals with ancestry other than European. In this group, the T2D PGS provided additional disease risk information beyond that offered by traditional screening methodologies. The T2D PGS also had predictive value for the age of onset and for prediabetes among T2D-negative Hispanic/Latino participants. These findings strengthen the notion that a T2D PGS could play a role in the clinical setting across multiple ancestries, potentially improving T2D screening practices, risk stratification, and disease management.

Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Underrecognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. RESEARCH QUESTION: The study addressed three questions: (1) Does a DTC testing service identify previously undetected individuals with AATD? (2) What was the interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and (3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? STUDY DESIGN AND METHODS: In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. RESULTS: Among 195,014 study participants, the allele frequency for the PI∗S and PI∗Z AATD variants was 21.6% (6.5% for PI∗Z and 15.1% for PI∗S); 0.63% were PI∗ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with health care providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI∗ZZ individuals shared their DTC result with an HCP. The OR for PI∗ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 (95% CI = 1.4-2.2) compared with those without a Z allele and for reduced alcohol consumption this was 4.0 (95% CI = 2.6-5.9). INTERPRETATION: In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

CYP2C19 Allele Frequencies in Over 2.2 Million Direct-to-Consumer Genetics Research Participants and the Potential Implication for Prescriptions in a Large Health System.

Understanding the prevalence of clinically relevant pharmacogenetic variants using large unselected populations is critical for gauging the potential clinical impact of widespread preemptive pharmacogenetic testing. To this end, we assessed the frequencies and ethnic distribution of the three most common CYP2C19 alleles (*2, *3, and *17) in 2.29 million direct-to-consumer genetics research participants (23andMe, Sunnyvale, CA). The overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17, and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele. To better understand how this high frequency might impact a real patient population, we examined the prescription rates (Rx) of high-pharmacogenetic-risk medications metabolized by CYP2C19 using the University of California at San Francisco (UCSF) health system's anonymized database of over 1.25 million patients. Between 2012 and 2019, a total of 151,068 UCSF patients (15.8%) representing 5 self-reported ethnicities were prescribed one or more high-pharmacogenetic-risk CYP2C19 medications: proton pump inhibitors (145,243 Rx), three selective serotonin reuptake inhibitor antidepressants (54,463 Rx), clopidogrel (14,376 Rx), and voriconazole (2,303 Rx).

GABRA2, alcohol, and illicit drug use: An event-level model of genetic risk for polysubstance use.

GABRA2, the gene encoding the α2 subunit of the GABAA receptor, potentially plays a role in the etiology of problematic drinking, as GABRA2 genotype has been associated with subjective response to alcohol and other alcohol-related reward processes. The GABRA2 gene has also been associated with illicit drug use, but the extent to which associations with drug use are independent of associations with alcohol use remains unclear, partly because most previous research has used a cross-sectional design that cannot discriminate comorbidity at the between-person level and co-occurrence within-persons. The present study used a daily monitoring method that assessed the effects of GABRA2 variation on substance use as it occurred in the natural environment during emerging adulthood. Non-Hispanic European participants provided DNA samples and completed daily reports of alcohol and drug use for 1 month per year across 4 years (N = 28,263 unique observations of N = 318 participants). GABRA2 variants were associated with illicit drug use in both sober and intoxicated conditions. Moreover, the effect of GABRA2 variation on drug use was moderated by an individual's degree of intoxication. These findings are consistent with recent genetic and neuroscience research, and they suggest GABRA2 variation influences drug-seeking behavior through both alcohol-related and alcohol-independent pathways. (PsycINFO Database Record

Developmentally Specific Associations Between CNR1 Genotype and Cannabis Use Across Emerging Adulthood.

