150 results on '"Vujkovic M"'
Search Results
2. The role of surface chemistry in the charge storage properties of graphene oxide
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Jovanovic, Z., Bajuk-Bogdanović, D., Jovanović, S., Mravik, Ž., Kovač, J., Holclajtner-Antunović, I., and Vujković, M.
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- 2017
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3. IDF2022-0368 Integrative analysis of genetic and single-cell omics data reveals cell-types in the pathogenesis of type 2 diabetes
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Suzuki, K., primary, Southam, L., additional, Hatzikotoulas, K., additional, Yin, X., additional, and Vujkovic, M., additional
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- 2023
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4. THE INFLUENCE OF INTERCALATED IONS ON CYCLIC STABILITY OF V2O5/GRAPHITE COMPOSITE IN AQUEOUS ELECTROLYTIC SOLUTIONS: EXPERIMENTAL AND THEORETICAL APPROACH
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Vujković, M., Pašti, I., Simatović, I.Stojković, Šljukić, B., Milenković, M., and Mentus, S.
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- 2015
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5. Versatile insertion capability of Na1.2V3O8 nanobelts in aqueous electrolyte solutions
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Vujković, M., Paunković, B. Sljukić, Simatović, I. Stojković, Mitrić, M., Sequeira, C.A.C., and Mentus, S.
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- 2014
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6. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.
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Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, Chambers, JC, Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, and Chambers, JC
- Abstract
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
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- 2022
7. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.
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Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, Chambers, JC, Loh, M, Zhang, W, Ng, HK, Schmid, K, Lamri, A, Tong, L, Ahmad, M, Lee, J-J, Ng, MCY, Petty, LE, Spracklen, CN, Takeuchi, F, Islam, MT, Jasmine, F, Kasturiratne, A, Kibriya, M, Mohlke, KL, Paré, G, Prasad, G, Shahriar, M, Chee, ML, de Silva, HJ, Engert, JC, Gerstein, HC, Mani, KR, Sabanayagam, C, Vujkovic, M, Wickremasinghe, AR, Wong, TY, Yajnik, CS, Yusuf, S, Ahsan, H, Bharadwaj, D, Anand, SS, Below, JE, Boehnke, M, Bowden, DW, Chandak, GR, Cheng, C-Y, Kato, N, Mahajan, A, Sim, X, McCarthy, MI, Morris, AP, Kooner, JS, Saleheen, D, and Chambers, JC
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- 2022
8. Lipid traits and type 2 diabetes risk in African ancestry individuals:a Mendelian Randomization study
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Soremekun, O. (Opeyemi), Karhunen, V. (Ville), He, Y. (Yiyan), Rajasundaram, S. (Skanda), Liu, B. (Bowen), Gkatzionis, A. (Apostolos), Soremekun, C. (Chisom), Udosen, B. (Brenda), Musa, H. (Hanan), Silva, S. (Sarah), Kintu, C. (Christopher), Mayanja, R. (Richard), Nakabuye, M. (Mariam), Machipisa, T. (Tafadzwa), Mason, A. (Amy), Vujkovic, M. (Marijana), Zuber, V. (Verena), Soliman, M. (Mahmoud), Mugisha, J. (Joseph), Nash, O. (Oyekanmi), Kaleebu, P. (Pontiano), Nyirenda, M. (Moffat), Chikowore, T. (Tinashe), Nitsch, D. (Dorothea), Burgess, S. (Stephen), Gill, D. (Dipender), Fatumo, S. (Segun), Soremekun, O. (Opeyemi), Karhunen, V. (Ville), He, Y. (Yiyan), Rajasundaram, S. (Skanda), Liu, B. (Bowen), Gkatzionis, A. (Apostolos), Soremekun, C. (Chisom), Udosen, B. (Brenda), Musa, H. (Hanan), Silva, S. (Sarah), Kintu, C. (Christopher), Mayanja, R. (Richard), Nakabuye, M. (Mariam), Machipisa, T. (Tafadzwa), Mason, A. (Amy), Vujkovic, M. (Marijana), Zuber, V. (Verena), Soliman, M. (Mahmoud), Mugisha, J. (Joseph), Nash, O. (Oyekanmi), Kaleebu, P. (Pontiano), Nyirenda, M. (Moffat), Chikowore, T. (Tinashe), Nitsch, D. (Dorothea), Burgess, S. (Stephen), Gill, D. (Dipender), and Fatumo, S. (Segun)
- Abstract
Background: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. Methods: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random–effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. Findings: Increased genetically proxied low-density lipoprotein cholesterol (LDL‐C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL‐C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL‐C) was associated with reduced T2DM liability (OR per SD increase in HDL‐C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase in genetically proxied triglyceride (TG) levels was 0.884 [0.773 to 1.011, P = 0.0
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- 2022
9. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
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Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers R, Schneider C, Park J, Lee K, Serper M, Carr R, Kaplan D, Haas M, MacLean M, Witschey W, Zhu X, Tcheandjieu C, Kember R, Kranzler H, Verma A, Giri A, Klarin D, Sun Y, Huang J, Huffman J, TownsendCreasy K, Hand N, Liu C, Long M, Yao J, Budoff M, Tan J, Li X, Lin H, Chen Y, Taylor K, Chang R, Krauss R, Vilarinho S, Brancale J, Nielsen J, Locke A, Jones M, Verweij N, Baras A, Reddy K, NeuschwanderTetri B, Schwimmer J, Sanyal A, Chalasani N, Ryan K, Mitchell B, Gill D, Wells A, Manduchi E, Saiman Y, Mahmud N, Miller D, Reaven P, Phillips L, Muralidhar S, DuVall S, Lee J, Assimes T, Pyarajan S, Cho K, Edwards T, Damrauer S, Wilson P, Gaziano J, ODonnell C, Khera A, Grant S, Brown C, Tsao P, Saleheen D, Lotta L, Bastarache L, Anstee QM, Daly A, Meigs J, Rotter JI, Lynch JA, Rader DJ, Voight BF, Chang KM
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- 2022
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10. Metabolic traits and stroke risk in individuals of African ancestry:mendelian randomization analysis
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Fatumo, S. (Segun), Karhunen, V. (Ville), Chikowore, T. (Tinashe), Sounkou, T. (Toure), Udosen, B. (Brenda), Ezenwa, C. (Chisom), Nakabuye, M. (Mariam), Soremekun, O. (Opeyemi), Daghlas, I. (Iyas), Ryan, D. K. (David K.), Taylor, A. (Amybel), Mason, A. M. (Amy M.), Damrauer, S. M. (Scott M.), Vujkovic, M. (Marijana), Keene, K. L. (Keith L.), Fornage, M. (Myriam), Järvelin, M.-R. (Marjo-Riitta), Burgess, S. (Stephen), and Gill, D. (Dipender)
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risk factor ,lipid ,ischemic stroke ,cholesterol ,mortality - Abstract
Background and Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals. Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy. Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07–1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04–1.21]; total cholesterol: 1.23 [1.06–1.43]; HDL-C, 0.93 [0.89–0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals. Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.
