ABSTRACT
The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.
ABSTRACT
BACKGROUND: Low level of responses (low LRs) to alcohol established using the Self-Report of the Effects of Alcohol (SRE) questionnaire are genetically influenced phenotypes related to heavy drinking and alcohol problems. To date, most studies using SREs focused on scores for the number of drinks needed for effects across the first 5 times of drinking (SRE-5), and few evaluated scores that also included the prior 3 months and heaviest drinking periods (SRE-T). This paper evaluates characteristics of SRE-5 and SRE-T within and across generations. METHODS: Data were extracted from 407 participants across 2 generations of 107 families in the San Diego Prospective Study (SDPS). Pearson's product-moment correlations for SRE-5 and SRE-T were determined across first-degree relatives both within and across generations and sexes, as well as correlations of each measure to maximum drinking quantities and alcohol problems. RESULTS: Responding to 4 hypotheses, first the analyses demonstrated significant within-generation positive correlations for both SRE measures across brother-brother and sister-sister pairs as well as cross-generation correlations for fathers and sons, although correlations for mothers and daughters were not robust. Second, both SRE-5 and SRE-T correlated with maximum drinks and alcohol problems for both sexes and both generations. Third, within parental and offspring generations SRE-T correlated more robustly than SRE-5 to maximum drinks and alcohol problems. Fourth, across generations SRE values for sons were more closely related to drinking quantities and problems than for their fathers, but the mother-daughter SRE relationships to adverse alcohol characteristics were not different. CONCLUSIONS: Both the SRE-5 and SRE-T offered useful information about propensities toward heavier drinking and alcohol problems in SDPS families. Correlations with adverse alcohol outcomes were greater for the more broad-based SRE-T, but both scores appeared to be genetically influenced and continue to operate in a robust manner in both generations of these families.
Subject(s)
Alcohol Drinking/psychology , Self Report , Surveys and Questionnaires , Adolescent , Adult , Age Factors , Aged , Alcoholism/diagnosis , Alcoholism/psychology , Fathers , Female , Humans , Male , Middle Aged , Mothers , Prospective Studies , Reproducibility of Results , Sex Factors , Siblings , Young AdultABSTRACT
OBJECTIVES: Sleep quality affects memory and executive function in older adults, but little is known about its effects in midlife. If it affects cognition in midlife, it may be a modifiable factor for later-life functioning. METHODS: We examined the association between sleep quality and cognition in 1220 middle-aged male twins (age 51-60 years) from the Vietnam Era Twin Study of Aging. We interviewed participants with the Pittsburgh Sleep Quality Index and tested them for episodic memory as well as executive functions of inhibitory and interference control, updating in working memory, and set shifting. Interference control was assessed during episodic memory, inhibitory control during working memory, and non-memory conditions and set shifting during working memory and non-memory conditions. RESULTS: After adjusting for covariates and correcting for multiple comparisons, sleep quality was positively associated with updating in working memory, set shifting in the context of working memory, and better visual-spatial (but not verbal) episodic memory, and at trend level, with interference control in the context of episodic memory. CONCLUSIONS: Sleep quality was associated with visual-spatial recall and possible resistance to proactive/retroactive interference. It was also associated with updating in working memory and with set shifting, but only when working memory demands were relatively high. Thus, effects of sleep quality on midlife cognition appear to be at the intersection of executive function and memory processes. Subtle deficits in these age-susceptible cognitive functions may indicate increased risk for decline in cognitive abilities later in life that might be reduced by improved midlife sleep quality. (JINS, 2018, 24, 67-76).
Subject(s)
Aging/physiology , Attention/physiology , Cognitive Dysfunction/physiopathology , Executive Function/physiology , Inhibition, Psychological , Memory, Episodic , Memory, Short-Term/physiology , Mental Recall/physiology , Sleep Wake Disorders/physiopathology , Sleep/physiology , Cognitive Dysfunction/epidemiology , Comorbidity , Humans , Male , Middle Aged , Sleep Wake Disorders/epidemiologyABSTRACT
OBJECTIVE: Positive psychological factors (PPFs) have been reported to have a significant impact on health in the general population. However, little is known about the relationship of these factors with mental and physical health in schizophrenia. METHOD: One hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65 years, were evaluated with scales of resilience, optimism, happiness, and perceived stress. Measures of mental and physical health were also obtained. Regression analyses examined associations of a PPF composite with health variables. RESULTS: Relative to the HCs, the schizophrenia group had lower levels of PPFs. However, there was considerable heterogeneity, with over one-third of schizophrenia participants having values within the 'normative' range. The PPF composite was positively related to mental and physical health variables and with biomarkers of inflammation and insulin resistance. The relationship between PPFs and mental health was particularly strong for individuals with schizophrenia. CONCLUSION: A sizable minority of adults with chronic schizophrenia have levels of resilience, optimism, happiness, and perceived stress similar to HCs. Psychosocial interventions to enhance PPFs should be tested in patients with serious mental illnesses, with the goal of improving their mental health (beyond controlling symptoms of psychosis) and their physical health.
