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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
Sung, Yun Ju; de Las Fuentes, Lisa; Winkler, Thomas W; Chasman, Daniel I; Bentley, Amy R; Kraja, Aldi T; Ntalla, Ioanna; Warren, Helen R; Guo, Xiuqing; Schwander, Karen; Manning, Alisa K; Brown, Michael R; Aschard, Hugues; Feitosa, Mary F; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Kilpeläinen, Tuomas O; Richard, Melissa A; Aslibekyan, Stella; Bartz, Traci M; Dorajoo, Rajkumar; Li, Changwei; Liu, Yongmei; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M; Tayo, Bamidele O; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kammerer, Candace M; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; Luan, Jian'an; Lyytikäinen, Leo-Pekka; McKenzie, Colin A; Nelson, Christopher P; Noordam, Raymond; Scott, Robert A; Sheu, Wayne H H; StanÄáková, Alena; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Waken, Robert J; Wang, Heming; Wang, Yajuan; Ware, Erin B; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Alfred, Tamuno; Amin, Najaf; Arking, Dan E; Aung, Tin; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Braund, Peter S; Brody, Jennifer A; Broeckel, Ulrich; Cade, Brian; Campbell, Archie; Canouil, Mickaël; Chakravarti, Aravinda; Cocca, Massimiliano; Collins, Francis S; Connell, John M; de Mutsert, Renée; de Silva, H Janaka; Dörr, Marcus; Duan, Qing; Eaton, Charles B; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D; Forouhi, Nita G; Franco, Oscar H; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Gu, C Charles; Gupta, Preeti; Hagenaars, Saskia P; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hofman, Albert; Howard, Barbara V; Hunt, Steven C; Irvin, Marguerite R; Jia, Yucheng; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A; Kooperberg, Charles B; Krieger, Jose E; Kubo, Michiaki; Kutalik, Zoltan; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Joseph H; Lehne, Benjamin; Levy, Daniel; Lewis, Cora E; Li, Yize; Lim, Sing Hui; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Yeheng; Loh, Marie; Lohman, Kurt K; Louie, Tin; Mägi, Reedik; Matsuda, Koichi; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Mosley, Thomas H; Nalls, Mike A; Nasri, Ubaydah; O'Connell, Jeff R; Ogunniyi, Adesola; Palmas, Walter R; Palmer, Nicholette D; Pankow, James S; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Porteous, David; Raitakari, Olli T; Renström, Frida; Rice, Treva K; Ridker, Paul M; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Sabanayagam, Charumathi; Salako, Babatunde L; Sandow, Kevin; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Sims, Mario; Sitlani, Colleen M; Smith, Blair H; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Wilson, Gregory; Wojczynski, Mary K; Xiang, Yong-Bing; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Chen, Yii-Der Ida; Weir, David R; de Faire, Ulf; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Forrester, Terrence; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost Bruno; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Lehtimäki, Terho; Liang, Kae-Woei; Magnusson, Patrik K E; Oldehinkel, Albertine J; Pereira, Alexandre C; Perls, Thomas; Rauramaa, Rainer; Redline, Susan; Rettig, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Wickremasinghe, Ananda R; Wu, Tangchun; Kamatani, Yoichiro; Laurie, Cathy C; Bouchard, Claude; Cooper, Richard S; Evans, Michele K; Gudnason, Vilmundur; Hixson, James; Kardia, Sharon L R; Kritchevsky, Stephen B; Psaty, Bruce M; van Dam, Rob M; Arnett, Donna K; Mook-Kanamori, Dennis O; Fornage, Myriam; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Reiner, Alex P; Rotimi, Charles N; Bierut, Laura J; Zhu, Xiaofeng; Cupples, L Adrienne; Province, Michael A; Rotter, Jerome I; Franks, Paul W; Rice, Kenneth; Elliott, Paul; Caulfield, Mark J; Gauderman, W James; Munroe, Patricia B; Rao, Dabeeru C; Morrison, Alanna C
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
PMID: 31127295
ISSN: 1460-2083
CID: 3967142
Nephropathy Progression in African Americans With a Family History of ESKD: Implications for Clinical Trials in APOL1-Associated Nephropathy [Letter]
Freedman, Barry I; Spainhour, Mitzie; Hicks, Pamela J; Turner, Jolyn; Robertson, Julia; Langefeld, Carl D; Murea, Mariana; Divers, Jasmin
PMID: 31076172
ISSN: 1523-6838
CID: 4318912
Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus
Liu, Mingxia; Frej, Cecilia; Langefeld, Carl D; Divers, Jasmin; Bowden, Donald W; Carr, J Jeffrey; Gebre, Abraham K; Xu, Jianzhao; Larsson, Benny; Dahlbäck, Björn; Freedman, Barry I; Parks, John S
apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.