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- 2021
11. Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling
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Karhunen, V. (Ville), Daghlas, I. (Iyas), Zuber, V. (Verena), Vujkovic, M. (Marijana), Olsen, A. K. (Anette K.), Knudsen, L. B. (Lotte Bjerre), Haynes, W. G. (William G.), Howson, J. M. (Joanna M. M.), Gill, D. (Dipender), Karhunen, V. (Ville), Daghlas, I. (Iyas), Zuber, V. (Verena), Vujkovic, M. (Marijana), Olsen, A. K. (Anette K.), Knudsen, L. B. (Lotte Bjerre), Haynes, W. G. (William G.), Howson, J. M. (Joanna M. M.), and Gill, D. (Dipender)
- Abstract
Aims/hypothesis: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Methods: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability > 0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Results: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units −0.16, 95% CI −0.30, −0.02), C-reactive protein (−0.13, 95% CI −0.19, −0.08) and triacylglycerol levels (−0.17, 95% CI −0.22, −0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. Conclusions/interpretation
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- 2021
12. The maternal homocysteine pathway is influenced by riboflavin intake and MTHFR polymorphisms without affecting the risk of orofacial clefts in the offspring
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Vujkovic, M, Steegers, E A, van Meurs, J, Yazdanpanah, N, van Rooij, I A, Uitterlinden, A G, and Steegers-Theunissen, R P
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- 2010
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13. A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study
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Bouwland-Both, MI, Steegers-Theunissen, RPM, Vujkovic, M, Lesaffre, EMEH, Mook-Kanamori, DO, Hofman, A, Lindemans, J, Russcher, H, Jaddoe, VWV, and Steegers, EAP
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- 2013
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14. A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring
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Obermann-Borst, S A, Vujkovic, M, de Vries, J H, Wildhagen, M F, Looman, C W, de Jonge, R, Steegers, E AP, and Steegers-Theunissen, R PM
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- 2011
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15. Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment
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Vujkovic, M, de Vries, JH, Dohle, GR, Bonsel, GJ, Lindemans, J, Macklon, NS, van der Spek, PJ, Steegers, EAP, and Steegers-Theunissen, RPM
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- 2009
16. The maternal Mediterranean dietary pattern is associated with a reduced risk of spina bifida in the offspring
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Vujkovic, M, Steegers, EA, Looman, CW, Ocké, MC, Spek, PJ van der, and Steegers-Theunissen, RP
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- 2009
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17. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
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Lindstrom, S., Wang, L., Smith, E.N., Gordon, W., Vlieg, A.V., Andrade, M. de, Brody, J.A., Pattee, J.W., Haessler, J., Brumpton, B., Chasman, D.I., Suchon, P., Chen, M.H., Turman, C., Germain, M., Wiggins, K.L., MacDonald, J., Braekkan, S.K., Armasu, S.M., Pankratz, N., Jackson, R.D., Nielsen, J.B., Giulianini, F., Puurunen, M.K., Ibrahim, M., Heckbert, S.R., Damrauer, S.M., Natarajan, P., Klarin, D., Vries, P.S. de, Sabater-Lleal, M., Huffman, J.E., Bammler, T.K., Frazer, K.A., McCauley, B.M., Taylor, K., Pankow, J.S., Reiner, A.P., Gabrielsen, M.E., Deleuze, J.F., O'Donnell, C.J., Kim, J., McKnight, B., Kraft, P., Hansen, J.B., Rosendaal, F.R., Heit, J.A., Psaty, B.M., Tang, W.H., Kooperberg, C., Hveem, K., Ridker, P.M., Morange, P.E., Johnson, A.D., Kabrhel, C., Tregouet, D.A., Smith, N.L., Busenkell, E., Judy, R., Lynch, J., Levin, M., Aragam, J.H.K., Chaffin, M., Haas, M., Assimes, T.L., Huang, J., Lee, K.M., Shao, Q., Huang, Y.F., Sun, Y.V., Vujkovic, M., Saleheen, D., Miller, D.R., Reaven, P., DuVall, S., Boden, W., Pyarajan, S., Henke, P., Gaziano, J.M., Concato, J., Rader, D.J., Cho, K., Chang, K.M., Wilson, P.W.F., Tsao, P.S., Kathiresan, S., Obi, A., Million Veteran Program, CHARGE Hemostasis Working Grp, INVENT Consortium, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, University of Washington [Seattle], The Scripps Translational Science Institute and Scripps Health, Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Minnesota System, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Brigham and Women's Hospital [Boston], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), National Institutes of Health [Bethesda] (NIH), Harvard T.H. Chan School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biorobotics Lab (University of Washington), University of South-Eastern Norway (USN), Department of Health Sciences Research, Ohio State University [Columbus] (OSU), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Los Angeles Biomedical Research Institute (LA BioMed), University of Augsburg [Augsburg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Epidemiology, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Department of Emergency Medicine, Massachusetts General Hospital [Boston], Universiteit Leiden-Universiteit Leiden, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Augsburg (UNIA), and Universiteit Leiden