OBJECTIVE: Previous studies have found preliminary evidence for associations between common single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor gene CNR1 and cannabis use and dependence. The present study examined a set of eight independent SNPs in or near CNR1 in relation to cannabis use measured longitudinally across emerging adulthood. METHOD: Using latent growth curve modeling of 10 waves of longitudinal data spanning mean ages 18.4-23.8 years in a sample of non-Hispanic White individuals (n = 334), we tested if genotype at each CNR1 SNP was associated with both level and growth of cannabis use over time. Peer group drug use, a known correlate of individual use, was evaluated as a time-varying predictor of cannabis use and as a moderator of the relationship between SNPs and individual use. RESULTS: After correction for multiple comparisons, one SNP, rs806374, was significantly associated with individual differences in level-but not growth-of cannabis use over time, such that C carriers were more likely to use cannabis more frequently at study onset (around age 18). Peer drug use was a predictor of individual cannabis use that grew in terms of effect size with time, but did not significantly moderate the effect of rs806374 genotype. CONCLUSIONS: C carriers at rs806374 may be at specific risk for increased odds of use during the transition out of high school (around age 18). Future studies should investigate potential mechanisms at this developmental stage, including individual differences in subjective response, innate tolerance, reinforcement mechanisms, or general liability for substance misuse.

Freshman year alcohol and marijuana use prospectively predict time to college graduation and subsequent adult roles and independence.

OBJECTIVE: This study examined how freshman year substance use prospectively predicted time to college graduation, and whether delayed graduation predicted postponed adoption of adult roles and future substance use. PARTICIPANTS: Participants were part of a longitudinal study that began in 2004. The first analyses focused on freshman year (N = 2,050). The second analyses corresponded to a subset of participants at age 27 (N = 575). METHODS: Measures included self-reported substance use, adult role adoption, and university reported graduation dates. RESULTS: Results indicated that frequent binge drinking and marijuana use during freshman year predicted delayed college graduation. Those who took longer to graduate were more likely to have lower incomes and were less likely to obtain a graduate degree. Taking 5-6 years to graduate was associated with greater likelihood of alcohol-related problems. CONCLUSIONS: Findings support the importance of interventions during freshman year of college to decrease substance use and promote timely graduation.

Number of Sexual Partners and Relationship Status Are Associated With Unprotected Sex Across Emerging Adulthood.

Sex with multiple partners, consecutively or concurrently, is a risk factor for contracting sexually transmitted infections (STIs) as multiple partner-partner contacts present increased opportunity for transmission. It is unclear, however, if individuals who tend to have more partners also use protection less reliably than those with sexual histories of fewer partners. Longitudinal data can elucidate whether an individual shows a consistent pattern of sex with multiple partners. We used latent class growth analyses to examine emerging adult survey data (N = 2244) spanning 10 waves of assessment across 6 years. We identified three trajectory classes described with respect to number of partners as (a) Multiple, (b) Single, and (c) Rare. Trajectory group, relationship status, and their interactions were tested as predictors of using protection against STIs and pregnancy at each wave. The Multiple Partners class had the greatest odds ratio of reporting sex without protection against STIs and pregnancy, followed by the Single and Rare classes. Exclusive relationship status was a risk factor for unprotected sex at earlier waves, but a protective factor at most later waves. There was no significant interaction between relationship status and trajectory class in predicting use of protection. The Multiple Partners class reported more permissive values on sex and an elevated proportion of homosexual behavior. This group overlaps with an already identified at-risk population, men who have sex with men. Potential mechanisms explaining the increased risk for sex without protection, including communication, risk assessment, and co-occurring risk behaviors are discussed as targets for intervention.

Alcohol-related genes show an enrichment of associations with a persistent externalizing factor.

