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9. Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients

Author

Sharma, Kumar, Zhang, Guanshi, Hansen, Jens, Bjornstad, Petter, Lee, Hak Joo, Menon, Rajasree, Hejazi, Leila, Liu, Jian-Jun, Franzone, Anthony, Looker, Helen C., Choi, Byeong Yeob, Fernandez, Roman, Venkatachalam, Manjeri A., Kugathasan, Luxcia, Sridhar, Vikas S., Natarajan, Loki, Zhang, Jing, Sharma, Varun S., Kwan, Brian, Waikar, Sushrut S., Himmelfarb, Jonathan, Tuttle, Katherine R., Kestenbaum, Bryan, Fuhrer, Tobias, Feldman, Harold I., de Boer, Ian H., Tucci, Fabio C., Sedor, John, Heerspink, Hiddo Lambers, Schaub, Jennifer, Otto, Edgar A., Hodgin, Jeffrey B., Kretzler, Matthias, Anderton, Christopher R., Alexandrov, Theodore, Cherney, David, Lim, Su Chi, Nelson, Robert G., Gelfond, Jonathan, and Iyengar, Ravi

Subjects
United States. National Center for Advancing Translational Sciences, Thermo Fisher Scientific Inc., Bayer AG, Boehringer Ingelheim GmbH, AstraZeneca PLC, Eli Lilly and Co., Novo Nordisk A/S, Sanofi S.A., Medical research -- Health aspects, Medicine, Experimental -- Health aspects, Scientific equipment and supplies industry -- Health aspects, Chronic kidney failure -- Health aspects, Medical colleges -- Health aspects, Type 2 diabetes -- Health aspects, Native Americans -- Health aspects, Pharmaceutical industry -- Health aspects, Purines -- Health aspects, Health care industry
Abstract

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD., Introduction Progression to organ failure is marked by fibrosis and loss of architecture in solid organs, such as the kidney. In almost all progressive chronic kidney diseases (CKDs), the features [...]

Published
2023
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10. Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes

Author

Wang, Jiexun, Liu, Jian-Jun, Gurung, Resham L., Liu, Sylvia, Lee, Janus, M, Yiamunaa, Ang, Keven, Shao, Yi Ming, Tang, Justin I-Shing, Benke, Peter I., Torta, Federico, Wenk, Markus R., Tavintharan, Subramaniam, Tang, Wern Ee, Sum, Chee Fang, and Lim, Su Chi

Published
2022
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12. A five-safes approach to a secure and scalable genomics data repository

Author

Shih, Chih Chuan, Chen, Jieqi, Lee, Ai Shan, Bertin, Nicolas, Hebrard, Maxime, Khor, Chiea Chuen, Li, Zheng, Juan Tan, Joanna Hui, Meah, Wee Yang, Peh, Su Qin, Mok, Shi Qi, Sim, Kar Seng, Liu, Jianjun, Wang, Ling, Wong, Eleanor, Li, Jingmei, Tin, Aung, Cheng, Ching-Yu, Heng, Chew-Kiat, Yuan, Jian-Min, Koh, Woon-Puay, Saw, Seang Mei, Friedlander, Yechiel, Sim, Xueling, Chai, Jin Fang, Chong, Yap Seng, Davila, Sonia, Goh, Liuh Ling, Lee, Eng Sing, Wong, Tien Yin, Karnani, Neerja, Leong, Khai Pang, Yeo, Khung Keong, Chambers, John C., Lim, Su Chi, Goh, Rick Siow Mong, Tan, Patrick, and Dorajoo, Rajkumar

Published
2023
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14. Glycolytic lactate in diabetic kidney disease

