The IL-6 Gene Promoter SNP and Plasma IL-6 in Response to Diet Intervention.

We recently reported that interleukin-6 (IL-6), an inflammatory marker associated with breast pathology and the development of breast cancer, decreases with diet intervention and weight loss in both insulin-sensitive and insulin-resistant obese women. Here, we tested whether an individual's genotype at an IL6 SNP, rs1800795, which has previously been associated with circulating IL-6 levels, contributes to changes in IL-6 levels or modifies the effect of diet composition on IL-6 in these women. We genotyped rs1800795 in overweight/obese women (N = 242) who were randomly assigned to a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich (18% energy), higher fat (35% energy), lower carbohydrate (45% energy) diet in a 1-year weight loss intervention study of obesity-related biomarkers for breast cancer incidence and mortality. Plasma IL-6 levels were measured at baseline, 6 and 12 months. At baseline, individuals with a CC genotype had significantly lower IL-6 levels than individuals with either a GC or GG genotype (p < 0.03; 2.72 pg/mL vs. 2.04 pg/mL), but this result was not significant when body mass index (BMI) was accounted for; the CC genotype group had lower BMI (p = 0.03; 32.5 kg/m² vs. 33.6 kg/m²). We did not observe a 2-way interaction of time*rs1800795 genotype or diet*rs1800795 genotype. Our findings provide evidence that rs1800795 is associated with IL-6 levels, but do not support a differential interaction effect of rs1800795 and diet composition or time on changes in circulating IL-6 levels. Diet intervention and weight loss are an important strategy for reducing plasma IL-6, a risk factor of breast cancer in women, regardless of their rs1800795 genotype

Effects of Diet Composition and Insulin Resistance Status on Plasma Lipid Levels in a Weight Loss Intervention in Women.

BackgroundOptimal macronutrient distribution of weight loss diets has not been established. The distribution of energy from carbohydrate and fat has been observed to promote differential plasma lipid responses in previous weight loss studies, and insulin resistance status may interact with diet composition and affect weight loss and lipid responses.Methods and resultsOverweight and obese women (n=245) were enrolled in a 1-year behavioral weight loss intervention and randomly assigned to 1 of 3 study groups: a lower fat (20% energy), higher carbohydrate (65% energy) diet; a lower carbohydrate (45% energy), higher fat (35% energy) diet; or a walnut-rich, higher fat (35% energy), lower carbohydrate (45% energy) diet. Blood samples and data available from 213 women at baseline and at 6 months were the focus of this analysis. Triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterol were quantified and compared between and within groups. Triglycerides decreased in all study arms at 6 months (P<0.05). The walnut-rich diet increased high-density lipoprotein cholesterol more than either the lower fat or lower carbohydrate diet (P<0.05). The walnut-rich diet also reduced low-density lipoprotein cholesterol in insulin-sensitive women, whereas the lower fat diet reduced both total cholesterol and high-density lipoprotein cholesterol in insulin-sensitive women (P<0.05). Insulin sensitivity and C-reactive protein levels also improved.ConclusionsWeight loss was similar across the diet groups, although insulin-sensitive women lost more weight with a lower fat, higher carbohydrate diet versus a higher fat, lower carbohydrate diet. The walnut-rich, higher fat diet resulted in the most favorable changes in lipid levels.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01424007

Genetic and environmental influences on sleep quality in middle‐aged men: a twin study

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.Accepted manuscrip

G protein-coupled receptor (GPCR) pharmacogenomics

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.</p

Human Tyrosine Hydroxylase Natural Allelic Variation: Influence on Autonomic Function and Hypertension

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

Positive mental health in schizophrenia and healthy comparison groups: relationships with overall health and biomarkers

ObjectivePositive 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.MethodOne hundred and thirty-five outpatients with schizophrenia and 127 healthy comparison subjects (HCs), aged 26-65&nbsp;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.ResultsRelative 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.ConclusionA 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

Proteomic Assessment of Fluid Shifts and Association with Visual Impairment and Intracranial Pressure in Twin Astronauts