Subject(s)
Health Status , Mental Health , Quality of Life , Resilience, Psychological , Schizophrenia/complications , Adult , Aged , Biomarkers/blood , Case-Control Studies , Cross-Sectional Studies , Female , Health Surveys , Humans , Male , Middle Aged , Schizophrenic Psychology , Self Concept , Severity of Illness IndexABSTRACT
Background: Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods: Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results: Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone's effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion: Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.
Subject(s)
Benzophenones/pharmacology , Brain Mapping , Brain/drug effects , Catechol O-Methyltransferase Inhibitors/pharmacology , Cognition/drug effects , Evoked Potentials/drug effects , Nitrophenols/pharmacology , Adolescent , Adult , Brain/physiology , Catechol O-Methyltransferase/genetics , Choice Behavior/drug effects , Cross-Over Studies , Double-Blind Method , Evoked Potentials/genetics , Female , Genotype , Healthy Volunteers , Humans , Learning/drug effects , Male , Neuropsychological Tests , Photic Stimulation , Tolcapone , Young AdultABSTRACT
In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific.
Subject(s)
Stress, Psychological/immunology , Adrenal Cortex/metabolism , Adult , Catecholamines/blood , Cross-Sectional Studies , Down-Regulation , Female , Gene Expression/genetics , Humans , Hydrocortisone/metabolism , Immunomodulation , Interleukin-12/blood , Interleukin-12/metabolism , Killer Cells, Natural/immunology , Leukocytes/immunology , Male , Sex Factors , Signal Transduction/immunology , Stress, Psychological/metabolism , Sweating, Gustatory , Toll-Like Receptors/blood , Toll-Like Receptors/metabolism , Transcriptome/immunology , Up-RegulationABSTRACT
OBJECTIVE: Optimism and resilience promote health and well-being in older adults, and previous reports suggest that these traits are heritable. We examined the association of selected single-nucleotide polymorphisms (SNPs) with optimism and resilience in older adults. DESIGN: Candidate gene association study that was a follow-on at the University of California, San Diego, sites of two NIH-funded multi-site longitudinal investigations: Women's Health Initiative (WHI) and SELenium and vitamin E Cancer prevention Trial (SELECT). PARTICIPANTS: 426 women from WHI older than age 50 years, and 509 men older than age 55 years (age 50 years for African American men) from SELECT. MEASUREMENTS: 65 candidate gene SNPs that were judged by consensus, based on a literature review, as being related to predisposition to optimism and resilience, and 31 ancestry informative marker SNPs, genotyped from blood-based DNA samples and self-report scales for trait optimism, resilience, and depressive symptoms. RESULTS: Using a Bonferroni threshold for significant association (p = 0.00089), there were no significant associations for individual SNPs with optimism or resilience in single-locus analyses. Exploratory multi-locus polygenic analyses with p <0.05 showed an association of optimism with SNPs in MAOA, IL10, and FGG genes, and an association of resilience with a SNP in MAOA gene. CONCLUSIONS: Correcting for Type I errors, there were no significant associations of optimism and resilience with specific gene SNPs in single-locus analyses. Positive psychological traits are likely to be genetically complex, with many loci having small effects contributing to phenotypic variation. Our exploratory multi-locus polygenic analyses suggest that larger sample sizes and complementary approaches involving methods such as sequence-based association studies, copy number variation analyses, and pathway-based analyses could be useful for better understanding the genetic basis of these positive psychological traits.