PMCID:6672033
PMID: 31133557
ISSN: 1539-7262
CID: 4318922
JC Viruria Is Associated With Reduced Risk of Diabetic Kidney Disease
Kruzel-Davila, Etty; Divers, Jasmin; Russell, Gregory B; Kra-Oz, Zipi; Cohen, Moran Szwarcwort; Langefeld, Carl D; Ma, Lijun; Lyles, Douglas S; Hicks, Pamela J; Skorecki, Karl L; Freedman, Barry I
PURPOSE/OBJECTIVE:African Americans who shed JC polyomavirus (JCV) in their urine have reduced rates of nondiabetic chronic kidney disease (CKD). We assessed the associations between urinary JCV and urine BK polyomavirus (BKV) with CKD in African Americans with diabetes mellitus. METHODS:African Americans with diabetic kidney disease (DKD) and controls lacking nephropathy from the Family Investigation of Nephropathy and Diabetes Consortium (FIND) and African American-Diabetes Heart Study (AA-DHS) had urine tested for JCV and BKV using quantitative PCR. Of the 335 individuals tested, 148 had DKD and 187 were controls. RESULTS:JCV viruria was detected more often in the controls than in the patients with DKD (FIND: 46.6% vs 32.2%; OR, 0.52; 95% CI, 0.29 to 0.93; P = 0.03; AA-DHS: 30.4% vs 26.2%; OR, 0.63; 95% CI, 0.27 to 1.48; P = 0.29). A joint analysis adjusted for age, sex, and study revealed that JC viruria was inversely associated with DKD (OR, 0.56; 95% CI, 0.35 to 0.91; P = 0.02). Statistically significant relationships between BKV and DKD were not observed. MAIN CONCLUSIONS/CONCLUSIONS:The results from the present study extend the inverse association between urine JCV and nondiabetic nephropathy in African Americans to DKD. These results imply that common pathways likely involving the innate immune system mediate coincident chronic kidney injury and restriction of JCV replication. Future studies are needed to explore causative pathways and characterize whether the absence of JC viruria can serve as a biomarker for DKD in the African American population.
