Metabolic Mechanism of Bacillus sp. LM24 under Abamectin Stress.

Abamectin (ABM) has been recently widely used in aquaculture. However, few studies have examined its metabolic mechanism and ecotoxicity in microorganisms. This study investigated the molecular metabolic mechanism and ecotoxicity of Bacillus sp. LM24 (B. sp LM24) under ABM stress using intracellular metabolomics. The differential metabolites most affected by the bacteria were lipids and lipid metabolites. The main significant metabolic pathways of B. sp LM24 in response to ABM stress were glycerolipid; glycine, serine, and threonine; and glycerophospholipid, and sphingolipid. The bacteria improved cell membrane fluidity and maintained cellular activity by enhancing the interconversion pathway of certain phospholipids and sn-3-phosphoglycerol. It obtained more extracellular oxygen and nutrients to adjust the lipid metabolism pathway, mitigate the impact of sugar metabolism, produce acetyl coenzyme A to enter the tricarboxylic acid (TCA) cycle, maintain sufficient anabolic energy, and use some amino acid precursors produced during the TCA cycle to express ABM efflux protein and degradative enzymes. It produced antioxidants, including hydroxyanigorufone, D-erythroascorbic acid 1'-a-D-xylopyranoside, and 3-methylcyclopentadecanone, to alleviate ABM-induced cellular and oxidative damage. However, prolonged stress can cause metabolic disturbances in the metabolic pathways of glycine, serine, threonine, and sphingolipid; reduce acetylcholine production; and increase quinolinic acid synthesis.

CD56dim NK Cell is an Important Factor in T Cell Depletion of cART-Treated AIDS Patients.

Purpose: To investigate factors involved in T-cell depletion in combination antiretroviral therapy (cART)-treated human immunodeficiency virus 1 (HIV-1)-positive patients. Patients and Methods: 29 HIV-1-positive patients were enrolled. The CD4+, CD8+ T cell subsets and CD56dim NK cells were detected by flow cytometry. The concentrations of cytokines were measured by enzyme-linked immunosorbent assay. Extraction, amplification, and viral load quantification of specimens were performed using the Roche Cobas Ampliprep/Cobas TaqMan HIV-1 test. Results: Compared with IR group, the total number of red blood cells (RBCs) and lymphocytes (LCs) in INR group was significantly reduced, and there was a significant positive correlation between the number of RBCs and that of LCs. The overall production rates of T cells-related cytokines were lower in INR group. However, the cell-surface expression of programmed death-1 (PD-1) on CD4+ T and CD8+ T cells were markedly elevated in INR group. Moreover, it was found that the proportion and the killing ability of CD56dim NK cells significantly increased in INR patients, and significantly correlated with apoptosis of T lymphocytes. Conclusion: A poor immune reconstitution in HIV-positive patients might result from multiple factors, including bone marrow suppression, high PD-1 expression on the surface of CD4+ T cells, and over-activation of T and NK cells. Besides, the activity of NK cells and RBCs count might be important auxiliary indicators for immune reconstitution and provided a reliable guidance for developing strategies to improve immune reconstitution.

DABCO as a practical catalyst for aromatic halogenation with N-halosuccinimides.

A simple and practical synthetic approach for synthesis of aromatic halides is developed. Simple Lewis base, DABCO, is used as the catalyst. This arene halogenation process proceedes conveniently and efficiently at ambient conditions, providing the desired products in good to excellent yields and selectivity.

A Natural Plant Ingredient, Menthone, Regulates T Cell Subtypes and Lowers Pro-inflammatory Cytokines of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with nearly 1.6 billion patients worldwide and an incidence of 0.5-1%. In recent years, basic and clinical studies have revealed that immune cell responses and corresponding secretion of inflammatory factors are important in the control of RA development. Our study found that a natural plant ingredient, menthone, could be used as a potential antirheumatism compound. In vivo observations demonstrated that menthone alleviates collagen II-induced arthritis (CIA) in mice. Furthermore, we found that menthone regulates the number of Th1 and Th17 cells in CIA mice. Importantly, menthone significantly inhibits the release of pro-inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, in CIA mice. Our study suggests a potential component for the development of drugs to treat rheumatoid arthritis.

Risk of conversion from mild cognitive impairment to dementia in low- and middle-income countries: A systematic review and meta-analysis.