Subject(s)
Aging/genetics , Fibrinogens, Abnormal/genetics , Interleukin-10/genetics , Monoamine Oxidase/genetics , Personality/genetics , Polymorphism, Single Nucleotide/genetics , Resilience, Psychological , Aged , Aged, 80 and over , Depression/genetics , Female , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Multifactorial Inheritance/genetics , White People/geneticsABSTRACT
Poor sleep quality is a risk factor for a number of cognitive and physiological age-related disorders. Identifying factors underlying sleep quality are important in understanding the etiology of these age-related health disorders. We investigated the extent to which genes and the environment contribute to subjective sleep quality in middle-aged male twins using the classical twin design. We used the Pittsburgh Sleep Quality Index to measure sleep quality in 1218 middle-aged twin men from the Vietnam Era Twin Study of Aging (mean age = 55.4 years; range 51-60; 339 monozygotic twin pairs, 257 dizygotic twin pairs, 26 unpaired twins). The mean PSQI global score was 5.6 [SD = 3.6; range 0-20]. Based on univariate twin models, 34% of variability in the global PSQI score was due to additive genetic effects (heritability) and 66% was attributed to individual-specific environmental factors. Common environment did not contribute to the variability. Similarly, the heritability of poor sleep-a dichotomous measure based on the cut-off of global PSQI>5-was 31%, with no contribution of the common environment. Heritability of six of the seven PSQI component scores (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, and daytime dysfunction) ranged from 0.15 to 0.31, whereas no genetic influences contributed to the use of sleeping medication. Additive genetic influences contribute to approximately one-third of the variability of global subjective sleep quality. Our results in middle-aged men constitute a first step towards examination of the genetic relationship between sleep and other facets of aging.
Subject(s)
Environment , Sleep/genetics , Sleep/physiology , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , Aging/genetics , Humans , Male , Middle Aged , Sleep Wake Disorders/genetics , Sleep Wake Disorders/physiopathology , Time FactorsABSTRACT
The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. Management of the pandemic has relied mainly on SARS-CoV-2 vaccines, while alternative approaches such as meditation, shown to improve immunity, have been largely unexplored. Here, we probe the relationship between meditation and COVID-19 disease and directly test the impact of meditation on the induction of a blood environment that modulates viral infection. We found a significant inverse correlation between length of meditation practice and SARS-CoV-2 infection as well as accelerated resolution of symptomology of those infected. A meditation "dosing" effect was also observed. In cultured human lung cells, blood from experienced meditators induced factors that prevented entry of pseudotyped viruses for SARS-CoV-2 spike protein of both the wild-type Wuhan-1 virus and the Delta variant. We identified and validated SERPINA5, a serine protease inhibitor, as one possible protein factor in the blood of meditators that is necessary and sufficient for limiting pseudovirus entry into cells. In summary, we conclude that meditation can enhance resiliency to viral infection and may serve as a possible adjuvant therapy in the management of the COVID-19 pandemic.
ABSTRACT
The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.
ABSTRACT
Cholinergic neurotransmission in the central and autonomic nervous systems regulates immediate variations in and longer-term maintenance of cardiovascular function with acetylcholinesterase (AChE) activity that is critical to temporal responsiveness. Butyrylcholinesterase (BChE), largely confined to the liver and plasma, subserves metabolic functions. AChE and BChE are found in hematopoietic cells and plasma, enabling one to correlate enzyme levels in whole blood with hereditary traits in twins. Using both twin and unrelated subjects, we found certain single nucleotide polymorphisms (SNPs) in the ACHE gene correlated with catalytic properties and general cardiovascular functions. SNP discovery from ACHE resequencing identified 19 SNPs: 7 coding SNPs (cSNPs), of which 4 are nonsynonymous, and 12 SNPs in untranslated regions, of which 3 are in a conserved sequence of an upstream intron. Both AChE and BChE activity traits in blood were heritable: AChE at 48.8 ± 6.1% and BChE at 81.4 ± 2.8%. Allelic and haplotype variations in the ACHE and BCHE genes were associated with changes in blood AChE and BChE activities. AChE activity was associated with BP status and SBP, whereas BChE activity was associated with features of the metabolic syndrome (especially body weight and BMI). Gene products from cDNAs with nonsynonymous cSNPs were expressed and purified. Protein expression of ACHE nonsynonymous variant D134H (SNP6) is impaired: this variant shows compromised stability and altered rates of organophosphate inhibition and oxime-assisted reactivation. A substantial fraction of the D134H instability could be reversed in the D134H/R136Q mutant. Hence, common genetic variations at ACHE and BCHE loci were associated with changes in corresponding enzymatic activities in blood.