Author

Darshi, Manjula, primary, Kugathasan, Luxcia, additional, Maity, Soumya, additional, Sridhar, Vikas S., additional, Fernandez, Roman, additional, Limonte, Christine P., additional, Grajeda, Brian I., additional, Saliba, Afaf, additional, Zhang, Guanshi, additional, Drel, Viktor R., additional, Kim, Jiwan J., additional, Montellano, Richard, additional, Tumova, Jana, additional, Montemayor, Daniel, additional, Wang, Zhu, additional, Liu, Jian-Jun, additional, Wang, Jiexun, additional, Perkins, Bruce A., additional, Lytvyn, Yuliya, additional, Natarajan, Loki, additional, Lim, Su Chi, additional, Feldman, Harold, additional, Toto, Robert, additional, Sedor, John R., additional, Patel, Jiten, additional, Waikar, Sushrut S., additional, Brown, Julia, additional, Osman, Yahya, additional, He, Jiang, additional, Chen, Jing, additional, Reeves, W. Brian, additional, de Boer, Ian H., additional, Roy, Sourav, additional, Vallon, Volker, additional, Hallan, Stein, additional, Gelfond, Jonathan A.L., additional, Cherney, David Z.I., additional, and Sharma, Kumar, additional

Published
2024
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15. Plasma ceramides predict all-cause and cause-specific mortality in individuals with type 2 diabetes

Author

Liu, Sylvia, primary, Tham, Wai Kin, additional, Lee, Janus, additional, Ang, Keven, additional, Zheng, Huili, additional, Chan, Clara, additional, Gurung, Resham L, additional, Tavintharan, Subramaniam, additional, Sum, Chee Fang, additional, Wenk, Markus R, additional, Torta, Federico, additional, Liu, Jian-Jun, additional, and Lim, Su Chi, additional

Published
2024
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16. Plasma proteomics of diabetic kidney disease among Asians with younger-onset type 2 diabetes

Author

Gurung, Resham Lal, primary, Zheng, Huili, additional, Koh, Hiromi Wai Ling, additional, Yiamunaa, M, additional, Liu, Jian-Jun, additional, Liu, Sylvia, additional, Chan, Clara, additional, Ang, Keven, additional, Tan, Clara Si Hua, additional, Sobota, Radoslaw Mikolaj, additional, Subramaniam, Tavintharan, additional, Sum, Chee Fang, additional, and Lim, Su Chi, additional

Published
2024
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17. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, van der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, de Borst, Martin H, De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, and Loeffler, Markus

Subjects
Animals, Humans, Drosophila melanogaster, Albuminuria, Diabetes Mellitus, Genetic Predisposition to Disease, Creatinine, Risk Factors, Chromosome Mapping, Gene Expression Regulation, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Phenomics
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Published
2019

22. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author

Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert V., Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I., Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I., Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K., Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel I., Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O’Connell, Jeffrey, Rotter, Jerome I., Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikäinen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O’Donoghue, Michelle L., Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimäki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tõnu, Haller, Toomas, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J., Stefansson, Kari, Böger, Carsten A., Hung, Adriana M., Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, and Heid, Iris M.

Published
2022
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23. Association Between Plasma LRG1 and Lower Cognitive Function in Asians With Type 2 Diabetes Mellitus.

Author

Low, Serena, Moh, Angela, Pandian, Bhuvaneswari, Tan, Xin Li, Pek, Sharon, Zheng, Huili, Ang, Keven, Tang, Wern Ee, Lim, Ziliang, Subramaniam, Tavintharan, Sum, Chee Fang, and Lim, Su Chi

Subjects
PULSE wave analysis, TYPE 2 diabetes, ENZYME-linked immunosorbent assay, COGNITIVE ability, ARTERIAL diseases
Abstract

Context Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. Objective Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian randomization (MR) and the role of arterial stiffness as a potential mediator. Methods T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism. Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. Results Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients −1.38 (95% CI −2.55 to −.21; P =.021) and −1.38 (95% CI −2.70 to −.07; P =.039), respectively. Genetically predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient −7.44 (95% CI −14.14 to −.74; P =.030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. Conclusion Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up. [ABSTRACT FROM AUTHOR]

Published
2024
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25. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Author

van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, McKeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia HT, Luk, Andrea OY, Lee, Heung Man, Lim, Cadmon KP, Szeto, Cheuk Chun, So, Wing Yee, Chan, Juliana CN, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, McKnight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Linda T, Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ma, Ronald CW, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin NA, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, McCarthy, Mark I, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, A-C, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kotka R, and Riihelä, M

Subjects
Diabetes, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Finnish Diabetic Nephropathy Study, Hong Kong Diabetes Registry Theme-based Research Scheme Project Group, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

