@article {6086, title = {Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.}, journal = {Lancet}, volume = {380}, year = {2012}, month = {2012 Nov 10}, pages = {1662-73}, abstract = {

BACKGROUND: Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown.

METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes.

FINDINGS: We analysed data for 1,024,977 participants (128,505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75,306 deaths occurred during a mean follow-up of 8{\textperiodcentered}5 years (SD 5{\textperiodcentered}0). In the 23 studies with data for cardiovascular mortality, 21,237 deaths occurred from cardiovascular disease during a mean follow-up of 9{\textperiodcentered}2 years (SD 4{\textperiodcentered}9). In the general and high-risk cohorts, mortality risks were 1{\textperiodcentered}2-1{\textperiodcentered}9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1{\textperiodcentered}73 m(2) [vs 95 mL/min per 1{\textperiodcentered}73 m(2)], HR 1{\textperiodcentered}35; 95\% CI 1{\textperiodcentered}18-1{\textperiodcentered}55; vs 1{\textperiodcentered}33; 1{\textperiodcentered}19-1{\textperiodcentered}48 and at ACR 30 mg/g [vs 5 mg/g], 1{\textperiodcentered}50; 1{\textperiodcentered}35-1{\textperiodcentered}65 vs 1{\textperiodcentered}52; 1{\textperiodcentered}38-1{\textperiodcentered}67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts.

INTERPRETATION: Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.

FUNDING: US National Kidney Foundation.

}, keywords = {Aged, Albuminuria, Cardiovascular Diseases, Cause of Death, Diabetic Nephropathies, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Risk Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(12)61350-6}, author = {Fox, Caroline S and Matsushita, Kunihiro and Woodward, Mark and Bilo, Henk J G and Chalmers, John and Heerspink, Hiddo J Lambers and Lee, Brian J and Perkins, Robert M and Rossing, Peter and Sairenchi, Toshimi and Tonelli, Marcello and Vassalotti, Joseph A and Yamagishi, Kazumasa and Coresh, Josef and de Jong, Paul E and Wen, Chi-Pang and Nelson, Robert G} } @article {8624, title = {Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.}, journal = {Kidney Int}, year = {2020}, month = {2020 Oct 30}, abstract = {

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25\% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95\% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.09.030}, author = {Gorski, Mathias and Jung, Bettina and Li, Yong and Matias-Garcia, Pamela R and Wuttke, Matthias and Coassin, Stefan and Thio, Chris H L and Kleber, Marcus E and Winkler, Thomas W and Wanner, Veronika and Chai, Jin-Fang and Chu, Audrey Y and Cocca, Massimiliano and Feitosa, Mary F and Ghasemi, Sahar and Hoppmann, Anselm and Horn, Katrin and Li, Man and Nutile, Teresa and Scholz, Markus and Sieber, Karsten B and Teumer, Alexander and Tin, Adrienne and Wang, Judy and Tayo, Bamidele O and Ahluwalia, Tarunveer S and Almgren, Peter and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Carroll, Robert J and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Coresh, Josef and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Franke, Andre and Freitag-Wolf, Sandra and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Gieger, Christian and Hamet, Pavel and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Xian Foo, Valencia Hui and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and K{\"a}h{\"o}nen, Mika and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and O{\textquoteright}Donoghue, Michelle L and Orho-Melander, Marju and Pendergrass, Sarah A and Penninx, Brenda W J H and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Sabanayagam, Charumathi and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Strauch, Konstantin and Szymczak, Silke and Taylor, Kent D and Tremblay, Johanne and Chaker, Layal and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Waldenberger, Melanie and Wallentin, Lars and Waterworth, Dawn M and White, Harvey D and Wilson, James G and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Yan and Snieder, Harold and Wanner, Christoph and B{\"o}ger, Carsten A and K{\"o}ttgen, Anna and Kronenberg, Florian and Pattaro, Cristian and Heid, Iris M} } @article {9093, title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.}, journal = {Kidney Int}, year = {2022}, month = {2022 Jun 16}, abstract = {