Research using twins has found that much of the variability in externalizing phenotypes-including alcohol and drug use, impulsive personality traits, risky sex, and property crime-is explained by genetic factors. Nevertheless, identification of specific genes and variants associated with these traits has proven to be difficult, likely because individual differences in externalizing are explained by many genes of small individual effect. Moreover, twin research indicates that heritable variance in externalizing behaviors is mostly shared across the externalizing spectrum rather than specific to any behavior. We use a longitudinal, "deep phenotyping" approach to model a general externalizing factor reflecting persistent engagement in a variety of socially problematic behaviors measured at 11 assessment occasions spanning early adulthood (ages 18 to 28). In an ancestrally homogenous sample of non-Hispanic Whites (N = 337), we then tested for enrichment of associations between the persistent externalizing factor and a set of 3,281 polymorphisms within 104 genes that were previously identified as associated with alcohol-use behaviors. Next, we tested for enrichment among domain-specific factors (e.g., property crime) composed of residual variance not accounted for by the common factor. Significance was determined relative to bootstrapped empirical thresholds derived from permutations of phenotypic data. Results indicated significant enrichment of genetic associations for persistent externalizing, but not for domain-specific factors. Consistent with twin research findings, these results suggest that genetic variants are broadly associated with externalizing behaviors rather than unique to specific behaviors. (PsycINFO Database Record

Trajectories of binge drinking and personality change across emerging adulthood.

College students binge drink more frequently than the broader population, yet most individuals "mature out" of binge drinking. Impulsivity and sensation seeking traits are important for understanding who is at risk for maintaining binge drinking across college and the transition to adult roles. We use latent class growth analysis (LCGA) to examine longitudinal binge-drinking trajectories spanning from the end of high school through 2 years after college (M ages = 18.4 to 23.8). Data were gathered over 10 waves from students at a large Southwestern university (N = 2,245). We use latent factor models to estimate changes in self-reported impulsive (IMP) and sensation-seeking (SS) personality traits across 2 time periods-(a) the end of high school to the end of college and (b) the 2-year transition out of college. LCGA suggested 7 binge-drinking trajectories: frequent, moderate, increasing, occasional, low increasing, decreasing, and rare. Models of personality showed that from high school through college, change in SS and IMP generally paralleled drinking trajectories, with increasing and decreasing individuals showing corresponding changes in SS. Across the transition out of college, only the increasing group demonstrated a developmentally deviant increase in IMP, whereas all other groups showed normative stability or decreases in both IMP and SS. These data indicate that "late bloomers," who begin binge drinking only in the later years of college, are a unique at-risk group for drinking associated with abnormal patterns of personality maturation during emerging adulthood. Our results indicate that personality targeted interventions may benefit college students.

Modeling behavioral reactivity to losses and rewards on the Balloon Analogue Risk Task (BART): moderation by alcohol problem severity.

The relationship between risk-taking behavior and substance dependence has proven to be complex, particularly when examining across participants expressing a range of substance use problem severity. While main indices of risk-taking in the Balloon Analogue Risk Task (BART) positively associate with problematic alcohol use in adolescent populations (e.g., MacPherson, Magidson, Reynolds, Kahler, & Lejuez, 2010), several studies have observed a negative relationship when examining behavior within adult substance using populations (Ashenhurst, Jentsch, & Ray, 2011; Campbell, Samartgis, & Crowe, 2013). To examine potential mechanisms that underlie this negative relationship, we implemented multilevel regression models on trial-by-trial BART data gathered from 295 adult problem drinkers. These models accounted for participant behavior on trials following balloon bursts or cash outs as indices of loss and reward reactivity, respectively, and included control variables including age, IQ, and individual delay discounting rate. Results revealed that individual trial pumping was significantly predicted by trial number, and by whether or not the previous trial was a big burst or a big cash out (i.e., large magnitude of potential gains) in a manner consistent with a "near-miss" effect. Furthermore, severity of alcohol problems moderated the effect of a previous trial big burst, but not of a big cash out, on subsequent trial behavior such that those with greater severity demonstrated relative insensitivity to this "near-miss" effect. These results extend previous studies suggesting that alcohol abusers are less risky on the BART by specifying a mechanism underlying this pattern, namely, diminished reactivity to large magnitude losses.

Dissecting impulsivity and its relationships to drug addictions.

