Person: Rosas, Sylvia
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Publication Genome-wide association study of kidney function decline in individuals of European descent
(2014) Gorski, Mathias; Tin, Adrienne; Garnaas, Maija; McMahon, Gearoid M.; Chu, Audrey Y.; Tayo, Bamidele O.; Pattaro, Cristian; Teumer, Alexander; Chasman, Daniel I.; Chalmers, John; Hamet, Pavel; Tremblay, Johanne; Woodward, Marc; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur; Harris, Tammara B.; Launer, Lenore J.; Smith, Albert V.; Mitchell, Braxton D.; O'Connell, Jeffrey R.; Shuldiner, Alan R.; Coresh, Josef; Li, Man; Freudenberger, Paul; Hofer, Edith; Schmidt, Helena; Schmidt, Reinhold; Holliday, Elizabeth G.; Mitchell, Paul; Wang, Jie Jin; de Boer, Ian H.; Li, Guo; Siscovick, David S.; Kutalik, Zoltan; Corre, Tanguy; Vollenweider, Peter; Waeber, Gérard; Gupta, Jayanta; Kanetsky, Peter A.; Hwang, Shih-Jen; Olden, Matthias; Yang, Qiong; de Andrade, Mariza; Atkinson, Elizabeth J.; Kardia, Sharon L.R.; Turner, Stephen T.; Stafford, Jeanette M.; Ding, Jingzhong; Liu, Yongmei; Barlassina, Cristina; Cusi, Daniele; Salvi, Erika; Staessen, Jan A; Ridker, Paul M; Grallert, Harald; Meisinger, Christa; Müller-Nurasyid, Martina; Krämer, Bernhard K.; Kramer, Holly; Rosas, Sylvia; Nolte, Ilja M.; Penninx, Brenda W.; Snieder, Harold; Del Greco, Fabiola; Franke, Andre; Nöthlings, Ute; Lieb, Wolfgang; Bakker, Stephan J.L.; Gansevoort, Ron T.; van der Harst, Pim; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Sedaghat, Sanaz; Uitterlinden, André G.; Coassin, Stefan; Haun, Margot; Kollerits, Barbara; Kronenberg, Florian; Paulweber, Bernhard; Aumann, Nicole; Endlich, Karlhans; Pietzner, Mike; Völker, Uwe; Rettig, Rainer; Chouraki, Vincent; Helmer, Catherine; Lambert, Jean-Charles; Metzger, Marie; Stengel, Benedicte; Lehtimäki, Terho; Lyytikäinen, Leo-Pekka; Raitakari, Olli; Johnson, Andrew; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Goessling, Wolfram; Köttgen, Anna; Kao, H. Linda; Fox, Caroline S.; Böger, Carsten A.Genome wide association studies (GWAS) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, SNPs at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1 and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11 and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
Publication Inflammatory Markers and Risk for Cognitive Decline in Chronic Kidney Disease: The CRIC Study
(Elsevier, 2016) Kurella Tamura, Manjula; Tam, Karman; Vittinghoff, Eric; Raj, Dominic; Sozio, Stephen M.; Rosas, Sylvia; Makos, Gail; Lora, Claudia; He, Jiang; Go, Alan S.; Hsu, Chi-yuan; Yaffe, Kristine; Appel, Lawrence J.; Feldman, Harold I.; Kusek, John W.; Lash, James P.; Ojo, Akinlolu; Rahman, Mahboob; Townsend, Raymond R.Introduction: Chronic kidney disease (CKD) is associated with an increased risk of cognitive decline, but the mechanisms remain poorly defined. We sought to determine the relation between serum inflammatory markers and risk of cognitive decline among adults with CKD. Methods: We studied 757 adults aged ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort Cognitive study. We measured interleukin (IL)−1β, IL-1 receptor antagonist, IL-6, tumor necrosis factor (TNF)−α, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen in baseline plasma samples. We assessed cognitive function at regular intervals in 4 domains and defined incident impairment as a follow-up score more than 1 SD poorer than the group mean. Results: The mean age of the sample was 64.3 ± 5.6 years, and the mean follow-up was 6.2 ± 2.5 years. At baseline, higher levels of each inflammatory marker were associated with poorer age-adjusted performance. In analyses adjusted for baseline cognition, demographics, comorbid conditions, and kidney function, participants in the highest tertile of hs-CRP, the highest tertile of fibrinogen, and the highest tertile of IL-1β had an increased risk of impairment in attention compared to participants in the lowest tertile of each marker. Participants in the highest versus lowest tertile of TNF-α had a lower adjusted risk of impairment in executive function. There was no association between other inflammatory markers and change in cognitive function. Discussion Among adults with CKD, higher levels of hs-CRP, fibrinogen, and IL-1β were associated with a higher risk of impairment in attention. Higher levels of TNF-α were associated with a lower risk of impaired executive function.