Subject(s)
Cardiovascular Diseases/genetics , Cholinesterases/genetics , Genetic Variation/genetics , Metabolic Diseases/genetics , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , Acetylcholinesterase/blood , Acetylcholinesterase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Butyrylcholinesterase/blood , Butyrylcholinesterase/genetics , Cardiovascular Diseases/enzymology , Cholinesterases/blood , Female , HEK293 Cells , Humans , Male , Metabolic Diseases/enzymology , Middle Aged , Polymorphism, Single Nucleotide/genetics , Protein Structure, Secondary , Quantitative Trait, Heritable , Young AdultABSTRACT
The activity of voltage-gated K(+) (K(V)) channels plays an important role in regulating pulmonary artery smooth muscle cell (PASMC) contraction, proliferation, and apoptosis. The highly conserved NH(2)-terminal tetramerization domain (T1) of K(V) channels is important for proper channel assembly, association with regulatory K(V) beta-subunits, and localization of the channel to the plasma membrane. We recently reported two nonsynonymous mutations (G182R and E211D) in the KCNA5 gene of patients with idiopathic pulmonary arterial hypertension, which localize to the T1 domain of KCNA5. To study the electrophysiological properties and expression patterns of the mutants compared with the wild-type (WT) channel in vitro, we transfected HEK-293 cells with WT KCNA5, G182R, E211D, or the double mutant G182R/E211D channel. The mutants form functional channels; however, whole cell current kinetic differences between WT and mutant channels exist. Steady-state inactivation curves of the G182R and G182R/E211D channels reveal accelerated inactivation; the mutant channels inactivated at more hyperpolarized potentials compared with the WT channel. Channel protein expression was also decreased by the mutations. Compared with the WT channel, which was present in its mature glycosylated form, the mutant channels are present in greater proportion in their immature form in HEK-293 cells. Furthermore, G182R protein level is greatly reduced in COS-1 cells compared with WT. Immunostaining data support the hypothesis that, while WT protein localizes to the plasma membrane, mutant protein is mainly retained in intracellular packets. Overall, these data support a role for the T1 domain in channel kinetics as well as in KCNA5 channel subcellular localization.
Subject(s)
Kv1.5 Potassium Channel/metabolism , Potassium/metabolism , 4-Aminopyridine/pharmacology , Amino Acid Sequence , Animals , Base Sequence , COS Cells , Chlorocebus aethiops , Glycosylation , Humans , Kinetics , Kv1.3 Potassium Channel/genetics , Kv1.3 Potassium Channel/metabolism , Kv1.5 Potassium Channel/antagonists & inhibitors , Kv1.5 Potassium Channel/chemistry , Kv1.5 Potassium Channel/genetics , Membrane Potentials , Models, Molecular , Molecular Sequence Data , Mutation , Polymorphism, Single Nucleotide , Potassium Channel Blockers/pharmacology , Protein Multimerization , Protein Processing, Post-Translational , Protein Structure, Quaternary , Protein Structure, Tertiary , Protein Transport , Recombinant Fusion Proteins/metabolism , Structure-Activity Relationship , TransfectionABSTRACT
GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.
Subject(s)
Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , GTP Cyclohydrolase/genetics , GTP Cyclohydrolase/metabolism , Genetic Predisposition to Disease , Nitric Oxide/metabolism , Polymorphism, Genetic/genetics , Adult , Animals , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Female , Genome, Human/genetics , Genotype , Haplotypes , Humans , Hypertension/enzymology , Hypertension/genetics , Male , Middle Aged , Phenotype , Phylogeny , RNA/genetics , Twins/geneticsABSTRACT
The catecholamine biosynthetic pathway consists of several enzymatic steps in series, beginning with the amino acids phenylalanine and tyrosine, and eventuating in the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline). Since the enzyme tyrosine hydroxylase (TH; tyrosine 3-mono-oxygenase; EC 1.14.16.2; chromosome 11p15.5) is generally considered to be rate-limiting in this pathway, probed as to whether common genetic variation at the TH gene occurred, and whether such variants contributed to inter-individual alterations in autonomic function, either biochemical or physiological. We began with sequencing a tetranucleotide (TCAT) repeat in the first intron, and found that the two most common versions, (TCAT)(6) and (TCAT)(10i), predicted heritable autonomic traits in twin pairs. We then conducted systematic polymorphism discovery across the ~8 kbp locus, and discovered numerous variants, principally non-coding. The proximal promoter block contained four common variants, and its haplotypes and SNPs (especially C-824T, rs10770141) predicted catecholamine secretion, environmental stress-induced BP increments, and hypertension. Finally, we found that two of the common promoter variants, C-824T (rs10770141) and A-581G (rs10770140), were functional in that they differentially affected transcriptional activity of the isolated promoter, disrupted recognition motifs for specific transcription factor binding, altered the promoter responses to the co-transfected (exogenous) factors, and bound the endogenous factors in the chromatin fraction of the nucleus. We concluded that common variation in the proximal TH promoter is functional, giving rise to changes in autonomic function and consequently cardiovascular risk.
