Cholesterol concentrations in blood are related to cardiovascular diseases. Recent genome-wide association studies (GWAS) of cholesterol levels identified a number of single-locus effects on total ...cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. Here, we report single-locus and epistasis SNP effects on TC and HDL-C using the Framingham Heart Study (FHS) data.
Single-locus effects and pairwise epistasis effects of 432,096 SNP markers were tested for their significance on log-transformed TC and HDL-C levels. Twenty nine additive SNP effects reached single-locus genome-wide significance (p < 7.2 x 10-8) and no dominance effect reached genome-wide significance. Two new gene regions were detected, the RAB3GAP1-R3HDM1-LCT-MCM6 region of chr02 for TC identified by six new SNPs, and the OSBPL8-ZDHHC17 region (chr12) for HDL-C identified by one new SNP. The remaining 22 single-locus SNP effects confirmed previously reported genes or gene regions. For TC, three SNPs identified two gene regions that were tightly linked with previously reported genes associated with TC, including rs599839 that was 10 bases downstream PSRC1 and 3.498 kb downstream CELSR2, rs4970834 in CELSR2, and rs4245791 in ABCG8 that slightly overlapped with ABCG5. For HDL-C, LPL was confirmed by 12 SNPs 8-45 kb downstream, CETP by two SNPs 0.5-11 kb upstream, and the LIPG-ACAA2 region by five SNPs inside this region. Two epistasis effects on TC and thirteen epistasis effects on HDL-C reached the significance of "suggestive linkage". The most significant epistasis effect (p = 5.72 x 10-13) was close to reaching "significant linkage" and was a dominance x dominance effect of HDL-C between LMBRD1 (chr06) and the LRIG3 region (chr12), and this pair of gene regions had six other D x D effects with "suggestive linkage".
Genome-wide association analysis of the FHS data detected two new gene regions with genome-wide significance, detected epistatic SNP effects on TC and HDL-C with the significance of suggestive linkage in seven pairs of gene regions, and confirmed some previously reported gene regions associated with TC and HDL-C.
Various plasticizers and flame retardants are contained in building materials and furniture produced for indoor environments. However, some of these material inclusions have been reported to cause ...endocrine-disrupting and mucosa-irritating effects. Because of the local climate, buildings in Sapporo are better insulated against cold weather than those in many other areas in Japan. In this study, we measured 59 compounds, including plasticizers (phthalates, adipates, and others) and flame retardants (organo-phosphates and brominated compounds), from indoor air samples from six houses in Sapporo. These compounds were measured separately in the gas phase and the particle phase using a two-stage cartridge equipped with a quartz fiber filter (1μmmesh) and C18 solid-phase extraction disk for sampling and analyzed by GC/MS and LC/MS/MS (for the detection of brominated flame retardants). Among the 59 compounds measured in this study, 34 compounds were detected from the indoor air of the six houses. The highest concentration among the 34 compounds found in a newly built house was 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate (TXIB) at 20.8μg/m3. Di(2-ethyl-1-hexyl)terephthalate (DEHT), which has been used in recent years as an alternative to di(2-ethyl-1-hexyl)phthalate (DEHP), was found in all six houses, although at low concentrations ranging from 0.005 to 0.027μg/m3. To our knowledge, this is the first report of DEHT in indoor air in Japan. Among the compounds detected in this study, those with lower molecular weights tended to be captured in the C18 solid-phase extraction disk rather than in the quartz fiber filter. These results suggest that compounds with higher volatility exist preferentially in the gas phase, whereas compounds with lower volatility exist preferentially in the particulate phase in indoor air.
•34 semi-volatile organic compounds were detected in the indoor air samples.•DEHT was detected in indoor air for the first time in Japan.•Compounds with higher volatility tended to exist in a gaseous phase in indoor air.•Compounds with lower volatility existed in a particulate phase in indoor air.•TXIB (20.8mg/m3) had the highest concentration among the 34 chemicals detected.
Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and ...cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10
−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10
−5
), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.
Hemorrhagic shock is a frequent cause of liver failure and often leads to a fatal outcome. Several studies have revealed that p38 MAPK is a key mediator in hemorrhagic damage of the primary organs ...through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. However, the precise role of these factors in liver damage following hemorrhagic shock is unclear. In this study, we used FR167653, a specific inhibitor of p38 MAPK phosphorylation, to examine the role of p38 MAPK in liver damage occurring up to 5 hours after a hemorrhagic episode in a rat model. Activation of p38 MAPK in the liver as well as an increase in hepatic mRNA expression and serum concentrations of TNF-α and IL-1β occurred during the early phase after hemorrhage. Increased serum levels of hepatic enzymes, as well as histological damage and activated neutrophil accumulation in the liver, were observed in the late phase following hemorrhagic shock. FR167653 inhibited the inflammation-related hepatic injury following hemorrhagic shock. Bacterial lipopolysaccharide (LPS) derived from the gut appeared to have little effects on the hepatic damage. These results demonstrate that p38 MAPK activation is induced by hepatic ischemia during hemorrhagic shock and plays an important role both in the hepatic expression of proinflammatory cytokines and in the development of inflammation-related liver damage.