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0301 basic medicine ,Genetics ,[SDV]Life Sciences [q-bio] ,Immunology ,Genome-wide association study ,Cell Biology ,Hematology ,030204 cardiovascular system & hematology ,Biology ,equipment and supplies ,Biochemistry ,3. Good health ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mendelian randomization ,Expression quantitative trait loci ,Gene expression ,cardiovascular diseases ,Gene ,Genetic association ,Whole blood - Abstract
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
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- 2019
18. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
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Flannick, J, Mercader, JM, Fuchsberger, C, Udler, MS, Mahajan, A, Wessel, J, Teslovich, TM, Caulkins, L, Koesterer, R, Barajas-Olmos, F, Blackwell, TW, Boerwinkle, E, Brody, JA, Centeno-Cruz, F, Chen, L, Chen, S, Contreras-Cubas, C, Córdova, E, Correa, A, Cortes, M, DeFronzo, RA, Dolan, L, Drews, KL, Elliott, A, Floyd, JS, Gabriel, S, Garay-Sevilla, ME, García-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, Jørgensen, ME, Kang, HM, Kelsey, M, Kim, B-J, Koistinen, HA, Kuusisto, J, Leader, JB, Linneberg, A, Liu, C-T, Liu, J, Lyssenko, V, Manning, AK, Marcketta, A, Malacara-Hernandez, JM, Martínez-Hernández, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, Ng, MCY, O'Dushlaine, C, Payne, AJ, Pihoker, C, Broad Genomics Platform, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, Rayner, NW, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WY, Soberón, X, Stringham, HM, Strom, TM, Tam, CHT, Thameem, F, Tomlinson, B, Torres, JM, Tracy, RP, van Dam, RM, Vujkovic, M, Wang, S, Welch, RP, Witte, DR, Wong, T-Y, Atzmon, G, Barzilai, N, Blangero, J, Bonnycastle, LL, Bowden, DW, Chambers, JC, Chan, E, Cheng, C-Y, Cho, YS, Collins, FS, de Vries, PS, Duggirala, R, Glaser, B, Gonzalez, C, Gonzalez, ME, Groop, L, Kooner, JS, Kwak, SH, Laakso, M, Lehman, DM, Nilsson, P, Spector, TD, Tai, ES, Tuomi, T, Tuomilehto, J, Wilson, JG, Aguilar-Salinas, CA, Bottinger, E, Burke, B, Carey, DJ, Chan, JCN, Dupuis, J, Frossard, P, Heckbert, SR, Hwang, MY, Kim, YJ, Kirchner, HL, Lee, J-Y, Lee, J, Loos, RJF, Ma, RCW, Morris, AD, O'Donnell, CJ, Palmer, CNA, Pankow, J, Park, KS, Rasheed, A, Saleheen, D, Sim, X, Small, KS, Teo, YY, Haiman, C, Hanis, CL, Henderson, BE, Orozco, L, Tusié-Luna, T, Dewey, FE, Baras, A, Gieger, C, Meitinger, T, Strauch, K, Lange, L, Grarup, N, Hansen, T, Pedersen, O, Zeitler, P, Dabelea, D, Abecasis, G, Bell, GI, Cox, NJ, Seielstad, M, Sladek, R, Meigs, JB, Rich, SS, Rotter, JI, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler, D, Burtt, NP, Scott, LJ, Morris, AP, Florez, JC, McCarthy, MI, Boehnke, M, Flannick, J, Mercader, JM, Fuchsberger, C, Udler, MS, Mahajan, A, Wessel, J, Teslovich, TM, Caulkins, L, Koesterer, R, Barajas-Olmos, F, Blackwell, TW, Boerwinkle, E, Brody, JA, Centeno-Cruz, F, Chen, L, Chen, S, Contreras-Cubas, C, Córdova, E, Correa, A, Cortes, M, DeFronzo, RA, Dolan, L, Drews, KL, Elliott, A, Floyd, JS, Gabriel, S, Garay-Sevilla, ME, García-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, Jørgensen, ME, Kang, HM, Kelsey, M, Kim, B-J, Koistinen, HA, Kuusisto, J, Leader, JB, Linneberg, A, Liu, C-T, Liu, J, Lyssenko, V, Manning, AK, Marcketta, A, Malacara-Hernandez, JM, Martínez-Hernández, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, Ng, MCY, O'Dushlaine, C, Payne, AJ, Pihoker, C, Broad Genomics Platform, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, Rayner, NW, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WY, Soberón, X, Stringham, HM, Strom, TM, Tam, CHT, Thameem, F, Tomlinson, B, Torres, JM, Tracy, RP, van Dam, RM, Vujkovic, M, Wang, S, Welch, RP, Witte, DR, Wong, T-Y, Atzmon, G, Barzilai, N, Blangero, J, Bonnycastle, LL, Bowden, DW, Chambers, JC, Chan, E, Cheng, C-Y, Cho, YS, Collins, FS, de Vries, PS, Duggirala, R, Glaser, B, Gonzalez, C, Gonzalez, ME, Groop, L, Kooner, JS, Kwak, SH, Laakso, M, Lehman, DM, Nilsson, P, Spector, TD, Tai, ES, Tuomi, T, Tuomilehto, J, Wilson, JG, Aguilar-Salinas, CA, Bottinger, E, Burke, B, Carey, DJ, Chan, JCN, Dupuis, J, Frossard, P, Heckbert, SR, Hwang, MY, Kim, YJ, Kirchner, HL, Lee, J-Y, Lee, J, Loos, RJF, Ma, RCW, Morris, AD, O'Donnell, CJ, Palmer, CNA, Pankow, J, Park, KS, Rasheed, A, Saleheen, D, Sim, X, Small, KS, Teo, YY, Haiman, C, Hanis, CL, Henderson, BE, Orozco, L, Tusié-Luna, T, Dewey, FE, Baras, A, Gieger, C, Meitinger, T, Strauch, K, Lange, L, Grarup, N, Hansen, T, Pedersen, O, Zeitler, P, Dabelea, D, Abecasis, G, Bell, GI, Cox, NJ, Seielstad, M, Sladek, R, Meigs, JB, Rich, SS, Rotter, JI, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler, D, Burtt, NP, Scott, LJ, Morris, AP, Florez, JC, McCarthy, MI, and Boehnke, M
- Abstract
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
- Published
- 2019
19. Effect of thermal treatment on the charge storage properties of graphene oxide/12-tungstophosphoric acid nanocomposite
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Jovanović, Z., Holclajtner-Antunović, I., Bajuk-Bogdanović, D., Jovanović, S., Mravik, Ž., and Vujković, M.