PMCID:6489692
PMID: 30715336
ISSN: 1945-7197
CID: 4318862
Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
de Vries, Paul S; Brown, Michael R; Bentley, Amy R; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Schwander, Karen; Kraja, Aldi T; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Deng, Xuan; Dorajoo, Rajkumar; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Evangelou, Evangelos; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Lee, Joseph H; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M; Pietzner, Maik; Riaz, Muhammad; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; StanÄáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Wang, Yajuan; Ware, Erin B; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Ballantyne, Christie; Boerwinkle, Eric; Broeckel, Ulrich; Campbell, Archie; Canouil, Mickaël; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Connell, John M; de Faire, Ulf; de Las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Ding, Jingzhong; Dominiczak, Anna F; Duan, Qing; Eaton, Charles B; Eppinga, Ruben N; Faul, Jessica D; Fisher, Virginia; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Ghanbari, Mohsen; Giulianini, Franco; Grabe, Hans J; Grove, Megan L; Gu, C Charles; Harris, Tamara B; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E; Howard, Barbara V; Ikram, M Arfan; Jacobs, David R; Johnson, Craig; Jonas, Jost Bruno; Kammerer, Candace M; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Koistinen, Heikki A; Kolcic, Ivana; Kooperberg, Charles; Krieger, Jose E; Kritchevsky, Steve B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lemaitre, Rozenn N; Li, Yize; Liang, Jingjing; Liu, Jianjun; Liu, Kiang; Loh, Marie; Louie, Tin; Mägi, Reedik; Manichaikul, Ani W; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Mosley, Thomas H; Mukamal, Kenneth J; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Sotoodehnia, Nona; O'Connell, Jeff R; Palmer, Nicholette D; Pazoki, Raha; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Reiner, Alex P; Rice, Treva K; Rich, Stephen S; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Blair H; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tan, Nicholas; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; van Heemst, Diana; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Lihua; Wang, Yujie; Wang, Zhe; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yu, Bing; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Leander, Karin; Lehtimäki, Terho; Magnusson, Patrik K E; Penninx, Brenda; Pereira, Alexandre C; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wang, Ya Xing; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Zheng, Wei; Elliott, Paul; North, Kari E; Bouchard, Claude; Evans, Michele K; Gudnason, Vilmundur; Liu, Ching-Ti; Liu, Yongmei; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Kardia, Sharon L R; Zhu, Xiaofeng; Rotimi, Charles N; Mook-Kanamori, Dennis O; Fornage, Myriam; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Liu, Jingmin; Rotter, Jerome I; Gauderman, W James; Province, Michael A; Munroe, Patricia B; Rice, Kenneth; Chasman, Daniel I; Cupples, L Adrienne; Rao, Dabeeru C; Morrison, Alanna C
A person'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 multiancestry 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 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of 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 stages 1 and 2, a total of 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 (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
PMCID:6545280
PMID: 30698716
ISSN: 1476-6256
CID: 4318852
A catalog of genetic loci associated with kidney function from analyses of a million individuals