Introduction: With no treatment for dementia, there is a need to identify high risk cases to focus preventive strategies, particularly in low- and middle-income countries (LMICs) where the burden of dementia is greatest. We evaluated the risk of conversion from mild cognitive ompairment (MCI) to dementia in LMICs. Methods: Medline, Embase, PsycINFO, and Scopus were searched from inception until June 30, 2020. The search was restricted to observational studies, conducted in population-based samples, with at least 1 year follow-up. There was no restriction on the definition of MCI used as long as it was clearly defined. PROSPERO registration: CRD42019130958. Results: Ten thousand six hundred forty-seven articles were screened; n = 11 retained. Of the 11 studies, most were conducted in China (n = 7 studies), with only two studies from countries classified as low income. A qualitative analysis of n = 11 studies showed that similar to high-income countries the conversion rate to dementia from MCI was variable (range 6 . 0%-44 . 8%; average follow-up 3 . 7 years [standard deviation = 1 . 2]). A meta-analysis of studies using Petersen criteria (n = 6 studies), found a pooled conversion rate to Alzheimer's disease (AD) of 23 . 8% (95% confidence interval = 15 . 4%-33.4%); approximately one in four people with MCI were at risk of AD in LMICs (over 3 . 0-5 . 8 years follow-up). Risk factors for conversion from MCI to dementia included demographic (e.g., age) and health (e.g., cardio-metabolic disease) variables. Conclusions: MCI is associated with high, but variable, conversion to dementia in LMICs and may be influenced by demographic and health factors. There is a notable absence of data from low-income settings and countries outside of China. This highlights the urgent need for research investment into aging and dementia in LMIC settings. Being able to identify those individuals with cognitive impairment who are at highest risk of dementia in LMICs is necessary for the development of risk reduction strategies that are contextualized to these unique settings.

Use of ixekizumab in an HIV-positive patient with psoriatic arthritis.

Psoriasis is a chronic immune-mediated disease of the skin. The incidence of psoriasis among people living with HIV (PLHIV) is higher than that in the general population. The mechanism is complex, the manifestations are varied, and the treatment is difficult. Biotherapy has greatly alleviated psoriasis, but clinical trials often exclude PLHIV, and evidence is limited to case reports. Here, we report a man living with psoriatic arthritis who had poor response to traditional treatments. After receiving the anti-interleukin (IL)-17 monoclonal antibody (ixekizumab), the arthritis symptoms were significantly relieved, while CD4+ T cell count increased and the viral load of HIV-1 remained undetectable in combination with antiretroviral therapy (ART). In conclusion, anti-IL-17 monoclonal antibody is a promising and safe treatment for psoriatic arthritis in HIV-positive patients.

Tin Oxide (SnO2) Nanoparticles: Facile Fabrication, Characterization, and Application in UV Photodetectors.

Tin oxide (SnO2) nanomaterials are of great interest in many fields such as catalytic, electrochemical, and biomedical applications, due to their low cost, suitable stability characteristics, high photosensitivity, etc. In this contribution, SnO2 NPs were facilely fabricated by calcination of tin (II) oxalate in air, followed by a liquid-phase exfoliation (LPE) method. Size-selected SnO2 NPs were easily obtained using a liquid cascade centrifugation (LCC) technique. The as-obtained SnO2 NPs displayed strong absorption in the UV region (~300 nm) and exhibited narrower absorption characteristics with a decrease in NP size. The as-fabricated SnO2 NPs were, for the first time, directly deposited onto a poly(ethylene terephthalate) (PET) film with a regular Ag lattice to fabricate a flexible working electrode for a photoelectrochemical (PEC)-type photodetector. The results demonstrated that the SnO2-NP-based electrode showed the strongest photoresponse signal in an alkaline electrolyte compared with those in neutral and acidic electrolytes. The maximum photocurrent density reached 14.0 µA cm-2, significantly outperforming black phosphorus nanosheets and black phosphorus analogue nanomaterials such as tin (II) sulfide nanosheets and tellurene. The as-fabricated SnO2 NPs with relatively larger size had better self-powered photoresponse performance. In addition, the as-fabricated SnO2-NP-based PEC photodetector exhibited strong cycling stability for on/off switching behavior under ambient conditions. It is anticipated that SnO2 nanostructures, as building blocks, can offer diverse availabilities for high-performance self-powered optoelectronic devices to realize a carbon-neutral or carbon-free environment.