Subject(s)
Alleles , Autonomic Nervous System/enzymology , Autonomic Nervous System/physiopathology , Genetic Variation , Hypertension/genetics , Hypertension/physiopathology , Tyrosine 3-Monooxygenase/genetics , Blood Pressure/genetics , Humans , Hypertension/enzymology , Microsatellite Repeats/genetics , Promoter Regions, Genetic/genetics , Transcription, GeneticABSTRACT
Alzheimer's dementia (AD) begins many years before its clinical symptoms. Metabolic dysfunction represents a core feature of AD and cognitive impairment, but few metabolomic studies have focused on cognitive aging in midlife. Using an untargeted metabolomics approach, we identified metabolic predictors of cognitive aging in midlife using fasting plasma sample from 30 middle-aged (mean age 57.2), male-male twin pairs enrolled in the Vietnam Era Twin Study of Aging (VETSA). For all twin pairs, one twin developed incident MCI, whereas his co-twin brother remained to be cognitively normal during an average 5.5-year follow-up. Linear mixed model was used to identify metabolites predictive of MCI conversion or cognitive change over time, adjusting for traditional risk factors. Results from twins were replicated in an independent cohort of middle-aged adults (mean age 59.1) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). Results in twins showed that higher baseline levels of four plasma metabolites, including sphingomyelin (d18:1/20:1 and d18:2/20:0), sphingomyelin (d18:1/22:1, d18:2/22:0, and d16:1/24:1), DAG (18:2/20:4), and hydroxy-CMPF, were significantly associated with a slower decrease in one or more domains of cognitive function. The association of sphingomyelin (d18:1/20:1 and d18:2/20:0) was replicated in WRAP. Our results support that metabolic perturbation occurs many years before cognitive impairment and plasma metabolites may serve as early biomarkers for prediction or monitoring of cognitive aging and AD in midlife.
ABSTRACT
Liquid biopsies based on cell-free DNA (cfDNA) or exosomes provide a noninvasive approach to monitor human health and disease but have not been utilized for astronauts. Here, we profile cfDNA characteristics, including fragment size, cellular deconvolution, and nucleosome positioning, in an astronaut during a year-long mission on the International Space Station, compared to his identical twin on Earth and healthy donors. We observed a significant increase in the proportion of cell-free mitochondrial DNA (cf-mtDNA) inflight, and analysis of post-flight exosomes in plasma revealed a 30-fold increase in circulating exosomes and patient-specific protein cargo (including brain-derived peptides) after the year-long mission. This longitudinal analysis of astronaut cfDNA during spaceflight and the exosome profiles highlights their utility for astronaut health monitoring, as well as cf-mtDNA levels as a potential biomarker for physiological stress or immune system responses related to microgravity, radiation exposure, and the other unique environmental conditions of spaceflight.
ABSTRACT
Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures. Although the coding region lacked common non-synonymous variants, we identified two polymorphisms in the DRD1 5'-UTR (G-94A, A-48G) that occurred with frequencies of 15 and 30%, respectively. In the twin/family study, renal traits were highly heritable, such that DRD1 G-94A significantly associated with eGFR, pCr, and FeUA. Homozygotes for the G-94A minor allele (A/A) exhibited lower eGFR, higher pCr, and lower FeUA. No effects were noted for DRD1 A-48G. Patients in the Kaiser group had similar effects of G-94A on eGFR and pCr. Kidney cells transfected with the -94A variant but not the wild type vectors had increased receptor density. Because the -94A allele is common and may reduce glomerular capillary hydrostatic pressure, G-94A profiling may aid in predicting survival of renal function in patients with progressive renal disease.
