24 research outputs found
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Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2âmillion individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures
Lipopolysaccharide Diversity Evolving in Helicobacter pylori Communities through Genetic Modifications in Fucosyltransferases
Helicobacter pylori persistently colonizes the gastric mucosa of half the human population. It is one of the most genetically diverse bacterial organisms and subvariants are continuously emerging within an H. pylori population. In this study we characterized a number of single-colony isolates from H. pylori communities in various environmental settings, namely persistent human gastric infection, in vitro bacterial subcultures on agar medium, and experimental in vivo infection in mice. The lipopolysaccharide (LPS) O-antigen chain revealed considerable phenotypic diversity between individual cells in the studied bacterial communities, as demonstrated by size variable O-antigen chains and different levels of Lewis glycosylation. Absence of high-molecular-weight O-antigen chains was notable in a number of experimentally passaged isolates in vitro and in vivo. This phenotype was not evident in bacteria obtained from a human gastric biopsy, where all cells expressed high-molecular-weight O-antigen chains, which thus may be the preferred phenotype for H. pylori colonizing human gastric mucosa. Genotypic variability was monitored in the two genes encoding α1,3-fucosyltransferases, futA and futB, that are involved in Lewis antigen expression. Genetic modifications that could be attributable to recombination events within and between the two genes were commonly detected and created a diversity, which together with phase variation, contributed to divergent LPS expression. Our data suggest that the surrounding environment imposes a selective pressure on H. pylori to express certain LPS phenotypes. Thus, the milieu in a host will select for bacterial variants with particular characteristics that facilitate adaptation and survival in the gastric mucosa of that individual, and will shape the bacterial community structure
Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use
Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6â11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures
Genetic diversity fuels gene discovery for tobacco and alcohol use
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe
Effectiveness and safety of opicapone in Parkinsonâs disease patients with motor fluctuations: the OPTIPARK open-label study
Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinsonâs disease and motor fluctuations were treated with opicapone 50âmg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinicianâs Global Impression of Change (CGI-C) after 3âmonths. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinsonâs Disease Rating Scale (UPDRS), Parkinsonâs Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3âmonths of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3âmonths, respectively (full analysis set). At 6âmonths, for UK subgroup only (nâ=â95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3âmonths showed statistically significant improvements in activities of daily living during OFF (meanâ±âSD change from baseline: ââ3.0â±â4.6, pâ<â0.0001) and motor scores during ON (ââ4.6â±â8.1, pâ<â0.0001). The meanâ±âSD improvements of ââ3.4â±â12.8 points for PDQ-8 and -6.8â±â19.7 points for NMSS were statistically significant versus baseline (both pâ<â0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50âmg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)
Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters
The human serotonin transporter (hSERT), the human dopamine
transporter
(hDAT), and the human norepinephrine transporter (hNET) facilitate
the active uptake of the neurotransmitters serotonin, dopamine, and
norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA
(streetname âecstasyâ) and certain 1-phenyl-piperazine
(PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their
stimulatory effect by elevating the synaptic concentration of serotonin
by blocking or reversing the normal transport activity of hSERT. Recent
data suggest that certain analogs of PP may be able to counteract
the addictive effect of cocaine. Little is still known about the precise
mechanism by which MDMA and PP analogs function at hSERT, hDAT, and
hNET and even less is known about the specific proteinâligand
interactions. In this study, we provide a comprehensive biochemical
examination of a repertoire of PP analogs in hSERT, hDAT, and hNET.
Combined with induced fit docking models and molecular dynamics simulations
of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT
and hDAT, we present detailed molecular insight into the promiscuous
binding of PP analogs in the monoamine transporters. We find that
PP analogs inhibit uptake as well as induce release in all three monoamine
transporters. We also find that the selectivity of the PP analogs
can be adjusted by carefully selecting substituents on the PP skeleton
Body Mass Index, Depression, and Condom Use Among HIV-Infected Men who have Sex with Men: A Longitudinal Moderation Analysis
Findings have been inconsistent regarding the association of obesity and sexual risk behaviors. The purpose of the current study was to assess the prospective nature of body mass index (BMI), depression, and their interaction in predicting condom use during anal intercourse among HIV-infected men who have sex with men (MSM). The sample (N = 490) was obtained from a large, HIV clinical cohort from four sites across the U.S. The following inclusion criteria were employed: identification as MSM and had completed at least one wave of patient-reported measures (e.g., depression, as measured by the PHQ-9) in the clinical cohort study. Longitudinal linear mixed-effects modeling revealed a significant BMI by depression interaction. Depressive symptoms were predictive of less frequent condom use for obese but not overweight men. Analogous results were found in regard to comparisons between normal weight and overweight men. Obesity, in the context of depression, is a risk factor for unprotected anal intercourse among HIV-infected MSM. Cognitive behavioral interventions to reduce HIV transmission risk behaviors among HIV-infected MSM should adopt an integrated perspective, combining sexual risk reduction with treatment for depression and body-related concerns