Mesenchymal Stem Cell-Derived Extracellular Vesicle-Shuttled microRNA-302d-3p Represses Inflammation and Cardiac Remodeling Following Acute Myocardial Infarction.

Our research intended to investigate the roles of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in acute myocardial infarction (AMI) via delivery of microRNA (miR)-302d-3p. AMI mouse models were established. EVs isolated from MSCs with miR-302d-3p mimic were injected near the infarct area or co-cultured with hypoxic cardiomyocytes to evaluate their effects. The expression of NF-κB pathway-related genes and inflammatory factors was determined. AMI mice exhibited downregulated miR-302d-3p and elevated MD2 and BCL6 levels. BCL6 was negatively targeted by miR-302d-3p and could bind to MD2 promoter to upregulate MD2 expression. MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing inactivated the NF-κB pathway and alleviated infarcted area, myocardial fibrosis, inflammation, apoptosis, and cardiac dysfunction in AMI mice. Besides, MSCs-EVs, MSCs-EVs carrying miR-302d-3p, or BCL6 or MD2 silencing diminished viability and inflammation but augmented apoptosis of hypoxic cardiomyocytes. Conclusively, MSCs-EVs carrying miR-302d-3p repressed inflammation and cardiac remodeling after AMI via BCL6/MD2/NF-κB axis.

Rapid, sensitive and cost-effective determination of immune checkpoint inhibitor activity using a magnetic bead-based binding assay.

Immune checkpoint Inhibitors (ICIs) are effective immunno-therapeutic agents for cancer. Rapid and sensitive determination of the blocking activity of ICIs is important for ICIs development and immunological research. Among various immune checkpoint (IC) binding assays, cell-based binding assays are widely regarded, and the functional ELISA is a convenient alternative. However, these methodologies are limited by time-consuming preparation of cell lines stably expressing IC molecules, or long turnaround time with high cost. In this study, two magnetic bead based binding assays were developed to evaluate activity of ICIs, which was determined by a soluble ligand/bead immobilized receptor based binding assay (sL/bR binding assay) that assessed efficacy to block binding of one soluble IC ligand on its cognate receptor immobilized beads, or by a soluble receptor/bead immobilized ligand based binding assay (sR/bL binding assay) that assessed efficacy to block binding of soluble IC receptor on its cognate ligand immobilized beads. Half maximal inhibitory concentration (IC50) values of ICIs were calculated to determine ICIs activity. The sL/bR binding assay accurately determined the activity of two TIGIT blocking antibodies, since the relative blocking activity of two TIGIT antibodies determined by the sL/bR binding assay established in this study and that by the cell based binding assay were almost identical. In contrast, the sR/bL binding assay showed significantly improved sensitivity to determine activity of two PD-1 blocking antibodies than the sL/bR binding assay that was tested in this study and previous reports. Moreover, both amount of the used recombinant protein of ICI receptor/ligand and turnaround time of the two binding assays were more than 10 times less than those of the functional ELISA. These data indicate that the two magnetic bead based binding assays are sensitive, rapid and cost-effective methods to determine blocking activity of ICIs.

Prevalence and Risk of Mild Cognitive Impairment in Low and Middle-Income Countries: A Systematic Review.

BACKGROUND: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. OBJECTIVE: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. METHODS: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs and were included as long as MCI was clearly defined. RESULTS: 5,568 articles were screened, and 78 retained. In total, n = 23 different LMICs were represented; mostly from China (n = 55 studies). Few studies were from countries defined as lower-middle income (n = 14), low income (n = 4), or from population representative samples (n = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n = 26). Prevalence of amnesic MCI (aMCI) (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. CONCLUSION: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning.

Specific PIWI-interacting small noncoding RNA expression patterns in pulmonary tuberculosis patients.

Aim: PIWI-interacting RNAs (piRNAs) play crucial roles in germline development and carcinogenesis. The expression patterns of piRNAs in pulmonary tuberculosis (PTB) are still unclear. Materials & methods: Small RNA sequencing was applied to investigate peripheral blood piRNA expression patterns in PTB patients and healthy individuals. Results: A total of 428 upregulated and 349 downregulated piRNAs were identified from PTB patients. Target genes of dysregulated piRNAs were mainly involved in transcription and protein binding. Dysregulated piRNAs were enriched in many pathways related with immunity. Many target genes were regulated by the same piRNAs. Nucleotide bias of these piRNAs showed that piRNAs in peripheral blood may be formed from the primary biogenesis pathway. Conclusion: Findings demonstrated that the PIWI-piRNA pathway is active in human peripheral blood, where it may represent a new player in the PTB pathogenesis.