Wuttke, Matthias; Li, Yong; Li, Man; Sieber, Karsten B; Feitosa, Mary F; Gorski, Mathias; Tin, Adrienne; Wang, Lihua; Chu, Audrey Y; Hoppmann, Anselm; Kirsten, Holger; Giri, Ayush; Chai, Jin-Fang; Sveinbjornsson, Gardar; Tayo, Bamidele O; Nutile, Teresa; Fuchsberger, Christian; Marten, Jonathan; Cocca, Massimiliano; Ghasemi, Sahar; Xu, Yizhe; Horn, Katrin; Noce, Damia; van der Most, Peter J; Sedaghat, Sanaz; Yu, Zhi; Akiyama, Masato; Afaq, Saima; Ahluwalia, Tarunveer S; Almgren, Peter; Amin, Najaf; Ärnlöv, Johan; Bakker, Stephan J L; Bansal, Nisha; Baptista, Daniela; Bergmann, Sven; Biggs, Mary L; Biino, Ginevra; Boehnke, Michael; Boerwinkle, Eric; Boissel, Mathilde; Bottinger, Erwin P; Boutin, Thibaud S; Brenner, Hermann; Brumat, Marco; Burkhardt, Ralph; Butterworth, Adam S; Campana, Eric; Campbell, Archie; Campbell, Harry; Canouil, Mickaël; Carroll, Robert J; Catamo, Eulalia; Chambers, John C; Chee, Miao-Ling; Chee, Miao-Li; Chen, Xu; Cheng, Ching-Yu; Cheng, Yurong; Christensen, Kaare; Cifkova, Renata; Ciullo, Marina; Concas, Maria Pina; Cook, James P; Coresh, Josef; Corre, Tanguy; Sala, Cinzia Felicita; Cusi, Daniele; Danesh, John; Daw, E Warwick; de Borst, Martin H; De Grandi, Alessandro; de Mutsert, Renée; de Vries, Aiko P J; Degenhardt, Frauke; Delgado, Graciela; Demirkan, Ayse; Di Angelantonio, Emanuele; Dittrich, Katalin; Divers, Jasmin; Dorajoo, Rajkumar; Eckardt, Kai-Uwe; Ehret, Georg; Elliott, Paul; Endlich, Karlhans; Evans, Michele K; Felix, Janine F; Foo, Valencia Hui Xian; Franco, Oscar H; Franke, Andre; Freedman, Barry I; Freitag-Wolf, Sandra; Friedlander, Yechiel; Froguel, Philippe; Gansevoort, Ron T; Gao, He; Gasparini, Paolo; Gaziano, J Michael; Giedraitis, Vilmantas; Gieger, Christian; Girotto, Giorgia; Giulianini, Franco; Gögele, Martin; Gordon, Scott D; Gudbjartsson, Daniel F; Gudnason, Vilmundur; Haller, Toomas; Hamet, Pavel; Harris, Tamara B; Hartman, Catharina A; Hayward, Caroline; Hellwege, Jacklyn N; Heng, Chew-Kiat; Hicks, Andrew A; Hofer, Edith; Huang, Wei; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Ikram, M Arfan; Indridason, Olafur S; Ingelsson, Erik; Ising, Marcus; Jaddoe, Vincent W V; Jakobsdottir, Johanna; Jonas, Jost B; Joshi, Peter K; Josyula, Navya Shilpa; Jung, Bettina; Kähönen, Mika; Kamatani, Yoichiro; Kammerer, Candace M; Kanai, Masahiro; Kastarinen, Mika; Kerr, Shona M; Khor, Chiea-Chuen; Kiess, Wieland; Kleber, Marcus E; Koenig, Wolfgang; Kooner, Jaspal S; Körner, Antje; Kovacs, Peter; Kraja, Aldi T; Krajcoviechova, Alena; Kramer, Holly; Krämer, Bernhard K; Kronenberg, Florian; Kubo, Michiaki; Kühnel, Brigitte; Kuokkanen, Mikko; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lange, Leslie A; Langefeld, Carl D; Lee, Jeannette Jen-Mai; Lehne, Benjamin; Lehtimäki, Terho; Lieb, Wolfgang; Lim, Su-Chi; Lind, Lars; Lindgren, Cecilia M; Liu, Jun; Liu, Jianjun; Loeffler, Markus; Loos, Ruth J F; Lucae, Susanne; Lukas, Mary Ann; Lyytikäinen, Leo-Pekka; Mägi, Reedik; Magnusson, Patrik K E; Mahajan, Anubha; Martin, Nicholas G; Martins, Jade; März, Winfried; Mascalzoni, Deborah; Matsuda, Koichi; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Metspalu, Andres; Mikaelsdottir, Evgenia K; Milaneschi, Yuri; Miliku, Kozeta; Mishra, Pashupati P; Mohlke, Karen L; Mononen, Nina; Montgomery, Grant W; Mook-Kanamori, Dennis O; Mychaleckyj, Josyf C; Nadkarni, Girish N; Nalls, Mike A; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M; Noordam, Raymond; O'Connell, Jeffrey; O'Donoghue, Michelle L; Olafsson, Isleifur; Oldehinkel, Albertine J; Orho-Melander, Marju; Ouwehand, Willem H; Padmanabhan, Sandosh; Palmer, Nicholette D; Palsson, Runolfur; Penninx, Brenda W J H; Perls, Thomas; Perola, Markus; Pirastu, Mario; Pirastu, Nicola; Pistis, Giorgio; Podgornaia, Anna I; Polasek, Ozren; Ponte, Belen; Porteous, David J; Poulain, Tanja; Pramstaller, Peter P; Preuss, Michael H; Prins, Bram P; Province, Michael A; Rabelink, Ton J; Raffield, Laura M; Raitakari, Olli T; Reilly, Dermot F; Rettig, Rainer; Rheinberger, Myriam; Rice, Kenneth M; Ridker, Paul M; Rivadeneira, Fernando; Rizzi, Federica; Roberts, David