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- 2017
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20. Validity of a questionnaire measuring the world health organization concept of health system responsiveness wit
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Kooy, J. (Jacoba) van der, Valentine, N.B. (Nicole), Birnie, E. (Erwin), Vujkovic, M. (Marijana), Graaf, J.P. (Hanneke) de, Denktaş, S. (Semiha), Steegers, E.A.P. (Eric), Bonsel, G.J. (Gouke), Kooy, J. (Jacoba) van der, Valentine, N.B. (Nicole), Birnie, E. (Erwin), Vujkovic, M. (Marijana), Graaf, J.P. (Hanneke) de, Denktaş, S. (Semiha), Steegers, E.A.P. (Eric), and Bonsel, G.J. (Gouke)
- Abstract
Background: The concept of responsiveness, introduced by the World Health Organization (WHO), addresses non-clinical aspects of health service quality that are relevant regardless of provider, country, health system or health condition. Responsiveness refers to "aspects related to the way individuals are treated and the environment in which they are treated" during health system interactions. This paper assesses the psychometric properties of a newly developed responsiveness questionnaire dedicated to evaluating maternal experiences of perinatal care services, called the Responsiveness in Perinatal and Obstetric Health Care Questionnaire (ReproQ), using the eight-domain WHO concept. Methods: The ReproQ was developed between October 2009 and February 2010 by adapting the WHO Responsiveness Questionnaire items to the perinatal care context. The psychometric properties of feasibility, construct validity, and discriminative validity were empirically assessed in a sample of Dutch women two weeks post partum. Results: A total of 171 women consented to participation. Feasibility: the interviews lasted between 20 and 40 minutes and the overall missing rate was 8%. Construct validity: mean Cronbach's alphas for the antenatal, birth and postpartum phase were: 0.73 (range 0.57-0.82), 0.84 (range 0.66-0.92), and 0.87 (range 0.62-0.95) respectively. The item-own scale correlations within all phases were considerably higher than most of the item-other scale correlations. Within the antenatal care, birth care and post partum phases, the eight factors explained 69%, 69%, and 76% of variance respectively. Discriminative validity: overall responsiveness mean sum scores were higher for women whose children were not admitted. This confirmed the hypothesis that dissatisfaction with health outcomes is transferred to their judgement on responsiveness of the perinatal services. Conclusions: The ReproQ interview-based questionnaire demonstrated satisfactory psychometric properties to descri
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- 2014
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21. The maternal homocysteine pathway is influenced by riboflavin intake and MTHFR polymorphisms without affecting the risk of orofacial clefts in the offspring.
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Vujkovic, M., Steegers, E.A.P., Meurs, J. van, Yazdanpanah, N., Rooij, I.A.L.M. van, Uitterlinden, A.G., Steegers-Theunissen, R.P.M., Vujkovic, M., Steegers, E.A.P., Meurs, J. van, Yazdanpanah, N., Rooij, I.A.L.M. van, Uitterlinden, A.G., and Steegers-Theunissen, R.P.M.
- Abstract
1 maart 2010, Item does not contain fulltext, BACKGROUND/OBJECTIVES: Riboflavin is a cofactor for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme involved in the homocysteine pathway. The aim of this study was to investigate the effects of maternal riboflavin intake and two MTHFR polymorphisms (677C>T; Ala222Val and 1298A>C; Glu429Ala substitutions) on the biomarkers of the homocysteine pathway, and investigate the risk of having offspring with an orofacial cleft (OFC). SUBJECTS/METHODS: In a case-control study design, dietary riboflavin intake and the MTHFR 677C>T and 1298A>C polymorphisms were evaluated in 123 OFC and 108 control mothers by using food frequency questionnaires and blood samples. Homocysteine (tHcy), folate and vitamin B12 concentrations in blood were analyzed in 70 cases and 68 controls. Linear and logistic regression analyses were applied. RESULTS: At 14 months postpartum riboflavin intake and MTHFR 677C>T and 1298A>C genotypes were not significantly different between cases and controls. The 677TT genotype showed lower folate concentrations compared to C-allele carriers with a mean difference of 2.8 nmol/l in serum and 174 nmol/l in red blood cell (both P's=0.01). Every mg per day increase of dietary riboflavin intake was positively associated with increase in vitamin B12 concentration by 52.1% (P<0.01). This effect was most pronounced in MTHFR 677TT homozygotes (205.1%, P=0.03). The riboflavin-adjusted MTHFR 677TT and 1298CC genotypes showed a trend toward an increasing risk for OFC, adjusted odds ratio 1.7 (confidence interval (95% CI), 0.7-4.5) and 1.6 (95% CI, 0.7-4.2), respectively. CONCLUSIONS: Maternal riboflavin intake is significantly associated with biomarkers of the homocysteine pathway, with the strongest effects in MTHFR 677TT homozygotes. The maternal risk of having OFC offspring, however, is not associated with dietary riboflavin intake.
- Published
- 2010
22. Dietary Patterns and Human Reproduction
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Vujkovic, M. (Marijana) and Vujkovic, M. (Marijana)
- Abstract
Part 1 of the thesis focuses on dietary patterns and fatty acid intake in couples undergoing IVF/ICSI fertility treatment. The studies described in Chapter 2, 3 and 4 are based on the FOod Lifestyle and Fertility Outcome study (FOLFO), a prospective cohort study examining the influence of preconception lifestyle exposures in subfertile couples on fertility parameters and pregnancy outcome. This study was conducted between 2004 and 2007 in the Erasmus University Medical Centre, Rotterdam, the Netherlands.24 Part 2 focuses on the role of the maternal dietary patterns periconception as a risk factor for congenital malformations in the offspring. The studies on risk factors for spina bifida (Chapter 5) and orofacial cleft (Chapter 7) offspring were conducted in a nationwide large-scale case-control triad study carried out between 1998 and 2004 at the Radboud University Nijmegen Medical Centre.25, 26 The findings on associations with congenital heart malformations in Chapter 6 are based on the HAVEN study (Hart Afwijkingen, Vasculaire status, Erfelijkheid en Nutriënten).7 The HAVEN study is an ongoing case-control triad study conducted in the Western part of the Netherlands. The study emphasizes nutrition, lifestyle and genes in the pathogenesis and prevention of congenital heart malformations and children and both parents were included. Data collected between March 2004 and August 2008 were used for analysis. Finally, Chapter 8 provides a general discussion of the thesis, a summary of the key findings, reflections on the strengths and limitations of the applied methods, implication for clinical practice and public health, and suggestions for future research.
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- 2010
23. A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study
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Bouwland-Both, MI, primary, Steegers-Theunissen, RPM, additional, Vujkovic, M, additional, Lesaffre, EMEH, additional, Mook-Kanamori, DO, additional, Hofman, A, additional, Lindemans, J, additional, Russcher, H, additional, Jaddoe, VWV, additional, and Steegers, EAP, additional
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- 2012
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24. The maternal homocysteine pathway is influenced by riboflavin intake and MTHFR polymorphisms without affecting the risk of orofacial clefts in the offspring
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Vujkovic, M, primary, Steegers, E A, additional, van Meurs, J, additional, Yazdanpanah, N, additional, van Rooij, I A, additional, Uitterlinden, A G, additional, and Steegers-Theunissen, R P, additional
- Published
- 2009
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25. Efficient timing closure without timing driven placement and routing.