Metabolic and proteomic mechanism of benzo[a]pyrene degradation by Brevibacillus brevis.

Benzo[a]pyrene (BaP) is a model compound of polycyclic aromatic hydrocarbons. The relationship between its toxicity and some target biomolecules has been investigated. To reveal the interactions of BaP biodegradation and metabolic network, BaP intermediates, proteome, carbon metabolism and ion transport were analyzed. The results show that 76% BaP was degraded by Brevibacillus brevis within 7 d through the cleavage of aromatic rings with the production of 1-naphthol and 2-naphthol. During this process, the expression of xylose isomerase was induced for xylose metabolism, whereas, α-cyclodextrin could no longer be metabolized. Lactic acid, acetic acid and oxalic acid at 0.1-1.2 mg dm-3 were released stemming from their enhanced biosynthesis in the pathways of pyruvate metabolism and citrate cycle, while 5-7 mg dm-3 of PO43- were transported for energy metabolism. The relative abundance of 43 proteins was significantly increased for pyruvate metabolism, citrate cycle, amino acid metabolism, purine metabolism, ribosome metabolism and protein synthesis.

Factors affecting the separation performance of proteins in capillary electrophoresis.

Capillary electrophoresis (CE) is an effective tool for protein separation and analysis. Compared with capillary gel electrophoresis (CGE), non-gel sieving capillary electrophoresis (NGSCE) processes the superiority on operation, repeatability and automaticity. Herein, we investigated the effect of polymer molecular weight and concentration, electric field strength, and the effective length of the capillary on the separation performance of proteins, and find that (1) polymer with high molecular weight and concentration favors the separation of proteins, although concentrated polymer hinders its injection into the channel of the capillary due to its high viscosity. (2) The resolution between the adjacent proteins decreases with the increase of electric field strength. (3) When the effective length of the capillary is long, the separation performance improves at the cost of separation time. (4) 1.4% (w/v) hydroxyethyl cellulose (HEC), 100 V/cm voltage and 12 cm effective length offers the best separation for the proteins with molecular weight from 14,400 Da to 97,400 Da. Finally, we employed the optimal electrophoretic conditions to resolve Lysozyme, Ovalbumin, BSA and their mixtures, and found that they were baseline resolved within 15 min.

Drug resistance mutation profiles of the drug-naïve and first-line regimen-treated HIV-1-infected population of Suzhou, China.

Little is known about the prevalence of drug-resistant mutations in HIV-1-positive individuals in Suzhou, China. To elucidate the transmitted drug resistance (TDR) and acquired drug resistance mutation (ADR) profiles, we collected blood specimens from 127 drug-naïve and 117 first-line drug-treated HIV-1-infected individuals sampled from 2014 to 2016 in Suzhou. We successfully amplified pol fragments from 100 drug-naïve and 20 drug-treated samples. We then determined the drug-resistant mutations to protease (PR) and reverse-transcriptase (RT) inhibitors according to the Stanford drug resistance database. Overall, 11 and 13 individuals had transmitted (drug-naïve group) and acquired (treated group) resistance mutations, respectively. Six transmitted drug-resistant mutations were found, including two mutations (L33F and L76V) in the protease region and four (K70N/E and V179D/E) in the RT region. Only L76V was a major mutation, and K70N/E and V179D/E are known to cause low-level resistance to RT inhibitors. All 13 treated participants who had major drug resistance mutations demonstrated intermediate to high resistance to efavirenz and nevirapine, and six had a treatment duration of less than three months. No major mutations to RT inhibitors were found, implying that the epidemic of transmitted resistance mutations was not significant in this area. Our results suggest that more frequent virus load and drug resistance mutation tests should be conducted for individuals receiving antiretroviral treatment, especially for newly treated patients. Our research provides insights into the occurrence of HIV-1 drug resistance in Suzhou and will help to optimize the treatment strategy for this population.

Effects of citrate acid concentrate (citrasate®) on heparin N requirements and hemodialysis adequacy: a multicenter, prospective noninferiority trial.