Addictions are often characterized as forms of impulsive behavior. That said, it is often noted that impulsivity is a multidimensional construct, spanning several psychological domains. This review describes the relationship between varieties of impulsivity and addiction-related behaviors, the nature of the causal relationship between the two, and the underlying neurobiological mechanisms that promote impulsive behaviors. We conclude that the available data strongly support the notion that impulsivity is both a risk factor for, and a consequence of, drug and alcohol consumption. While the evidence indicating that subtypes of impulsive behavior are uniquely informative--either biologically or with respect to their relationships to addictions--is convincing, multiple lines of study link distinct subtypes of impulsivity to low dopamine D2 receptor function and perturbed serotonergic transmission, revealing shared mechanisms between the subtypes. Therefore, a common biological framework involving monoaminergic transmitters in key frontostriatal circuits may link multiple forms of impulsivity to drug self-administration and addiction-related behaviors. Further dissection of these relationships is needed before the next phase of genetic and genomic discovery will be able to reveal the biological sources of the vulnerability for addiction indexed by impulsivity.

Interactive effects of OPRM1 and DAT1 genetic variation on subjective responses to alcohol.

AIMS: Subjective response to alcohol represents a marker of alcoholism risk. The A118G single-nucleotide polymorphism (SNP) of the mu opioid receptor (OPRM1) gene has been associated with subjective response to alcohol. Recently, the dopamine transporter (DAT1) variable number of tandem repeat (VNTR; SLC6A3) has been found to interact with the OPRM1 A118G SNP in predicting neural and behavioral responses to naltrexone and to alcohol. This exploratory study examines the OPRM1 × DAT1 interaction on subjective responses to alcohol. METHODS: Non-treatment-seeking problem drinkers (n = 295) were assessed in the laboratory for alcohol dependence. Following prospective genotyping for the OPRM1 gene, 43 alcohol-dependent individuals were randomized to two intravenous infusion sessions, one of alcohol (target BrAC = 0.06 g/dl) and one of saline. Measures of subjective responses to alcohol were administered in both infusion sessions. RESULTS: Analyses revealed significant Alcohol × OPRM1 × DAT1 interactions for alcohol-induced stimulation, vigor and positive mood as well as significant Alcohol × OPRM1 × DAT1 × Time interactions for stimulation and positive mood. These effects were such that, compared with other genotype groups, OPRM1 G-allele carriers + DAT1 A10 homozygotes reported steeper increases in stimulation and positive mood across rising BrAC, when compared with placebo. All Alcohol × OPRM1 × DAT1 interactions remained significant when analyses were restricted to a subsample of Caucasian participants (n = 34); however, 4-way interactions did not reach statistical significance in this subsample. CONCLUSIONS: This study suggests that the contribution of OPRM1 genotype to alcohol-induced stimulation, vigor and positive mood is moderated by DAT1 genotype. These findings are consistent with the purported interaction between opioidergic and dopaminergic systems in determining the reinforcing properties of alcohol.

Craving and subjective responses to alcohol administration: validation of the desires for alcohol questionnaire in the human laboratory.

OBJECTIVE: The abbreviated Desires for Alcohol Questionnaire (DAQ) is a self-report assessment of craving comprising the following subscales: (a) strong desires/intentions to drink, (b) negative reinforcement, and (c) positive reinforcement and ability to control drinking. Although the DAQ is sensitive to changes in alcohol craving precipitated by alcohol administration and/or cue exposure, no studies to date have examined the relationship between DAQ scores and subjective responses to alcohol. This study addresses this gap in the literature by testing the relationship between subjective responses to alcohol during alcohol administration and DAQ scores assessed 1 month later. METHOD: Individuals with alcohol dependence (n = 32) completed a randomized, single-blinded, intravenous alcohol administration in the laboratory in which subjective responses to the alcohol were measured, followed by a visit to the laboratory 1 month later to complete the DAQ. RESULTS: Analyses revealed robust associations between DAQ scores and alcohol craving during alcohol administration (partial correlations: r = .43-.50, ps < .01), with the exception of the positive reinforcement subscale (r = .20, p = .30). Subjective intoxication and sedation were only associated with the negative reinforcement subscale of the DAQ (r = .38, p < .05 and r = .33, p < .05, respectively). CONCLUSIONS: Craving, captured by the DAQ, is reliably and positively associated with alcohol-induced craving. The DAQ is also associated with specific dimensions of subjective responses to alcohol. These results support the clinical utility of the DAQ, particularly in large samples where experimental manipulations may not be feasible.

Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol.

Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibility that single nucleotide polymorphisms (SNPs) in the kappa and delta opioid receptor (OPRK1 and OPRD1) genes may contribute to naltrexone pharmacogenetics. Therefore, the goal of this exploratory study was to re-examine data from a double-blind placebo controlled laboratory trial of naltrexone for pharmacogenetic effects at kappa and delta opioid receptor tag SNPs. Participants were 40 heavy drinkers (12 female) who underwent an intravenous alcohol challenge paradigm after receiving naltrexone (50mg) or placebo in randomized and crossover fashion. Dependent variables were self-reported alcohol-induced stimulation, sedation, and craving. Multilevel models revealed a significant Naltrexone×OPRK1 Genotype (rs997917) interaction predicting alcohol-induced sedation, such that TT homozygotes reported lower naltrexone-induced alcohol sedation as compared to carriers of the C allele. Moreover, there was a significant Naltrexone×OPRD1 Genotype (rs4654327) interaction predicting alcohol-induced stimulation and craving, such that carriers of the A allele at this locus reported greater naltrexone-induced blunting of alcohol stimulation and alcohol craving compared to GG homozygotes. These findings suggest that additional pharmacogenetic effects in the opioid receptor system may account for individual differences in response to naltrexone in the human laboratory.

Responding in a test of decision-making under risk is under moderate genetic control in the rat.

BACKGROUND: Risk-taking, measured with laboratory tasks such as the Balloon Analog Risk Task (BART), is associated with real-life manifestations of risky behaviors, which may be an important component of inherited liability to alcohol use disorders. To identify genomic factors that influence these traits, the current study (i) characterized performance of a rodent version of the BART in multiple inbred rat strains, (ii) tested the degree to which performance was under genetic control, (iii) explored sex differences in performance, and (iv) evaluated the risk-taking behavior of F1 progeny of high-risk- and low-risk-taking strains to examine modes of inheritance. METHODS: Male and female rats (N = 100) from 5 inbred strains (Wistar-Furth, Fischer-344, Lewis, Spontaneously Hypertensive, Brown Norway) and Wistar-Furth × Fischer-344 hybrids were tested in the rat-BART, as well as in tests of locomotor activity, sucrose preference, and general motivation. RESULTS: About 55% of the variance in risk-taking behavior was attributable to heritable factors. The Fischer-344 strain was the most risk-taking and the most variable in responding. The mating of low-risk-taking Wistar-Furth and Fischer-344 rats produced progeny that behaved most like the Fischer-344 strain. Consistent with prior research in this laboratory (Jentsch et al., 2010), all rats were sensitive to changes in both risk and reinforcement parameters in the rat-BART; rats decreased voluntary risk-taking in the face of increasing risk and increased lever pressing when reinforcement probabilities were reduced. CONCLUSIONS: Our results endorse a moderately heritable pattern of risk-taking behavior in rats. The behavior of the hybrid progeny suggests a polygenic model with most gene effects transmitted by mode of dominant inheritance. The identification of high-risk and low-risk strains allows for isolation of quantitative trait loci associated with task performance and for probing the relationships between risk-taking and dimensions of alcohol use disorders.

Risk-taking and alcohol use disorders symptomatology in a sample of problem drinkers.