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Vujkovic, M., Wadkins, D., Swartz, B., and Sechen, C.
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- 2004
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26. Optimized power-delay curve generation for standard cell ICs.
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Vujkovic, M. and Sechen, C.
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- 2002
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27. The electrochemical behaviour of re-synthesized cathode material from spent Li-ion batteries in an organic electrolyte
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Senćanski Jelena V., Vujković Milica J., and Stojković-Simatović Ivana B.
- Subjects
lithium-ion batteries ,the recycling of lithium-ion batteries ,the co-precipitation method ,LiNi1/3Mn1/3Co1/3O2 ,an organic electrolyte ,Engineering (General). Civil engineering (General) ,TA1-2040 - Abstract
The excessive use of Li-ion batteries has resulted in the growing necessity of developing a recycling procedure for them, particularly stemming from their negative impact on the environment as well as the fact that the natural-ore metals contained in them can be replaced. This work presents a re-synthesis of cathode material obtained from spent Li-ion batteries using the co-precipitation method in order to recycle it. The structure of the re-synthesized metal was characterized by XRD and the morphology by SEM. The chemical content of the spent cathode material was determined by FAAS. In order to prove functionality, the electrochemical behaviour was examined in a 1M solution of LiClO4 in propylene carbonate by galvanostatic charging and discharging. Since the initial capacity of the re-synthesized material was 70.6 mAh g-1 when the current of charging/discharging was 100 mA g-1, the fade of capacity was 13% after the initial five cycles. The electrochemical properties of the re-synthesized material were then finally compared to the material re-synthesized by the citrate gel combustion method.
- Published
- 2018
28. Psychotraumatic Reactions of Invalids
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Spasojevic, V., primary, Milavic-Vujkovic, M., additional, and Dimitrijevic, M., additional
- Published
- 1997
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29. Maternal Western dietary patterns and the risk of developing a cleft lip with or without a cleft palate.
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Vujkovic M, Ocke MC, van der Spek PJ, Yazdanpanah N, Steegers EA, and Steegers-Theunissen RP
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- 2007
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30. Recycling of LiCo0.59Mn0.26Ni0.15O2 cathodic material from spent Li-ion batteries by the method of the citrate gel combustion
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Senćanski Jelena V., Vujković Milica J., Stojković Ivana B., Majstorović Divna M., Bajuk-Bogdanović Danica V., Pastor Ferenc T., and Mentus Slavko V.
- Subjects
recycling of spent Li-ion batteries ,cathodic material ,sol-gel method ,Chemical technology ,TP1-1185 - Abstract
The Li-ion batteries are the main power source for the high technology devices, such as mobile phones and electric vehicles. Because of that, the number of spent Li-ion batteries significantly increases. Today, the number of active mobile phones crossed 7.19 billion. It is estimated that the mass of the spent lithium ion batteries in China will exceed 500,000 t by 2020. The trouble is in the ingredients of these batteries. They contain Li, Co, Mn, Ni, Cu, Al and toxic and flammable electrolytes which have a harmful affection to the environment. Because of that, the recycling procedure attracts raising attention of researches. Several commercial spent Li-ion batteries were recycled by the relatively fast, economic and simple procedure. The three ways of separating the cathode material from Al collector were examined after the manual dismantling of the components of batteries with the Li(Co–Mn–Ni)O2 as cathode material. These were: 1. dissolution of the Al collector in the alkali medium, 2. peeling off with N-methylpyrrolidone and 3. thermal decomposition of the adhesive at 700°C. The procedure with the highest yield was the one with the dissolution in alkali medium. The chemical analysis of the single batteries'' components (the crust, Al/Cu collector, cathode material) were done by the atomic absorption spectrometry. The components, before the analysis, were dissolved. The re-synthesis of the cathode material by the method of the citrate gel combustion was done after the separating the cathode material and dissolving it in the nitric acid. The obtained product was, after annealing, characterized by the methods of X-ray diffraction and Raman spectroscopy. The recycled product was LiCo0.59Mn0.26Ni0.15O2 stoichiometry, with the hexagonal layered structure α-NaFeO2 type. The functionalization of the resynthesized material was examined in the 1 M solution LiClO4 in the propylene carbonate, by galvanostatic charging, with the current density of 0.7C. The recycled material showed relatively good capacities of charging and discharging which are 94.9 i 64.8 mA h g–1, respectively. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III45014]
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- 2017
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31. Synthesis and electrochemical properties of Na1.2V3O8/LTX as anodic material in sodium ion batteries
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Stojković-Simatović Ivana B., Vujković Milica J., Radisavljević Lazar J., Hercigonja Radmila V., and Mentus Slavko V.
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Na1.2V3O8 ,Na-ion batteries ,anodic material ,cycling life ,Engineering (General). Civil engineering (General) ,TA1-2040 - Abstract
In this paper, the synthesis of composite Na1.2V3O8/LTX by sol-gel method was described. The synthesized powders were characterized by X-ray powder diffraction (XRD) and thermogravimetric analysis (TGA) while the electrochemical performances were investigated by cycling voltammetry (CV) by different scan rate. After thermal treatment, the part of carbon was 7%. The initial discharge capacity was 100.44 mAhg-1. The most capacity fade was after 2nd cycle (14%) but capacity fade from 6th to 10th cycle was only 10%. The efficiency of Na1.2V3O8/LTX is around 95%.
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- 2016
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32. Comparison of lithium and sodium intercalation materials
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Vujković Milica
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sodium and lithium storage capacity ,metal-ion aqueous batteries ,Chemistry ,QD1-999 - Abstract
Low abundance of lithium in Earth’s crust and its high participation in overall cost of lithium-ion batteries incited intensive investigation of sodium-ion batteries, in hope that they may become similar in basic characteristics: specific energy and specific power. Furthermore, over the last years the research has been focused on the replacement of organic electrolytes of Li- and Na-ion batteries, by aqueous electrolytes, in order to simplify the production and improve safety of use. In this lecture, some recent results on the selected intercalation materials are presented: layered structure vanadium oxides, olivine and nasicon phosphates, potentially usable in both Li and Na aqueous rechargeable batteries. After their characterization by X-ray diffraction and electron microscopy, the electrochemical behavior was studied by both cyclic voltammetry and hronopotenciometry. By comparing intercalation kinetics and coulombic capacity of these materials in LiNO3 and NaNO3 solutions, it was shown that the following ones: Na1.2V3O8, Na2V6O16/C , NaFePO4/C and NaTi2(PO4)3/C may be used as electrode materials in aqueous alkali-ion batteries.