BACKGROUND: Citrasate®, citric acid dialysate (CD), contains 2.4 mEq of citric acid (citrate), instead of acetic acid (acetate) as in standard bicarbonate dialysate. Previous studies suggest CD may improve dialysis adequacy and decrease heparin requirements, presumably due to nonsystemic anticoagulant effects in the dialyzer. METHODS: We prospectively evaluated 277 hemodialysis patients in eight outpatient facilities to determine if CD with reduced heparin N (HN) would maintain dialyzer clearance. Subjects progressed through four study periods [baseline (B): bicarbonate dialysate + 100% HN; period 1 (P1): CD + 100% HN; period 2 (P2): CD + 80% HN; period 3 (P3): CD + 66.7% HN]. The predefined primary endpoint was noninferiority (margin -8%) of the percent change in mean dialyzer conductivity clearance between baseline and P2. RESULTS: Subjects were 57.4% male, 41.7% white, 54.3% black, and 44.4% diabetic; mean age was 59 ± 14.4 years; mean time on dialysis was 1,498 ± 1,165 days; 65.7% had arteriovenous fistula, 19.9% arteriovenous graft, 14.4% catheters, and 27.8% used antiplatelet agents. Mean dialyzer clearance increased 0.9% (P1), 1.0% (P2), and 0.9% (P3) with CD despite heparin reduction. SpKt/V remained stable (B: 1.54 ± 0.29; P1: 1.54 ± 0.28; P2: 1.55 ± 0.27; P3: 1.54 ± 0.26). There was no significant difference in dialyzer/dialysis line thrombosis, post-HD time to hemostasis, percent of subjects with adverse events (AEs), or study-related AEs. CONCLUSIONS: CD was safe, effective, and met all study endpoints. Dialyzer clearance increased approximately 1% with CD despite 20-33% heparin reduction. Over 92% of P3 subjects demonstrated noninferiority of dialyzer clearance with CD and 33% HN reduction. There was no significant difference in dialyzer clotting, bleeding, or adverse events.

Validation of the sleep impact scale in patients with major depressive disorder and insomnia.

OBJECTIVES: Chronic insomnia and depression are often associated. Measuring the impact on quality of life associated with changes in sleep in co-treatment of insomnia and depression requires a valid and reliable patient reported outcome (PRO) instrument. This study aimed to assess the validity of the Sleep Impact Scale (SIS), a sleep-specific PRO instrument, in a population comorbid with Major Depressive Disorder (MDD) and insomnia to support its use in clinical or clinical trial applications. RESEARCH DESIGN AND METHODS: Data from 379 subjects enrolled in a 27 week US, multi-center, phase IV, randomized, double-blind, parallel group, placebo-controlled trial of zolpidem tartrate extended-release taken in combination with escitalopram vs. placebo combined with escitalopram were pooled across treatment groups. Results from multi-trait analyses, tests of internal consistency and test-retest reliability, concurrent validity, known-groups validity, responsiveness, and thresholds for minimal important difference (MID) were examined. RESULTS: Mean baseline scores on the SIS ranged from 22.85 (+/-13.41) on Satisfaction with Sleep to 43.49 (+/-21.12) on Mental Fatigue, reflecting impairments due to sleep problems. The SIS was found to be internally consistent (alpha > or = 0.70 for all domains) and have good construct validity. The item-domain correlations were > or = 0.52 with no instance of an item correlating more highly with a domain other than its own. There were some floor and no ceiling effects. The test-retest reliability of the SIS domains ranged between 0.68 and 0.83. Clinical validity assessed through known groups methods was supported. The SIS was responsive to changes on all domains. Preliminary estimates of minimum important difference (MID) were obtained to interpret changes in SIS domains. LIMITATIONS: Limitations include the need for further qualitative research on content validity and the lack of a patient global assessment of change. CONCLUSIONS: This study yielded adequate evidence of the validity of the SIS for use in clinical trials and research on MDD patients with comorbid insomnia.

Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study.