J; Robino, Antonietta; Rossing, Peter; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Ryan, Kathleen A; Saba, Yasaman; Sabanayagam, Charumathi; Salomaa, Veikko; Salvi, Erika; Saum, Kai-Uwe; Schmidt, Helena; Schmidt, Reinhold; Schöttker, Ben; Schulz, Christina-Alexandra; Schupf, Nicole; Shaffer, Christian M; Shi, Yuan; Smith, Albert V; Smith, Blair H; Soranzo, Nicole; Spracklen, Cassandra N; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Svensson, Per O; Szymczak, Silke; Tai, E-Shyong; Tajuddin, Salman M; Tan, Nicholas Y Q; Taylor, Kent D; Teren, Andrej; Tham, Yih-Chung; Thiery, Joachim; Thio, Chris H L; Thomsen, Hauke; Thorleifsson, Gudmar; Toniolo, Daniela; Tönjes, Anke; Tremblay, Johanne; Tzoulaki, Ioanna; Uitterlinden, André G; Vaccargiu, Simona; van Dam, Rob M; van der Harst, Pim; van Duijn, Cornelia M; Velez Edward, Digna R; Verweij, Niek; Vogelezang, Suzanne; Völker, Uwe; Vollenweider, Peter; Waeber, Gerard; Waldenberger, Melanie; Wallentin, Lars; Wang, Ya Xing; Wang, Chaolong; Waterworth, Dawn M; Bin Wei, Wen; White, Harvey; Whitfield, John B; Wild, Sarah H; Wilson, James F; Wojczynski, Mary K; Wong, Charlene; Wong, Tien-Yin; Xu, Liang; Yang, Qiong; Yasuda, Masayuki; Yerges-Armstrong, Laura M; Zhang, Weihua; Zonderman, Alan B; Rotter, Jerome I; Bochud, Murielle; Psaty, Bruce M; Vitart, Veronique; Wilson, James G; Dehghan, Abbas; Parsa, Afshin; Chasman, Daniel I; Ho, Kevin; Morris, Andrew P; Devuyst, Olivier; Akilesh, Shreeram; Pendergrass, Sarah A; Sim, Xueling; Böger, Carsten A; Okada, Yukinori; Edwards, Todd L; Snieder, Harold; Stefansson, Kari; Hung, Adriana M; Heid, Iris M; Scholz, Markus; Teumer, Alexander; Köttgen, Anna; Pattaro, Cristian
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
PMID: 31152163
ISSN: 1546-1718
CID: 3936112
A randomized pilot study comparing graft-first to fistula-first strategies in older patients with incident end-stage kidney disease: Clinical rationale and study design
Murea, Mariana; Geary, Randolph L; Edwards, Matthew S; Moossavi, Shahriar; Davis, Ross P; Goldman, Matthew P; Hurie, Justin; Williams, Timothy K; Velazquez-Ramirez, Gabriela; Robinson, Todd W; Bagwell, Benjamin; Tuttle, Audrey B; Callahan, Kathryn E; Rocco, Michael V; Houston, Denise K; Pajewski, Nicholas M; Divers, Jasmin; Freedman, Barry I; Williamson, Jeff D
Timely placement of an arteriovenous (AV) vascular access (native AV fistula [AVF] or prosthetic AV graft [AVG]) is necessary to limit the use of tunneled central venous catheters (TCVC) in patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD). National guidelines recommend placement of AVF as the AV access of first choice in all patients to improve patient survival. The benefits of AVF over AVG are less certain in the older adults, as age-related biological changes independently modulate patient outcomes. This manuscript describes the rationale, study design and protocol for a randomized controlled pilot study of the feasibility and effects of AVG-first access placement in older adults with no prior AV access surgery. Fifty patients age ≥65 years, with incident ESKD on HD via TCVC or advanced kidney disease facing imminent HD initiation, and suitable upper extremity vasculature for initial placement of an AVF or AVG, will be randomly assigned to receive either an upper extremity AVG-first (intervention) or AVF-first (comparator) access. The study will establish feasibility of randomizing older adults to the two types of AV access surgery, evaluate relationships between measurements of preoperative physical function and vascular access development, compare vascular access outcomes between groups, and gather longitudinal assessments of upper extremity muscle strength, gait speed, performance of activities of daily living, and patient satisfaction with their vascular access and quality of life. Results will assist with the planning of a larger, multicenter trial assessing patient-centered outcomes.