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95\% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95\% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2022.05.021}, author = {Gorski, Mathias and Rasheed, Humaira and Teumer, Alexander and Thomas, Laurent F and Graham, Sarah E and Sveinbjornsson, Gardar and Winkler, Thomas W and G{\"u}nther, Felix and Stark, Klaus J and Chai, Jin-Fang and Tayo, Bamidele O and Wuttke, Matthias and Li, Yong and Tin, Adrienne and Ahluwalia, Tarunveer S and Arnl{\"o}v, Johan and {\r A}svold, Bj{\o}rn Olav and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Biino, Ginevra and B{\"o}hnke, Michael and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Brumpton, Ben and Carroll, Robert J and Chaker, Layal and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Chu, Audrey Y and Ciullo, Marina and Cocca, Massimiliano and Cook, James P and Coresh, Josef and Cusi, Daniele and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Evans, Michele K and Feitosa, Mary F and Franke, Andre and Freitag-Wolf, Sandra and Fuchsberger, Christian and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Ghasemi, Sahar and Giedraitis, Vilmantas and Gieger, Christian and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hishida, Asahi and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Holm, Hilma and Hoppmann, Anselm and Horn, Katrin and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Karabegovi{\'c}, Irma and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Kuusisto, Johanna and Laakso, Markku and Lange, Leslie A and Lehtim{\"a}ki, Terho and Li, Man and Lieb, Wolfgang and Lind, Lars and Lindgren, Cecilia M and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Matias-Garcia, Pamela R and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Morris, Andrew P and Mychaleckyj, Josyf C and Nadkarni, Girish N and Naito, Mariko and Nakatochi, Masahiro and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Nutile, Teresa and O{\textquoteright}Donoghue, Michelle L and O{\textquoteright}Connell, Jeffrey and Olafsson, Isleifur and Orho-Melander, Marju and Parsa, Afshin and Pendergrass, Sarah A and Penninx, Brenda W J H and Pirastu, Mario and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rheinberger, Myriam and Rice, Kenneth M and Rizzi, Federica and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Ruggiero, Daniela and Ryan, Kathleen A and Sabanayagam, Charumathi and Salvi, Erika and Schmidt, Helena and Schmidt, Reinhold and Scholz, Markus and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Sieber, Karsten B and Sim, Xueling and Sims, Mario and Snieder, Harold and Stanzick, Kira J and Thorsteinsdottir, Unnur and Stocker, Hannah and Strauch, Konstantin and Stringham, Heather M and Sulem, Patrick and Szymczak, Silke and Taylor, Kent D and Thio, Chris H L and Tremblay, Johanne and Vaccargiu, Simona and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Wakai, Kenji and Waldenberger, Melanie and Wallentin, Lars and Wallner, Stefan and Wang, Judy and Waterworth, Dawn M and White, Harvey D and Willer, Cristen J and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yerges-Armstrong, Laura M and Zimmermann, Martina and Zonderman, Alan B and Bergler, Tobias and Stefansson, Kari and B{\"o}ger, Carsten A and Pattaro, Cristian and K{\"o}ttgen, Anna and Kronenberg, Florian and Heid, Iris M} } @article {9579, title = {X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Jan 18}, pages = {586}, abstract = {

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

}, keywords = {Androgens, Chromosomes, Human, X, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Male, Polymorphism, Single Nucleotide, Response Elements, Tetraspanins}, issn = {2041-1723}, doi = {10.1038/s41467-024-44709-1}, author = {Scholz, Markus and Horn, Katrin and Pott, Janne and Wuttke, Matthias and K{\"u}hnapfel, Andreas and Nasr, M Kamal and Kirsten, Holger and Li, Yong and Hoppmann, Anselm and Gorski, Mathias and Ghasemi, Sahar and Li, Man and Tin, Adrienne and Chai, Jin-Fang and Cocca, Massimiliano and Wang, Judy and Nutile, Teresa and Akiyama, Masato and {\r A}svold, Bj{\o}rn Olav and Bansal, Nisha and Biggs, Mary L and Boutin, Thibaud and Brenner, Hermann and Brumpton, Ben and Burkhardt, Ralph and Cai, Jianwen and Campbell, Archie and Campbell, Harry and Chalmers, John and Chasman, Daniel I and Chee, Miao Ling and Chee, Miao Li and Chen, Xu and Cheng, Ching-Yu and Cifkova, Renata and Daviglus, Martha and Delgado, Graciela and Dittrich, Katalin and Edwards, Todd L and Endlich, Karlhans and Michael Gaziano, J and Giri, Ayush and Giulianini, Franco and Gordon, Scott D and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hartman, Catharina A and Hayward, Caroline and Heid, Iris M and Hellwege, Jacklyn N and Holleczek, Bernd and Holm, Hilma and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Isermann, Berend and Jonas, Jost B and Joshi, Peter K and Kamatani, Yoichiro and Kanai, Masahiro and Kastarinen, Mika and Khor, Chiea Chuen and Kiess, Wieland and Kleber, Marcus E and K{\"o}rner, Antje and Kovacs, Peter and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuokkanen, Mikko and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lash, James P and Lehtim{\"a}ki, Terho and Li, Hengtong and Lin, Bridget M and Liu, Jianjun and Loeffler, Markus and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Martin, Nicholas G and Matsuda, Koichi and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and M{\"a}rz, Winfried and Nauck, Matthias and Nikus, Kjell and Nolte, Ilja M and Noordam, Raymond and Okada, Yukinori and Olafsson, Isleifur and Oldehinkel, Albertine J and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Polasek, Ozren and Porteous, David J and Poulain, Tanja and Psaty, Bruce M and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Rasheed, Humaira and Reilly, Dermot F and Rice, Kenneth M and Richmond, Anne and Ridker, Paul M and Rotter, Jerome I and Rudan, Igor and Sabanayagam, Charumathi and Salomaa, Veikko and Schneiderman, Neil and Sch{\"o}ttker, Ben and Sims, Mario and Snieder, Harold and Stark, Klaus J and Stefansson, Kari and Stocker, Hannah and Stumvoll, Michael and Sulem, Patrick and Sveinbjornsson, Gardar and Svensson, Per O and Tai, E-Shyong and Taylor, Kent D and Tayo, Bamidele O and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomas, Laurent F and Tremblay, Johanne and T{\"o}njes, Anke and van der Most, Peter J and Vitart, Veronique and V{\"o}lker, Uwe and Wang, Ya Xing and Wang, Chaolong and Wei, Wen Bin and Whitfield, John B and Wild, Sarah H and Wilson, James F and Winkler, Thomas W and Wong, Tien-Yin and Woodward, Mark and Sim, Xueling and Chu, Audrey Y and Feitosa, Mary F and Thorsteinsdottir, Unnur and Hung, Adriana M and Teumer, Alexander and Franceschini, Nora and Parsa, Afshin and K{\"o}ttgen, Anna and Schlosser, Pascal and Pattaro, Cristian} }