Subject(s)
Polymorphism, Genetic , Receptors, Dopamine D1/genetics , Adult , Alleles , Cohort Studies , Creatinine/blood , Female , Gene Frequency , Glomerular Filtration Rate/genetics , Humans , Male , Uric Acid/metabolismABSTRACT
Endocytosis and vesicle trafficking are required for optimal neural transmission. Yet, little is currently known about the evolution of neuronal proteins regulating these processes. Here, we report the first phylogenetic study of NEEP21, calcyon, and P19, a family of neuronal proteins implicated in synaptic receptor endocytosis and recycling, as well as in membrane protein trafficking in the somatodendritic and axonal compartments of differentiated neurons. Database searches identified orthologs for P19 and NEEP21 in bony fish, but not urochordate or invertebrate phyla. Calcyon orthologs were only retrieved from mammalian databases and distant relatives from teleost fish. In situ localization of the P19 zebrafish ortholog, and extant progenitor of the gene family, revealed a CNS specific expression pattern. Based on non-synonymous nucleotide substitution rates, the calcyon genes appear to be under less intense negative selective pressure. Indeed, a functional group II WW domain binding motif was detected in primate and human calcyon, but not in non-primate orthologs. Sequencing of the calcyon gene from 80 human subjects revealed a non-synonymous single nucleotide polymorphism that abrogated group II WW domain protein binding. Altogether, our data indicate the NEEP21/calcyon/P19 gene family emerged, and underwent two rounds of gene duplication relatively late in metazoan evolution (but early in vertebrate evolution at the latest). As functional studies suggest NEEP21 and calcyon play related, but distinct roles in regulating vesicle trafficking at synapses, and in neurons in general, we propose the family arose in chordates to support a more diverse range of synaptic and behavioral responses.
Subject(s)
Central Nervous System/metabolism , Endocytosis/genetics , Evolution, Molecular , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Phylogeny , Vertebrates/genetics , Amino Acid Motifs , Amino Acid Sequence , Animals , Central Nervous System/embryology , Conserved Sequence , Gene Expression Regulation, Developmental , Humans , Invertebrates/genetics , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Molecular Sequence Data , Multigene Family/genetics , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , Primates/genetics , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Alignment , Species Specificity , Zebrafish/embryology , Zebrafish/geneticsABSTRACT
Nicotinic acetylcholine receptors (nAChRs) are combinations of subunits arranged as pentamers encircling a central cation channel. At least nine alpha and four beta subunits are expressed in the central and peripheral nervous systems; their presence in autonomic ganglia, the adrenal medulla, and central nervous system, with accompanying responses elicited by nicotinic agonists, point to their involvement in cardiovascular homeostasis. nAChRs formed by alpha3, alpha5, and beta4 subunits may regulate blood pressure (BP) by mediating release of catestatin, the endogenous nicotinic antagonist fragment of chromogranin A (CHGA) and potent inhibitor of catecholamine secretion. Genes encoding these subunits (CHRNA3, CHRNA5, and CHRNB4) are clustered on human chromosome 15q24. Because variation in this cluster may alter autonomic regulation of BP, we sequenced approximately 15 kilobase pairs in 15q24 containing their coding and 5'- and 3'-untranslated regions in 80 individuals. We identified 63 variants: 25 in coding regions of CHRNA3, CHRNA5, and CHRNB4 and 48 noncoding single-nucleotide polymorphisms (SNPs). Haplotype frequencies varied across ethnic populations. We assessed the contribution of six SNPs in the putative catestatin binding region of CHRNA3 and CHRNB4 to autonomic traits. In twins, catestatin and BP were heritable. CHRNA3 SNPs and haplotypes containing K95K (G285A) associated with circulating plasma catestatin, epinephrine levels, as well as systolic BP, suggesting altered coupling of the nAChRs to BP. Studies of chromaffin cells in vitro reveal that nicotinic agonist stimulation releases catecholamines and CHGA, a process augmented by overexpression of CHRNA3 and blocked by catestatin. These cellular events suggest a homeostatic mechanism underlying the pleiotropic actions of CHRNA3 genetic variation on autonomic function observed in twins.
Subject(s)
Autonomic Nervous System/physiology , Chromosomes, Human, Pair 15/genetics , Neurons/metabolism , Receptors, Nicotinic/genetics , Receptors, Nicotinic/physiology , Acetylcholinesterase/blood , Alleles , Catecholamines/blood , Chromogranin A/genetics , Chromogranins/genetics , Ethnicity , Exocytosis/drug effects , Gene Frequency , Haplotypes , Humans , Linkage Disequilibrium/genetics , Models, Molecular , Multigene Family , Neurons/physiology , Peptide Fragments/genetics , Phenotype , Phylogeny , Polymorphism, Single Nucleotide/genetics , Reverse Transcriptase Polymerase Chain Reaction , United States/epidemiologyABSTRACT
Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic "braking" system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5') region, G-462A-->T-415C-->C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3'-end, C11825T (3'-UTR, C+87T)-->G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3'-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.