BACKGROUND: Apolipoprotein A5 gene (APOA5) variation is associated with plasma triglycerides (TGs). However, little is known about whether dietary fat modulates this association. METHODS AND RESULTS: We investigated the interaction between APOA5 gene variation and dietary fat in determining plasma fasting TGs, remnant-like particle (RLP) concentrations, and lipoprotein particle size in 1001 men and 1147 women who were Framingham Heart Study participants. Polymorphisms -1131T>C and 56C>G, representing 2 independent haplotypes, were analyzed. Significant gene-diet interactions between the -1131T>C polymorphism and polyunsaturated fatty acid (PUFA) intake were found (P<0.001) in determining fasting TGs, RLP concentrations, and particle size, but these interactions were not found for the 56C>G polymorphism. The -1131C allele was associated with higher fasting TGs and RLP concentrations (P<0.01) in only the subjects consuming a high-PUFA diet (>6% of total energy). No heterogeneity by sex was found. These interactions showed a dose-response effect when PUFA intake was considered as a continuous variable (P<0.01). Similar interactions were found for the sizes of VLDL and LDL particles. Only in carriers of the -1131C allele did the size of these particles increase (VLDL) or decrease (LDL) as PUFA intake increased (P<0.01). We further analyzed the effects of n-6 and n-3 fatty acids and found that the PUFA-APOA5 interactions were specific for dietary n-6 fatty acids. CONCLUSIONS: Higher n-6 (but not n-3) PUFA intake increased fasting TGs, RLP concentrations, and VLDL size and decreased LDL size in APOA5 -1131C carriers, suggesting that n-6 PUFA-rich diets are related to a more atherogenic lipid profile in these subjects.

Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study.

High density lipoprotein cholesterol (HDL-C) is inversely associated with coronary heart disease and has a genetic component; however, linkage to HDL-C is not conclusive. Subfractions of HDL, such as HDL(3)-C, may be better phenotypes for linkage studies. Using HDL(3)-C levels measured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite markers spaced approximately 10 centimorgan (cM) apart. Nine candidate genes were identified and annotated using a bioinformatics approach in the region of the highest linkage peak. Twenty-eight single nucleotide polymorphisms (SNPs) were selected from these candidate genes, and linkage and family-based association fine mapping were conducted using these SNPs. The highest multipoint log-of-the-odds (LOD) score from the initial linkage analysis was 3.7 at 133 cM on chromosome 6. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Family-based association analysis revealed that SNP rs2257104 in PLAGL1 at approximately 143 cM was associated with multivariable adjusted HDL(3) (P = 0.03). Further study of the linkage region and exploration of other variants in PLAGL1 are warranted to define the potential functional variants of HDL-C metabolism.

Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study.

Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; -1131T>C, -3A>G, 56C>G IVS3+ 476G>A, and 1259T>C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C>G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population. SNP analyses revealed that the -1131T>C and 56C>G SNPs were significantly associated with higher plasma TG concentrations in both men and women. For RLP and lipoprotein subclasses, we observed gender-specific association for the -1131T>C and 56C>G SNPs. Female carriers of the -1131C allele had higher RLP concentrations, whereas in males, significant associations for RLPs were observed for the 56G allele. Moreover, haplotype analyses confirmed these findings and revealed that the 22122 and 11211 haplotypes exhibited different associations with HDL cholesterol concentrations. In women, the -1131C allele was associated with a higher hazard ratio for CVD (1.85; 95% confidence interval, 1.03-3.34; P = 0.04), in agreement with the association of this SNP with higher RLPs.

The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore.

Singapore comprises three ethnic groups: Chinese (76.7%), Malays (14%), and Asian-Indians (7.9%). Overall, Singaporeans experience coronary heart disease rates similar to those found in the United States. However, there is a dramatic interethnic gradient, with Asian-Indians having significantly higher risk than Chinese and Malays. These differences are associated with HDL cholesterol levels and cannot be solely explained by environmental exposure, and may be driven by genetic factors. The gene encoding apolipoprotein A-V (APOA5) has been located on chromosome 11, and it is emerging as an important candidate gene for lipoprotein metabolism. We investigated associations between APOA5 polymorphisms and plasma lipids in 3,971 Singaporeans to establish whether they accounted for some of the ethnic differences in plasma lipids. We found significant associations between the minor alleles at each of four common polymorphisms and higher plasma triglycerides (TGs) across ethnic groups. Haplotype analyses showed significant associations with TGs, explaining 6.9%, 5.2%, and 2.7% of the TG variance in Malays, Asian-Indians, and Chinese, respectively. Conversely, we observed significant inverse associations between the minor alleles and HDL cholesterol concentrations for Chinese and Malays. These data suggest that APOA5 plays a role in the ethnic differences observed for plasma TG and HDL cholesterol concentrations.