The relationship between risk-taking behavior and alcohol use disorder (AUD) symptoms is poorly understood. This study employed a modified version of a behavioral measure of risk-taking, the Balloon Analogue Risk Task (BART), to examine its relationship to alcohol use and related symptoms in a community sample of individuals with or at risk for AUD. A total of 158 (71.9% male) participants completed a testing battery that included the BART, a structured diagnostic interview for AUD, and measures of alcohol use and related problems. Estimates of IQ and working memory were assessed as covariates. Results indicated that the relationship between risk-taking propensity, as assessed by the BART, and alcohol problems was significant and negative. Individuals with higher symptom count made fewer pumps per trial on the BART, indicating less risk-taking. It is important to note that this relationship was attenuated when controlling for estimated IQ and working memory span. Further examination demonstrated that IQ and age mediated the relationship between risk-taking propensity and symptom count. The main negative relationship observed between risk-taking on the BART and alcohol use and AUD symptomatology in this sample stands in contrast to the positive relationships observed in adolescent and nonclinical samples. Together, these findings highlight the need to consider development and the course of addiction to fully elucidate the effects of risky-decision making on AUD liability. Furthermore, our results demonstrate the importance of inclusion of neurocognitive covariates (IQ), as well as demographic variables (age) when using this task.

Naltrexone selectively elevates GABAergic neuroactive steroid levels in heavy drinkers with the Asp40 allele of the OPRM1 gene: a pilot investigation.

BACKGROUND: Preclinical studies have implicated GABAergic neurosteroids in behavioral responses to alcohol. Naltrexone is thought to blunt the reinforcing effects of alcohol, and a few studies have found that the effects of naltrexone are moderated by the Asn40Asp polymorphisms of the OPRM1 gene. The present study seeks to integrate these lines of research by testing (i) the moderating role of the functional Asn40Asp polymorphism of the OPRM1 gene on naltrexone-induced alternations in GABAergic neurosteroid levels, namely (3alpha,5alpha)-3-hydroxypregnan-20-one (allopregnanolone, ALLO); and (ii) the combined effects of naltrexone or genotype with alcohol administration on neurosteroid levels in a sample of at-risk drinkers. METHODS: Participants were 32 (9 females) nontreatment-seeking heavy drinkers who completed a placebo-controlled laboratory study of naltrexone (50 mg/d for 3 days) and provided complete sets of serum samples for ALLO assays before and after alcohol administration under both naltrexone and placebo conditions. RESULTS: Naltrexone treatment raised ALLO levels among carriers of the Asp40 allele, but not homozygotes for the Asn40 allele. The Asn40Asp polymorphism did not moderate effects of naltrexone on cortisol levels. Ethanol infusion modestly reduced ALLO levels in all subjects, independent of genotype or naltrexone exposure. CONCLUSIONS: Naltrexone increased ALLO levels among individuals with the Asn40Asp allele suggesting a potential neurosteroid contribution to the neuropharmacological effects of naltrexone among Asp40 carriers.

Intermolecular oxidative cross-coupling of arenes.

Biaryls constitute an important subunit found in medicinal agents, functional materials, and natural products. While the Suzuki reaction and related processes currently represent the method of choice for the construction of arene-arene bonds, the direct-coupling of two unfunctionalized arenes mediated by the addition of an oxidant represents a powerful alternative strategy for biaryl synthesis. This tutorial review describes recent progress in this rapidly developing field, focusing on intermolecular examples of selective arene oxidation strategies and metal-catalyzed oxidative cross-coupling via C-H activation.

Total synthesis of (+)-11,11'-dideoxyverticillin A.

The fungal metabolite (+)-11,11'-dideoxyverticillin A, a cytotoxic alkaloid isolated from a marine Penicillium sp., belongs to a fascinating family of densely functionalized, stereochemically complex, and intricate dimeric epidithiodiketopiperazine natural products. Although the dimeric epidithiodiketopiperazines have been known for nearly 4 decades, none has succumbed to total synthesis. We report a concise enantioselective total synthesis of (+)-11,11'-dideoxyverticillin A via a strategy inspired by our biosynthetic hypothesis for this alkaloid. Highly stereo- and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions, as well as a mild strategy for the introduction of the epidithiodiketopiperazine core in the final step, were developed to address this highly sensitive substructure. Our rapid functionalization of the advanced molecular framework aims to mimic plausible biosynthetic steps and offers an effective strategy for the chemical synthesis of other members of this family of alkaloids.