The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to ...identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults.
At baseline, 962 adults (women, 54·4%; age range, 21–98 years) participated in the InCHIANTI, “Aging in the Chianti Area” study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis).
Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality.
Cellular senescence may contribute to the association between RDW and mortality.
This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a ‘targeted project’ by the Italian Ministry of Health and in part by the U.S. NIA.
Superior mesenteric artery (SMA) syndrome occurs when the third portion of duodenum becomes tightly compressed between the SMA and the abdominal aorta (AA). Several causes of the SMA syndrome have ...been postulated such as marked weight loss, external compression of the abdomen, anatomic variation, and surgical alterations of anatomy. This is an autopsy case of a subject with atypical duodenal obstruction related SMA syndrome.
A 71-year-old woman died one and a half days after eating a large meal of roast meat and vegetables and experiencing subsequent nausea and abdominal pain. At autopsy, fatal acute gastric dilatation was confirmed. The posterior parietal peritoneum around the duodenum was scarred and pulled the root of the mesentery involving the SMA. The complex compressed and narrowed the third portion of the duodenum. The root of the mesentery was also thickened and had adhered to the surface of the duodenum, which may have been due to past peritonitis and disturbance of duodenal motility. Aggregation of an excessively large food mass obstructed the lumen of the duodenum. The cause of death was diagnosed as SMA syndrome with intra-duodenal aggregation of an excessively large mass of food in the narrowed duodenal lumen.
This is an atypical fatal case of acute gastric dilatation, through an excessively large mass of food obstruction at the latent narrowed duodenum.
Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel activated by capsaicin. TRPV1 is expressed not only on human sensory neurons but also on human epidermal and ...hair follicle keratinocytes. Therefore, TRPV1 could have the potential to be a therapeutic target for skin disorders. To search for novel TRPV1 agonists, we screened 31 essential oils by using human TRPV1-expressing HEK293 cells. TRPV1 was activated by 4 essential oils: rose, thyme geraniol, palmarosa, and tolu balsam. The dose–response curves for TRPV1 activation by the essential oils revealed a rank order potency the half-maximal effective concentration (EC50) of rose>palmarosa>thyme geraniol>tolu balsam, and rank order efficiency (% activity in response to 1 μM capsaicin) of tolu balsam>rose>palmarosa>thyme geraniol. Moreover, the dose–response curves for TRPV1 activation by citronellol (main constituent of rose oil) and geraniol (main constituent of thyme geraniol and palmarosa oils) were consistent with the potency and efficiency of each essential oil. In contrast, benzyl cinnamate and benzyl benzoate (main constituent of tolu balsam oil) and geranyl acetate (main constituent of thyme geraniol oil) did not show TRPV1 activity. In this first-of-its-kind study, we successfully investigated the role of some essential oils in promoting human TRPV1 activation, and also identified two monoterpenes, citronellol and geraniol, as new human TRPV1 agonists.
To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by ...cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.
Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific ...pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups (
q
-value < 0.05). Metabolites differentially abundant were enriched for lysophosphatidylcholines (lysoPC C18:0,C16:0,C17:0,C18:1,C18:2), ceramides (d18:2/24:0,d16:1/24:0,d16:1/23:0), and amino acids (glycine) classes. Compared to no decline, the dual decline group showed greater declines in lysoPC C18:0, homoarginine synthesis, and the metabolite module containing mostly triglycerides, and showed a greater increase in indoleamine 2,3-dioxygenase (IDO) activity. Metabolites distinguishing dual decline and no decline groups were implicated in metabolic pathways of the aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, histidine metabolism, and sphingolipid metabolism. Older adults with dual decline exhibit the most extensive alterations in metabolic profiling of lysoPCs, ceramides, IDO activity, and homoarginine synthesis. Alterations in these metabolites may indicate mitochondrial dysfunction, compromised immunity, and elevated burden of cardiovascular and kidney pathology.
Introduction
Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions.
Methods
In 997 adults from the ...InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case‐control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume.
Results
We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti‐related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy.
Discussion
These proteins may be useful as non‐invasive biomarkers of dementia and cognitive impairment.
PDF