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- 2015
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33. Electrochemical behavior of nanostructured MnO2/C (Vulcan®) composite in aqueous electrolyte LiNO3
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Vujković Milica, Cvjetićanin Nikola, Gavrilov Nemanja, Stojković Ivana, and Mentus Slavko
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aqueous lithium-ion batteries ,li-ion intercalation ,manganese oxide ,Chemical technology ,TP1-1185 - Abstract
The electrolytic solutions of contemporary Li-ion batteries are made exclusively with the organic solvents since anodic materials of these batteries have potentials with greater negativity than the potential of the water reduction, thus the organic electrolytes can withstand the voltages of 3-5 V that are characteristic for these batteries. Ever since it was discovered that some materials can electrochemically intercalate and deintercalate Li+ ions in aqueous solutions, numerous studies have been conducted with the aim of extending operational time of the aqueous Li-ion batteries. Manganese oxide has been studied as the electrode material in rechargeable lithium-ion batteries with organic electrolytes. In this paper its electrochemical behavior as an anode material in aqueous electrolyte solutions was examined. MnO2 as a component of nanodispersed MnO2/C (Vulcan®) composite was successfully synthesized hydrothermally. Electrochemical properties of this material were investigated in aqueous saturated LiNO3 solution by both cyclic voltammetry and galvanostatic charging/discharging (LiMn2O4 as cathode material) techniques. The obtained composite shows a relatively good initial discharge capacity of 96.5 mAh/g which, after 50th charging/discharging cycles, drops to the value of 57mAh/g. MnO2/C (Vulcan®) composite, in combination with LiMn2O4 as a cathode material, shows better discharge capacity compared to other anodic materials used in aqueous Li-ion batteries according to certain studies that have been conducted. Its good reversibility and cyclability, and the fact that hydrothermal method is simple and effective, makes MnO2/C(Vulcan®) composite a promising anodic material for aqueous Li-ion batteries.
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- 2011
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34. Optimized power-delay curve generation for standard cell ICs
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Vujkovic, M., primary and Sechen, C., additional
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35. Post-layout energy-delay analysis of parallel multipliers.
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Jinyao Zhang, Vujkovic, M., Wadkins, D., and Sechen, C.
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- 2006
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36. The effect of a mediolateral episiotomy during operative vaginal delivery on the risk of developing obstetrical anal sphincter injuries.
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de Vogel J, van der Leeuw-van Beek A, Gietelink D, Vujkovic M, de Leeuw JW, van Bavel J, and Papatsonis D
- Abstract
OBJECTIVE: The objective of the study was to evaluate the frequency of obstetrical anal sphincter injuries (OASIS) in women undergoing operative vaginal deliveries (OVD) and to assess whether a mediolateral episiotomy is protective for developing OASIS in these deliveries. STUDY DESIGN: We performed a retrospective cohort study. Maternal and obstetrical characteristics of the 2861 women who delivered liveborn infants by an OVD at term in the years 2001-2009 were extracted from a clinical obstetrics database and were analyzed in a logistic regression model. RESULTS: The frequency of OASIS was 5.7%. Women with a mediolateral episiotomy were at significantly lower risk for OASIS compared with the women without a mediolateral episiotomy in case of an OVD (adjusted odds ratio, 0.17; 95% confidence interval, 0.12-0.24). CONCLUSION: We found a 6-fold decreased odds for developing OASIS when a mediolateral episiotomy was performed in OVD. Therefore, we advocate the use of a mediolateral episiotomy in all operative vaginal deliveries to reduce the incidence of OASIS. [ABSTRACT FROM AUTHOR]
- Published
- 2012
37. Major dietary patterns and blood pressure patterns during pregnancy: the Generation R Study.
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Timmermans S, Steegers-Theunissen RP, Vujkovic M, Bakker R, den Breeijen H, Raat H, Russcher H, Lindemans J, Hofman A, Jaddoe VW, and Steegers EA
- Abstract
OBJECTIVE: We sought to evaluate associations between dietary patterns and systolic blood pressure (SBP) and diastolic blood pressure during pregnancy. STUDY DESIGN: This was a prospective study of 3187 pregnant women. Participants completed a food-frequency questionnaire in early pregnancy. The Mediterranean dietary pattern, comprising high intake of vegetables, vegetable oils, pasta, fish, and legumes, and the Traditional dietary pattern, comprising high intake of meat and potatoes, were identified using factor analysis. RESULTS: A higher SBP was observed among mothers with high Traditional pattern adherence. Low adherence to the Mediterranean pattern was also associated with higher SBP but only in early and mid pregnancy. A higher diastolic blood pressure throughout pregnancy was observed in mothers with high adherence to the Traditional pattern and low adherence to the Mediterranean pattern. These effect estimates were most pronounced in mid pregnancy. CONCLUSION: Low adherence to a Mediterranean and high adherence to a Traditional dietary pattern is associated with a higher blood pressure in pregnancy. [ABSTRACT FROM AUTHOR]
- Published
- 2011
38. Enhancing genetic association power in endometriosis through unsupervised clustering of clinical subtypes identified from electronic health records.
- Author
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Guare LA, Humphrey LA, Rush M, Pollie M, Jaworski J, Akerele AT, Luo Y, Weng C, We WQ, Kottyan L, Jarvik G, Elhadad N, Zondervan K, Missmer S, Vujkovic M, Velez-Edwards D, Senapati S, and Setia-Verma S
- Abstract
Endometriosis is a complex and heterogeneous condition affecting 10% of reproductive-age women, and yet, it often goes undiagnosed for several years. Limited observed heritability (7%) of large genetic association studies may be attributable to underlying heterogeneity of disease mechanisms. Therefore, we conducted this study to investigate genetic associations across sub-phenotypes of endometriosis. We performed unsupervised clustering of 4,078 women with endometriosis based on known endometriosis risk factors, symptoms, and concomitant conditions. The clusters were characterized by examining electronic health record (EHR) data and comprehensive chart reviews. We then performed genetic association for each cluster with 39 endometriosis-associated loci (Total N
endometriosis cases = 12,350). We identified five sub-phenotype clusters: (1) pain comorbidities, (2) uterine disorders, (3) pregnancy complications, (4) cardiometabolic comorbidities, and (5) HER-asymptomatic. Bonferroni significant loci included PDLIM5 for the cluster 1, GREB1 for cluster 2, WNT4 for cluster 3, RNLS for cluster 4, and ABO for cluster 5. The difference in associations between the groups suggests complex and varied genetic mechanisms of endometriosis and its symptoms. This study enhances our understanding of the clinical patterns of endometriosis sub-phenotypes, showcasing the innovative approach employed to investigate this complex disease.- Published
- 2024
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39. Multi-omics characterization of type 2 diabetes associated genetic variation.