PMCID:6475715
PMID: 31016270
ISSN: 2451-8654
CID: 4318902
Occurrence of severe hypoglycaemic events among US youth and young adults with type 1 or type 2 diabetes
Saydah, Sharon; Imperatore, Giuseppina; Divers, Jasmin; Bell, Ronny; Henkin, Leora; Mayer-Davis, Elizabeth; Zhong, Victor W; Dabelea, Dana; Lawrence, Jean M; Pihoker, Catherine
Objective/UNASSIGNED:Although severe hypoglycaemia (SH) can lead to adverse health outcomes, little is known about its occurrence and re-occurrence among youth with type 1 or type 2 diabetes. Methods/UNASSIGNED:This study included 2740 participants aged <20Â years at diabetes diagnosis and 5-14Â years diabetes duration from the SEARCH for Diabetes in Youth Cohort Study. Participants reported SH events in the past 6Â months. Differences in SH events by demographic and clinical factors were tested using logistic regression models. Results/UNASSIGNED:Â <Â 0.002). The median number of SH events per youth who had at least one SH event in the past 6Â months was 1 for both type 1 type 2 diabetes. For youth with type 1 diabetes, those who reported SH events were older, were more likely to have obesity or to be physically active, and had lower HbA1c. After adjustments, one unit increase in HbA1c was associated with 16% lower likelihood (OR 0.84, 95% CI 0.75, 0.94) and being physically active was associated with an 87% higher likelihood (OR 1.87, 95% CI 1.23, 2.86) of reporting a SH event. There were too few SH events among youth with type 2 diabetes to analyse further. Conclusions/UNASSIGNED:In youth with diabetes, SH was common even within a short 6-month window. Better understanding the causes of SH may help prevent them from occurring.
PMCID:6458461
PMID: 31008365
ISSN: 2398-9238
CID: 4318892
Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids
Bentley, Amy R; Sung, Yun J; Brown, Michael R; Winkler, Thomas W; Kraja, Aldi T; Ntalla, Ioanna; Schwander, Karen; Chasman, Daniel I; Lim, Elise; Deng, Xuan; Guo, Xiuqing; Liu, Jingmin; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Richard, Melissa A; Noordam, Raymond; Baker, Jenna; Chen, Guanjie; Aschard, Hugues; Bartz, Traci M; Ding, Jingzhong; Dorajoo, Rajkumar; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Zhao, Wei; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Evangelou, Evangelos; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Hung, Yi-Jen; Jackson, Anne U; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Leander, Karin; Lin, Keng-Hung; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M; Pietzner, Maik; Prins, Bram; Riaz, Muhammad; Robino, Antonietta; Said, M Abdullah; Schupf, Nicole; Scott, Robert A; Sofer, Tamar; Stancáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Wang, Tzung-Dau; Wang, Yajuan; Ware, Erin B; Wen, Wanqing; Xiang, Yong-Bing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Adeyemo, Adebowale; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Arzumanyan, Zorayr; Aung, Tin; Ballantyne, Christie; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Broeckel, Ulrich; Brown, Morris; Cade, Brian E; Campbell, Archie; Canouil, Mickaël; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Christensen, Kaare; Concas, Maria Pina; Connell, John M; de Las Fuentes, Lisa; de Silva, H Janaka; de Vries, Paul S; Doumatey, Ayo; Duan, Qing; Eaton, Charles B; Eppinga, Ruben N; Faul, Jessica D; Floyd, James S; Forouhi, Nita G; Forrester, Terrence; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gharib, Sina A; Gigante, Bruna; Giulianini, Franco; Grabe, Hans J; Gu, C Charles; Harris, Tamara B; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E; Ikram, M Arfan; Jia, Yucheng; Joehanes, Roby; Johnson, Craig; Jonas, Jost Bruno; Justice, Anne E; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Kolcic, Ivana; Kooperberg, Charles; Krieger, Jose E; Kritchevsky, Stephen B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Liang, Jingjing; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Kiang; Loh, Marie; Lohman, Kurt