Published
2018

26. Urine tricarboxylic acid cycle metabolites and risk of end stage kidney disease in patients with type 2 diabetes

Author

Liu, Jian-Jun, primary, Liu, Sylvia, additional, Zheng, Huili, additional, Lee, Janus, additional, Gurung, Resham L, additional, Chan, Clara, additional, Lee, Lye Siang, additional, Ang, Keven, additional, Ching, Jianhong, additional, Kovalik, Jean-Paul, additional, Tavintharan, Subramaniam, additional, Sum, Chee Fang, additional, Sharma, Kumar, additional, Coffman, Thomas M, additional, and Lim, Su Chi, additional

Published
2024
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33. Association between depressive symptoms and pulse wave velocity is mediated by increased adiposity in older adults with type 2 diabetes

Author

Moh, Mei Chung, Low, Serena, Ng, Tze Pin, Ang, Su Fen, Ang, Keven, Sum, Chee Fang, Subramaniam, Tavintharan, and Lim, Su Chi

Subjects
Depression in old age -- Diagnosis -- Risk factors, Adipose tissues -- Health aspects, Type 2 diabetes -- Demographic aspects -- Complications and side effects, Health, Psychology and mental health
Abstract

Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off [greater than or equal to] 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist- circumference, waist-to-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity., Introduction The leading cause of morbidity and mortality in type 2 diabetes (T2D) is cardiovascular disease. Mounting evidence supports increased arterial stiffness as a powerful risk factor for cardiovascular disease. [...]

Published
2021
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36. Correction: Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes

Author

Wang, Jiexun, Liu, Jian-Jun, Gurung, Resham L., Liu, Sylvia, Lee, Janus, Yiamunaa, M., Ang, Keven, Shao, Yi Ming, Tang, Justin I-Shing, Benke, Peter I., Torta, Federico, Wenk, Markus R., Tavintharan, Subramaniam, Tang, Wern Ee, Sum, Chee Fang, and Lim, Su Chi

Published
2022
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39. Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes

Author

Liu, Jian-Jun, primary, Ching, Jianhong, additional, Wee, Hai Ning, additional, Liu, Sylvia, additional, Gurung, Resham L., additional, Lee, Janus, additional, M., Yiamunaa, additional, Zheng, Huili, additional, Lee, Lye Siang, additional, Ang, Keven, additional, Shao, Yi Ming, additional, Kovalik, Jean-Paul, additional, Subramaniam, Tavintharan, additional, Sum, Chee Fang, additional, Sharma, Kumar, additional, Kestenbaum, Bryan R., additional, and Lim, Su Chi, additional

Published
2023
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41. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population

Author

Chang, Xuling, Gurung, Resham L., Wang, Ling, Jin, Aizhen, Li, Zheng, Wang, Renwei, Beckman, Kenneth B., Adams-Haduch, Jennifer, Meah, Wee Yang, Sim, Kar Seng, Lim, Weng Khong, Davila, Sonia, Tan, Patrick, Teo, Jing Xian, Yeo, Khung Keong, M., Yiamunaa, Liu, Sylvia, Lim, Su Chi, Liu, Jianjun, van Dam, Rob M., Friedlander, Yechiel, Koh, Woon-Puay, Yuan, Jian-Min, Khor, Chiea Chuen, Heng, Chew-Kiat, and Dorajoo, Rajkumar

Published
2021
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45. Deep learning algorithms to detect diabetic kidney disease from retinal photographs in multiethnic populations with diabetes

Author

Betzler, Bjorn Kaijun, primary, Chee, Evelyn Yi Lyn, additional, He, Feng, additional, Lim, Cynthia Ciwei, additional, Ho, Jinyi, additional, Hamzah, Haslina, additional, Tan, Ngiap Chuan, additional, Liew, Gerald, additional, McKay, Gareth J, additional, Hogg, Ruth E, additional, Young, Ian S, additional, Cheng, Ching-Yu, additional, Lim, Su Chi, additional, Lee, Aaron Y, additional, Wong, Tien Yin, additional, Lee, Mong Li, additional, Hsu, Wynne, additional, Tan, Gavin Siew Wei, additional, and Sabanayagam, Charumathi, additional

Published
2023
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