Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding Information: GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file : Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

The Implications of Socially Responsible Retailing Platform on Channel Structure Choice and Product Quality Decisions

At present, corporate social responsibility has been widely mentioned by the international society, especially platform enterprises. For a platform that assumes social responsibilities, consumer surplus is a rather critical aspect, and product quality is one of the most important factors directly related to consumers. This paper studies a supply chain consisting of a manufacturer and a retailing platform, in which the retailing platform procures products from the manufacturer. The manufacturer produces the products and decides the product quality. We consider two channel structures of the manufacturer and the retailing platform in the reseller mode and marketplace mode. Based on the model analysis and discussions, we obtain some managerial insights that are helpful in commercial practice. For the retailing platform, it has to suffer a loss in economic profit to care more about consumer surplus and become a social responsibility platform. In addition, its social responsibility plays different roles in different channel structures. In the marketplace mode, a social responsibility retailing platform helps to improve product quality. In the reseller mode, the retailing platform’s social responsibility does not make a change in product quality. Furthermore, the product quality in the reseller mode is always higher than that in the marketplace mode. From the perspective of economic profits, the manufacturer obtains higher profits in the reseller mode than the marketplace mode. The retailing platform obtains higher profits in the marketplace mode than the reseller mode

The Implications of Socially Responsible Retailing Platform on Channel Structure Choice and Product Quality Decisions

At present, corporate social responsibility has been widely mentioned by the international society, especially platform enterprises. For a platform that assumes social responsibilities, consumer surplus is a rather critical aspect, and product quality is one of the most important factors directly related to consumers. This paper studies a supply chain consisting of a manufacturer and a retailing platform, in which the retailing platform procures products from the manufacturer. The manufacturer produces the products and decides the product quality. We consider two channel structures of the manufacturer and the retailing platform in the reseller mode and marketplace mode. Based on the model analysis and discussions, we obtain some managerial insights that are helpful in commercial practice. For the retailing platform, it has to suffer a loss in economic profit to care more about consumer surplus and become a social responsibility platform. In addition, its social responsibility plays different roles in different channel structures. In the marketplace mode, a social responsibility retailing platform helps to improve product quality. In the reseller mode, the retailing platform’s social responsibility does not make a change in product quality. Furthermore, the product quality in the reseller mode is always higher than that in the marketplace mode. From the perspective of economic profits, the manufacturer obtains higher profits in the reseller mode than the marketplace mode. The retailing platform obtains higher profits in the marketplace mode than the reseller mode

Effect of Transcutaneous Electrical Acupoint Stimulation on One-Lung Ventilation-Induced Lung Injury in Patients Undergoing Esophageal Cancer Operation

Objective. To investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on one-lung ventilation-induced injury in patients undergoing esophageal cancer operation. Methods. The participants (n = 121) were randomly assigned into TEAS and sham groups. The TEAS group was given transcutaneous electrical stimulation therapy. The acupoints selected were Feishu (BL13), Hegu (L14), and Zusanli (ST36) and were treated 30 minutes before induction of anesthesia; treatment lasts 30 minutes. The sham group was connected to the electrode on the same acupoints, but electronic stimulation was not applied. The levels of oxygenation index (PaO2/FiO2) and alveolar-arterial oxygen tension difference (A-aDO2) before one-lung ventilation (T1), 30 minutes after one-lung ventilation (T2), 2 hours after one-lung ventilation (T3), and 1 hour after the operation (T4) and the levels of serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) at T1, T2, T3, and 24 hours after the operation (T5) were taken as the primary endpoints. The incidence of postoperative pulmonary complications, removal time of thoracic drainage tube, and length of hospital stay were taken as the secondary endpoints. Results. Compared with that, in the sham group, the level of PaO2/FiO2 in the TEAS group was significantly increased at T2, T3, and T4, and the level of A-aDO2 was significantly reduced at T2 and T3 (P<0.05). Besides, compared with that, in the sham group, the level of serum TNF-α at T2, T3, and T5, as well as the level of serum IL-6 at T3 and T5, was significantly reduced, whereas the level of serum IL-10 at T3 was significantly increased (P<0.05). The incidences of pulmonary infection and pleural effusion in the TEAS group were significantly lower than that in the sham group, and the removal time of thoracic drainage tube and the length of hospital stay in the TEAS group were significantly shorter than that in the sham group (P<0.05). Conclusions. TEAS could effectively increase the levels of PaO2/FiO2 and IL-10, reduce the levels of A-aDO2, TNF-α, and IL-6, and reduce the incidence of pulmonary complications. Moreover, it could also contribute to shorten the removal time of thoracic drainage tube and the length of hospital stay