K; Louie, Tin; Luzzi, Anna; Mägi, Reedik; Mahajan, Anubha; Manichaikul, Ani W; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Momozawa, Yukihide; Morris, Andrew P; Murray, Alison D; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; North, Kari E; O'Connell, Jeffrey R; Palmer, Nicholette D; Papanicolau, George J; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Poulter, Neil; Raitakari, Olli T; Reiner, Alex P; Renström, Frida; Rice, Treva K; Rich, Stephen S; Robinson, Jennifer G; Rose, Lynda M; Rosendaal, Frits R; Rudan, Igor; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Stringham, Heather M; Tan, Nicholas Y Q; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Tiemeier, Henning; Turner, Stephen T; Uitterlinden, André G; van Heemst, Diana; Waldenberger, Melanie; Wang, Heming; Wang, Lan; Wang, Lihua; Wei, Wen Bin; Williams, Christine A; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Young, Kristin; Yu, Caizheng; Yuan, Jian-Min; Zhou, Jie; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Cooper, Richard S; de Faire, Ulf; Deary, Ian J; Elliott, Paul; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L; Juang, Jyh-Ming Jimmy; Kamatani, Yoichiro; Kammerer, Candace M; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Laurie, Cathy C; Lee, I-Te; Lehtimäki, Terho; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Pereira, Alexandre C; Rauramaa, Rainer; Redline, Susan; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wang, Jun-Sing; Wang, Ya Xing; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zeggini, Eleftheria; Zheng, Wei; Bouchard, Claude; Evans, Michele K; Gudnason, Vilmundur; Kardia, Sharon L R; Liu, Yongmei; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Mook-Kanamori, Dennis O; Fornage, Myriam; Province, Michael A; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Franceschini, Nora; Rotter, Jerome I; Zhu, Xiaofeng; Bierut, Laura J; Gauderman, W James; Rice, Kenneth; Munroe, Patricia B; Morrison, Alanna C; Rao, Dabeeru C; Rotimi, Charles N; Cupples, L Adrienne
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
PMCID:6467258
PMID: 30926973
ISSN: 1546-1718
CID: 4094682
Mechanisms of Injury in APOL1-associated Kidney Disease
Ma, Lijun; Divers, Jasmin; Freedman, Barry I
BACKGROUND:An improved understanding of the pathogenesis in apolipoprotein L1 (APOL1) gene-associated chronic kidney disease (CKD) arose from observations in kidney transplantation. APOL1 genotyping could soon improve the safety of living kidney donation in individuals with recent African ancestry and alter the allocation of deceased donor kidneys. METHODS:This article reviews the potential mechanisms that underlie development of APOL1-associated nephropathy. Roles for circulating APOL1 protein versus intrinsic renal expression of APOL1 are discussed, as well as the requirement for modifying genetic and/or environmental factors. RESULTS:Abundant evidence supports local kidney production of APOL1 renal-risk variant protein in the development of nephropathy; this is true in both native kidney disease and after renal transplantation. Only a minority of kidneys from individuals with APOL1 high-risk genotypes will develop CKD or manifest shorter renal allograft survival after transplantation. Therefore, modifying factors that explain why only a subset of kidneys develops nephropathy remain critical to identify. It appears likely that environmental exposures, as opposed to major APOL1-second gene interactions, will prove to be stronger modifiers of the risk for nephropathy. CONCLUSIONS:The evolving understanding of the pathogenesis in APOL1-associated nephropathy will identify biomarkers predicting nephropathy in individuals at high genetic risk and lead to novel therapies to prevent or slow native CKD progression and prolong survival of transplanted kidneys. In the interim, the National Institutes of Health-sponsored "APOL1 Long-term Kidney Transplantation Outcomes" Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation.
PMCID:6226011
PMID: 30371607
ISSN: 1534-6080
CID: 4318832
