Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions.(School of Hygiene and Public Health of Johns Hopkins University,Baltimore., 2019) de Vries, P. S.; Brown, M. R.; Bentley, A. R.; Sung, Y. J.; Winkler, T. W.; Ntalla, I.; Schwander, K.; Kraja, A. T.; Guo, X.; Franceschini, N.; Cheng, C. Y.; Sim, X.; Vojinovic, D.; Huffman, J. E.; Musani, S. K.; Li, C.; Feitosa, M.F.; Richard, M.A.; Noordam, R.; Aschard, H.; Bartz, T. M.; Bielak, L. F.; Deng, X.; Dorajoo, R.; Lohman, K.K.; Manning, A. K.; Rankinen, T.; Smith, A. V.; Tajuddin, S. M.; Evangelou, E.; Graff, M.; Alver, M.; Boissel, M.; Chai, J. F.; Chen, X.; Divers, J.; Gandin, I.; Gao, C.; Goel, A.; Hagemeijer, Y.; Harris, S. E.; Hartwig, F. P.; He, M.; Horimoto, A. R. V. R.; Hsu, F. C.; Jackson, A. U.; Kasturiratne, A.; Komulainen, P.; Kühnel, B.; Laguzzi, F.; Lee, J. H.; Luan, J.; Lyytikäinen, L. P.; Matoba, N.; Nolte, I. M.; Pietzner, M.; Riaz, M.; Said, M. A.; Scott, R. A.; Sofer, T.; Stancáková, A.; Takeuchi, F.; Tayo, B. O.; van der Most, P. J.; Varga, T. V.; Wang, Y.; Ware, E. B.; Wen, W.; Yanek, L. R.; Zhang, W.; Zhao, J. H.; Afaq, S.; Amin, N.; Amini, M.; Arking, D. E.; Aung, T.; Ballantyne, C.; Boerwinkle, E.; Broeckel, U.; Campbell, A.; Canouil, M.; Charumathi, S.; Chen, Y. I.; Connell, J. M.; de Faire, U.; de Las Fuentes, L.; de Mutsert, R.; de Silva, H.J.; Ding, J.; Dominiczak, A. F.; Duan, Q.; Eaton, C. B.; Eppinga, R.N.; Faul, J. D.; Fisher, V.; Forrester, T.; Franco, O. H.; Friedlander, Y.; Ghanbari, M.; Giulianini, F.; Grabe, H. J.; Grove, M. L.; Gu, C. C.; Harris, T. B.; Heikkinen, S.; Heng, C. K.; Hirata, M.; Hixson, J. E.; Howard, B. V.; Ikram, M. A.; InterAct Consortium; Jr. Jacobs, D. R.; Johnson, C.; Jonas, J. B.; Kammerer, C. M.; Katsuya, T.; Khor, C. C.; Kilpeläinen, T. O.; Koh, W. P.; Koistinen, H. A.; Kolcic, I.; Kooperberg, C.; Krieger, J. E.; Kritchevsky, S. B.; Kubo, M.; Kuusisto, J.; Lakka, T. A.; Langefeld, C. D.; Langenberg, C.; Launer, L. J.; Lehne, B.; Lemaitre, R. N.; Li, Y.; Liang, J.; Liu, J.; Liu, K.; Loh, M.; Louie, T.; Mägi, R.; Manichaikul, A. W.; McKenzie, C. A.; Meitinger, T.; Metspalu, A.; Milaneschi, Y.; Milani, L.; Mohlke, K. L.; Jr. Mosley, T. H.; Nelson, C. P.; Mukamal, K. J.; Nalls, M. A.; Nauck, M.; Sotoodehnia, N.; O'Connell, J. R.; Palmer, N. D.; Pazoki, R.; Pedersen, N. L.; Peters, A.; Peyser, P. A.; Polasek, O.; Poulter, N.; Raffel, L. J.; Raitakari, O. T.; Reiner, A. P.; Rice, T. K.; Rich, S. S.; Robino, A.; Robinson, J. G.; Rose, L. M.; Rudan, I.; Schmidt, C. O.; Schreiner, P. J.; Scott, W. R.; Sever, P.; Shi, Y.; Sidney, S.; Sims, M.; Smith, B. H.; Smith, J. A.; Snieder, H.; Starr, J. M.; Strauch, K.; Tan, N.; Taylor, K. D.; Teo, Y. Y.; Tham, Y. C.; Uitterlinden, A. G.; van Heemst, D.; Vuckovic, D.; Waldenberger, M.; Wang, L.; Wang, Y.; Wang, Z.; Wei, W. B.; Williams, C.; Sr Wilson, G.; Wojczynski, M. K.; Yao, J.; Yu, B.; Yu, C.; Yuan, J. M.; Zhao, W.; Zonderman, A. B.; Becker, D. M.; Boehnke, M.; Bowden, D. W.; Chambers, J. C.; Deary, I. J.; Esko, T.; Farrall, M.; Franks, P. W.; Freedman, B. I.; Froguel, P.; Gasparini, P.; Gieger, C.; Horta, B. L.; Kamatani, Y.; Kato, N.; Kooner, J. S.; Laakso, M.; Leander, K.; Lehtimäki, T.; Lifelines Cohort, Groningen,; The Netherlands (Lifelines Cohort Study); Magnusson, P. K. E.; Penninx, B.; Pereira, A. C.; Rauramaa, R.; Samani, N.J.; Scott, J.; Shu, X. O.; van der Harst, P.; Wagenknecht, L. E.; Wang, Y. X.; Wareham, N. J.; Watkins, H.; Weir, D. R.; Wickremasinghe, A.R.; Zheng, W.; Elliott, P.; North, K. E.; Bouchard, C.; Evans, M. K.; Gudnason, V.; Liu, C. T.; Liu, Y.; Psaty, B. M.; Ridker, P. M.; van Dam, R. M.; Kardia, S. L. R.; Zhu, X.; Rotimi, C. N.; Mook-Kanamori, D. O.; Fornage, M.; Kelly, T. N.; Fox, E. R.; Hayward, C.; van Duijn, C. M.; Tai, E. S.; Wong, T. Y.; Liu, J.; Rotter, J. I.; Gauderman, W. J.; Province, M. A.; Munroe, P. B.; Rice, K.; Chasman, D. I.; Cupples, L. A.; Rao, D. C.; Morrison, A. C.An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.Item Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort(Blackwell Scientific Publications, 2019) O'Reilly, M. W.; Glisic, M.; Kumarendran, B.; Subramanian, A.; Manolopoulos, K. N.; Tahrani, A. A.; Keerthy, D.; Muka, T.; Toulis, K. A.; Hanif, W.; Thomas, G. N.; Franco, O. H.; Arlt, W.; Nirantharakumar, K.OBJECTIVE: Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. DESIGN: A retrospective cohort study in a UK primary care database. PATIENTS: We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results. MEASUREMENTS: We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). RESULTS: Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively. CONCLUSIONS/INTERPRETATION: In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.