BACKGROUND: Astronauts participating in long duration space missions are at an increased risk of physiological disruptions. The development of visual impairment and intracranial pressure (VIIP) syndrome is one of the leading health concerns for crew members on long-duration space missions; microgravity-induced fluid shifts and chronic elevated cabin CO2 may be contributing factors. By studying physiological and molecular changes in one identical twin during his 1-year ISS mission and his ground-based co-twin, this work extends a current NASA-funded investigation to assess space flight induced "Fluid Shifts" in association with the development of VIIP. This twin study uniquely integrates physiological and -omic signatures to further our understanding of the molecular mechanisms underlying space flight-induced VIIP. We are: (i) conducting longitudinal proteomic assessments of plasma to identify fluid regulation-related molecular pathways altered by long-term space flight; and (ii) integrating physiological and proteomic data with genomic data to understand the genomic mechanism by which these proteomic signatures are regulated. PURPOSE: We are exploring proteomic signatures and genomic mechanisms underlying space flight-induced VIIP symptoms with the future goal of developing early biomarkers to detect and monitor the progression of VIIP. This study is first to employ a male monozygous twin pair to systematically determine the impact of fluid distribution in microgravity, integrating a comprehensive set of structural and functional measures with proteomic, metabolomic and genomic data. This project has a broader impact on Earth-based clinical areas, such as traumatic brain injury-induced elevations of intracranial pressure, hydrocephalus, and glaucoma. HYPOTHESIS: We predict that the space-flown twin will experience a space flight-induced alteration in proteins and peptides related to fluid balance, fluid control and brain injury as compared to his pre-flight protein/peptide signatures. Conversely, the trajectory of these protein signatures will remain relatively constant in his ground based co-twin. METHODS: We are using proteomic and standard immunoelectrophoresis techniques to delineate the change in protein signatures throughout the course of a long duration space flight in relation to the development of VIIP. We are also applying a novel cell-based metaboloic organ system assay ("Organs on a Plate") to address how these circulating biomarkers affect physiological processes at the cellular and organ level which could result in VIIP symptoms. These molecular data will be correlated with physiological measures (eg. extra and intracellular fluid volume, vascular filling/flow patterns, MRI, and Optic Coherence Tomography. DISCUSSION: Pre- and in-flight data collection is in progress for the space-flown twin, and similar data have been obtained from the ground-based twin. Biosamples will be batch processed when received from ISS after the conclusion of the 1-year mission. Omic and Physiological measures from the twin astronauts will be compared to similar data being collected on twin subjects who participated in simulated microgravity study. bed rest study

Screened non-bonded interactions in native proteins manipulate optimal paths for robust residue communication

A protein structure is represented as a network of residues whereby edges are determined by intra-molecular contacts. We introduce inhomogeneity into these networks by assigning each edge a weight that is determined by amino-acid pair potentials. Two methodologies are utilized to calculate the average path lengths (APLs) between pairs: To minimize (i) the maximum weight in the strong APL, and (ii) the total weight in the weak APL. We systematically screen edges that have higher than a cutoff potential and calculate the shortest APLs in these reduced networks, while keeping chain connectivity. Therefore, perturbations introduced at a selected region of the residue network propagate to remote regions only along the non-screened edges that retain their ability to disseminate the perturbation. The shortest APLs computed from the reduced homogeneous networks with only the strongest few non-bonded pairs closely reproduce the strong APLs from the weighted networks. The rate of change in the APL in the reduced residue network as compared to its randomly connected counterpart remains constant until a lower bound. Upon further link removal, this property shows an abrupt increase, towards a random coil behavior. Under different perturbation scenarios, diverse optimal paths emerge for robust residue communication.Comment: 21 pages with 6 figure

Population and molecular evolution studies on the Melanocortin 1 receptor locus implicate its role in human pigmentation variation

Human pigmentation is a complex trait with the observed variation caused by the varied production of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) by the melanocytes. The melanocortin 1 receptor (MC1R), a G protein-coupled receptor expressed in the melanocytes, is a regulator eu- and phaeomelanin synthesis, and MC1R mutations causing skin and coat color changes are known in many mammals. To understand the role of MC1R in human pigmentation variation, I have sequenced the MC1R gene in 121 individuals sampled from world populations. In addition, I have sequenced the MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon to study the evolution of MC1R and to infer the ancestral human MC1R sequence. The ancestral MC1R sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. To further evaluate the role of MC1R variants in human pigmentation variation, I have combined these molecular evolution and population studies with functional assays on MC1R variants and primate MC1Rs