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Mandla R, Lorenz K, Yin X, Bocher O, Huerta-Chagoya A, Arruda AL, Piron A, Horn S, Suzuki K, Hatzikotoulas K, Southam L, Taylor H, Yang K, Hrovatin K, Tong Y, Lytrivi M, Rayner NW, Meigs JB, McCarthy MI, Mahajan A, Udler MS, Spracklen CN, Boehnke M, Vujkovic M, Rotter JI, Eizirik DL, Cnop M, Lickert H, Morris AP, Zeggini E, Voight BF, and Mercader JM
- Abstract
Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis - and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies., Competing Interests: Disclosures J.B.M is an academic associate for Quest Diagnostics Inc. Endocrine R&D. MIMcC is now an employee of Genentech and a holder of Roche stock.
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- 2024
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40. Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).
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Yang PK, Jackson SL, Charest BR, Cheng YJ, Sun YV, Raghavan S, Litkowski EM, Legvold BT, Rhee MK, Oram RA, Kuklina EV, Vujkovic M, Reaven PD, Cho K, Leong A, Wilson PWF, Zhou J, Miller DR, Sharp SA, Staimez LR, North KE, Highland HM, and Phillips LS
- Subjects
- Humans, Male, Middle Aged, Female, Adult, Aged, Genetic Predisposition to Disease, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 epidemiology, Risk Factors, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 epidemiology, Veterans statistics & numerical data
- Abstract
Objective: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates., Research Design and Methods: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%)., Results: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001., Conclusions: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates., (© 2024 by the American Diabetes Association.)
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- 2024
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41. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.
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Ghouse J, Sveinbjörnsson G, Vujkovic M, Seidelin AS, Gellert-Kristensen H, Ahlberg G, Tragante V, Rand SA, Brancale J, Vilarinho S, Lundegaard PR, Sørensen E, Erikstrup C, Bruun MT, Jensen BA, Brunak S, Banasik K, Ullum H, Verweij N, Lotta L, Baras A, Mirshahi T, Carey DJ, Kaplan DE, Lynch J, Morgan T, Schwantes-An TH, Dochtermann DR, Pyarajan S, Tsao PS, Laisk T, Mägi R, Kozlitina J, Tybjærg-Hansen A, Jones D, Knowlton KU, Nadauld L, Ferkingstad E, Björnsson ES, Ulfarsson MO, Sturluson Á, Sulem P, Pedersen OB, Ostrowski SR, Gudbjartsson DF, Stefansson K, Olesen MS, Chang KM, Holm H, Bundgaard H, and Stender S
- Subjects
- Humans, Liver Neoplasms genetics, Carcinoma, Hepatocellular genetics, Alanine Transaminase blood, Polymorphism, Single Nucleotide, Male, Lipase genetics, Female, gamma-Glutamyltransferase genetics, Membrane Proteins genetics, Cohort Studies, Case-Control Studies, Multifactorial Inheritance genetics, Risk Factors, Genetic Variation, Liver Cirrhosis genetics, Genome-Wide Association Study, Genetic Predisposition to Disease
- Abstract
We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis., (© 2024. The Author(s).)
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- 2024
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42. A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids.
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Hehl L, Creasy KT, Vitali C, Scorletti E, Seeling KS, Vell MS, Rendel MD, Conlon D, Vujkovic M, Zandvakili I, Trautwein C, Schneider KM, Rader DJ, and Schneider CV
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Alanine Transaminase blood, Cholesterol, HDL blood, Genetic Predisposition to Disease, Lipase genetics, Lipase blood, Lipids blood, Membrane Proteins genetics, Membrane Proteins blood, Mutation, Missense, Acyltransferases, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Fatty Liver genetics, Fatty Liver blood, Phospholipases A2, Calcium-Independent, Triglycerides blood
- Abstract
Background: Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear., Methods: We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank., Results: Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol., Conclusions: Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
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- 2024
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43. Enhancing Genetic Association Power in Endometriosis through Unsupervised Clustering of Clinical Subtypes Identified from Electronic Health Records.
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Guare L, Humphrey LA, Rush M, Pollie M, Luo Y, Weng C, Wei WQ, Kottyan L, Jarvik G, Elhadad N, Zondervan K, Missmer S, Vujkovic M, Velez-Edwards D, Senapati S, and Setia-Verma S
- Abstract
Background: Endometriosis affects 10% of reproductive-age women, and yet, it goes undiagnosed for 3.6 years on average after symptoms onset. Despite large GWAS meta-analyses (N > 750,000), only a few dozen causal loci have been identified. We hypothesized that the challenges in identifying causal genes for endometriosis stem from heterogeneity across clinical and biological factors underlying endometriosis diagnosis., Methods: We extracted known endometriosis risk factors, symptoms, and concomitant conditions from the Penn Medicine Biobank (PMBB) and performed unsupervised spectral clustering on 4,078 women with endometriosis. The 5 clusters were characterized by utilizing additional electronic health record (EHR) variables, such as endometriosis-related comorbidities and confirmed surgical phenotypes. From four EHR-linked genetic datasets, PMBB, eMERGE, AOU, and UKBB, we extracted lead variants and tag variants 39 known endometriosis loci for association testing. We meta-analyzed ancestry-stratified case/control tests for each locus and cluster in addition to a positive control (Total N
endometriosis cases = 10,108)., Results: We have designated the five subtype clusters as pain comorbidities, uterine disorders, pregnancy complications, cardiometabolic comorbidities, and EHR-asymptomatic based on enriched features from each group. One locus, RNLS , surpassed the genome-wide significant threshold in the positive control. Thirteen more loci reached a Bonferroni threshold of 1.3 x 10-3 (0.05 / 39) in the positive control. The cluster-stratified tests yielded more significant associations than the positive control for anywhere from 5 to 15 loci depending on the cluster. Bonferroni significant loci were identified for four out of five clusters, including WNT4 and GREB1 for the uterine disorders cluster, RNLS for the cardiometabolic cluster, FSHB for the pregnancy complications cluster, and SYNE1 and CDKN2B-AS1 for the EHR-asymptomatic cluster. This study enhances our understanding of the clinical presentation patterns of endometriosis subtypes, showcasing the innovative approach employed to investigate this complex disease.- Published
- 2024
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44. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
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Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Melloni GEM, Kanoni S, Rayner NW, Bocher O, Arruda AL, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Thangam M, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Hakaste L, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kamanu FK, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Melander O, Metspalu A, Mo H, Morris AD, Moura FA, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Ahlqvist E, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Marston NA, Ruff CT, van Heel DA, Finer S, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
- Subjects
- Humans, Adipocytes metabolism, Chromatin genetics, Chromatin metabolism, Coronary Artery Disease complications, Coronary Artery Disease genetics, Diabetic Nephropathies complications, Diabetic Nephropathies genetics, Endothelial Cells metabolism, Enteroendocrine Cells, Epigenomics, Islets of Langerhans metabolism, Multifactorial Inheritance genetics, Peripheral Arterial Disease complications, Peripheral Arterial Disease genetics, Single-Cell Analysis, Diabetes Mellitus, Type 2 classification, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 physiopathology, Disease Progression, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
- Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes
1,2 and molecular mechanisms that are often specific to cell type3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)- Published
- 2024
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45. Clinical correlates of CT imaging-derived phenotypes among lean and overweight patients with hepatic steatosis.