Involvement of Acylated Homoserine Lactones (AHLs) of Aeromonas sobria in Spoilage of Refrigerated Turbot (Scophthalmus maximus L.)

One quorum sensing strain was isolated from spoiled turbot. The species was determined by 16S rRNA gene analysis and classical tests, named Aeromonas sobria AS7. Quorum-sensing (QS) signals (N-acyl homoserine lactones (AHLs)) were detected by report strains and their structures were further determined by GC-MS. The activity changes of AHLs on strain growth stage as well as the influence of different culture conditions on secretion activity of AHLs were studied by the punch method. The result indicated that strain AS7 could induce report strains to produce typical phenotypic response. N-butanoyl-dl-homoserine lactone (C4–HSL), N-hexanoyl-dl-homoserine lactone (C6–HSL), N-octanoyl-dl-homoserine lactone (C8–HSL), N-decanoyl-dl-homoserine lactone (C10–HSL), N-dodecanoyl-dl-homoserine lactone (C12–HSL) could be detected. The activities of AHLs were density-dependent and the max secretion level was at pH 8, sucrose culture, 1% NaCl and 32 h, respectively. The production of siderophore in strain AS7 was regulated by exogenous C8–HSL, rather than C6–HSL. Exogenous C4–HSL and C8–HSL accelerated the growth rate and population density of AS7 in turbot samples under refrigerated storage. However, according to the total viable counts and total volatile basic nitrogen (TVB-N) values of the fish samples, exogenous C6–HSL did not cause spoilage of the turbot fillets. In conclusion, our results suggested that QS was involved in the spoilage of refrigerated turbot

The Quantitative Research on Atmospheric Environmental Corrosion of Aluminum Alloy Products

In this paper, we conduct quantitative research on the atmospheric environmental corrosion of aluminum alloy based on the atmospheric environmental factors. we apply the elastic network regression method to construct a regression model for corrosion rates based on the identified damage factors, which allows us to calculate the dependent variable as long as we know the main environmental factors in a specific year. Finally, we introduce a measure of atmospheric environment corrosion based on the established regression which can characterize the severity of corrosion with different transformations

Optimization of Air Flotation and the Combination of Air Flotation and Membrane Filtration in Microalgae Harvesting

On account of its small size and poor sedimentation performance, microalgae harvesting is restricted from a wider application. Air flotation is an efficient and fast solid&ndash;liquid separation technology, which has the potential to overcome the impediments of microalgae harvesting. In this study, factors influencing microalgae harvesting by air flotation were investigated. The results illustrated that bound extracellular organic matter (bEOM) had a greater effect on microalgae harvesting by air flotation, compared with dissolved extracellular organic matter (dEOM). Microalgae harvesting by air flotation in different growth stages proceeded, and the effect of air flotation in the heterotrophic stage was better than the autotrophic stage. The molecular weight distributions demonstrated that after air flotation, the proportion of high MW substance increased, while the proportion of low MW substance decreased, regardless of whether dEOM or bEOM. Membrane filtration was carried out for the algal solutions before and after air flotation. The membrane of pre-flotation algal solution had a higher critical flux of 51 L/m2&middot;h than that of no-pre-flotation (24 L/m2&middot;h), and, thus, pre-flotation had an active effect on membrane filtration in microalgae harvesting. Moreover, the combination of air flotation and membrane filtration provided an efficient technology for microalgae harvesting