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Song I, Thompson EW, Verma A, MacLean MT, Duda J, Elahi A, Tran R, Raghupathy P, Swago S, Hazim M, Bhattaru A, Schneider C, Vujkovic M, Torigian DA, Kahn CE, Gee JC, Borthakur A, Kripke CM, Carson CC, Carr R, Jehangir Q, Ko YA, Litt H, Rosen M, Mankoff DA, Schnall MD, Shou H, Chirinos J, Damrauer SM, Serper M, Chen J, Rader DJ, Witschey WRT, and Sagreiya H
- Subjects
- Humans, Overweight complications, Overweight diagnostic imaging, Tomography, X-Ray Computed methods, Phenotype, Cardiovascular Diseases complications, Diabetes Mellitus, Type 2 complications, Fatty Liver complications, Non-alcoholic Fatty Liver Disease complications
- Abstract
The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m
2 and hepatic steatosis with threshold SHAD ≥ - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI., (© 2023. The Author(s).)- Published
- 2024
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46. Session Introduction: Drug-repurposing and discovery in the era of "big" real-world data: how the incorporation of observational data, genetics, and other -omic technologies can move us forward.
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Shuey MM, Hellwege JN, Khankari N, Vujkovic M, and Edwards TL
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- Humans, Proteomics, Computational Biology, Drug Repositioning methods
- Abstract
This PSB 2024 session discusses the many broad biological, computational, and statistical approaches currently being used for therapeutic drug target identification and repurposing of existing treatments. Drug repurposing efforts have the potential to dramatically improve the treatment landscape by more rapidly identifying drug targets and alternative strategies for untreated or poorly managed diseases. The overarching theme for this session is the use and integration of real-world data to identify drug-disease pairs with potential therapeutic use. These drug-disease pairs may be identified through genomic, proteomic, biomarkers, protein interaction analyses, electronic health records, and chemical profiling. Taken together, this session combines novel applications of methods and innovative modeling strategies with diverse real-world data to suggest new pharmaceutical treatments for human diseases.
- Published
- 2024
47. Assessing Long-Term Liver Safety of Statins and PCSK9 Inhibitors Using Human Genetics.
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Vujkovic M
- Subjects
- Humans, PCSK9 Inhibitors, Proprotein Convertase 9 genetics, Liver, Human Genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects
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- 2024
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48. Profiling the genome and proteome of metabolic dysfunction-associated steatotic liver disease identifies potential therapeutic targets.
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Liu J, Hu S, Chen L, Daly C, Prada Medina CA, Richardson TG, Traylor M, Dempster NJ, Mbasu R, Monfeuga T, Vujkovic M, Tsao PS, Lynch JA, Voight BF, Chang KM, Million VA, Cobbold JF, Tomlinson JW, van Duijn CM, and Howson JMM
- Abstract
Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity., Methods: We analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD., Results: We found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity., Conclusions: This study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD., Competing Interests: Conflict of interest statement: The authors declare the following competing interests: S.H., L.C., C.D., C.A.P.M., M.T., R.M., T.M. and J.M.M.H. are full-time employees of Novo Nordisk. T.G.R. was part-time employee of Novo Nordisk during the project running. J.L. is supported by a University of Oxford Novo Nordisk Research Fellowship. N.D. was supported by a University of Oxford Novo Nordisk Research Training Fellowship. The remaining authors declare no competing interests.
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- 2023
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49. A missense variant in human perilipin 2 ( PLIN2 Ser251Pro) reduces hepatic steatosis in mice.
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Scorletti E, Saiman Y, Jeon S, Schneider CV, Buyco DG, Lin C, Himes BE, Mesaros CA, Vujkovic M, Creasy KT, Furth EE, Billheimer JT, Hand NJ, Kaplan DE, Chang KM, Tsao PS, Lynch JA, Dempsey JL, Harkin J, Bayen S, Conlon D, Guerraty M, Phillips MC, Rader DJ, and Carr RM
- Abstract
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2 -Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans., Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks., Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects., Conclusions: In mice lacking endogenous Plin2 , expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251 . Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD., Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)
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- 2023
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50. Mendelian randomization study of diabetes and dementia in the Million Veteran Program.
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Litkowski EM, Logue MW, Zhang R, Charest BR, Lange EM, Hokanson JE, Lynch JA, Vujkovic M, Phillips LS, Hauger RL, Lange LA, and Raghavan S
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- Humans, Genome-Wide Association Study, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Aged, Alzheimer Disease epidemiology, Alzheimer Disease genetics, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics, Veterans
- Abstract
Introduction: Diabetes and dementia are diseases of high health-care burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases., Methods: We conducted a one-sample Mendelian randomization (MR) analysis in the US Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data., Results: For each standard deviation increase in genetically predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: odds ratio [OR] = 1.07 [1.05-1.08], P = 3.40E-18; vascular: OR = 1.11 [1.07-1.15], P = 3.63E-09, Alzheimer's disease [AD]: OR = 1.06 [1.02-1.09], P = 6.84E-04) and non-Hispanic Black participants (all-cause: OR = 1.06 [1.02-1.10], P = 3.66E-03, vascular: OR = 1.11 [1.04-1.19], P = 2.20E-03, AD: OR = 1.12 [1.02-1.23], P = 1.60E-02) but not in Hispanic participants (all P > 0.05)., Discussion: We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies using two-sample MR techniques., (© 2023 the Alzheimer's Association.)
- Published
- 2023
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