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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
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
Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
Kilpeläinen, Tuomas O; Bentley, Amy R; Noordam, Raymond; Sung, Yun Ju; Schwander, Karen; Winkler, Thomas W; Jakupović, Hermina; Chasman, Daniel I; Manning, Alisa; Ntalla, Ioanna; Aschard, Hugues; Brown, Michael R; de Las Fuentes, Lisa; Franceschini, Nora; Guo, Xiuqing; Vojinovic, Dina; Aslibekyan, Stella; Feitosa, Mary F; Kho, Minjung; Musani, Solomon K; Richard, Melissa; Wang, Heming; Wang, Zhe; Bartz, Traci M; Bielak, Lawrence F; Campbell, Archie; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P; Horimoto, Andrea R V R; Li, Changwei; Lohman, Kurt K; Marten, Jonathan; Sim, Xueling; Smith, Albert V; Tajuddin, Salman M; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Evangelou, Evangelos; Gao, Chuan; Graff, Mariaelisa; Harris, Sarah E; He, Meian; Hsu, Fang-Chi; Jackson, Anne U; Zhao, Jing Hua; Kraja, Aldi T; Kühnel, Brigitte; Laguzzi, Federica; Lyytikäinen, Leo-Pekka; Nolte, Ilja M; Rauramaa, Rainer; Riaz, Muhammad; Robino, Antonietta; Rueedi, Rico; Stringham, Heather M; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Verweij, Niek; Ware, Erin B; Wen, Wanqing; Li, Xiaoyin; Yanek, Lisa R; Amin, Najaf; Arnett, Donna K; Boerwinkle, Eric; Brumat, Marco; Cade, Brian; Canouil, Mickaël; Chen, Yii-Der Ida; Concas, Maria Pina; Connell, John; de Mutsert, Renée; de Silva, H Janaka; de Vries, Paul S; Demirkan, AyÅŸe; Ding, Jingzhong; Eaton, Charles B; Faul, Jessica D; Friedlander, Yechiel; Gabriel, Kelley P; Ghanbari, Mohsen; Giulianini, Franco; Gu, Chi Charles; Gu, Dongfeng; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hunt, Steven C; Ikram, M Arfan; Jonas, Jost B; Koh, Woon-Puay; Komulainen, Pirjo; Krieger, Jose E; Kritchevsky, Stephen B; Kutalik, Zoltán; Kuusisto, Johanna; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Leander, Karin; Lemaitre, Rozenn N; Lewis, Cora E; Liang, Jingjing; Liu, Jianjun; Mägi, Reedik; Manichaikul, Ani; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Mohlke, Karen L; Mosley, Thomas H; Murray, Alison D; Nalls, Mike A; Nang, Ei-Ei Khaing; Nelson, Christopher P; Nona, Sotoodehnia; Norris, Jill M; Nwuba, Chiamaka Vivian; O'Connell, Jeff; Palmer, Nicholette D; Papanicolau, George J; Pazoki, Raha; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Porteous, David J; Poveda, Alaitz; Raitakari, Olli T; Rich, Stephen S; Risch, Neil; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Schreiner, Pamela J; Scott, Robert A; Sidney, Stephen S; Sims, Mario; Smith, Jennifer A; Snieder, Harold; Sofer, Tamar; Starr, John M; Sternfeld, Barbara; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Tsai, Michael Y; Tuomilehto, Jaakko; Uitterlinden, André G; van der Ende, M Yldau; van Heemst, Diana; Voortman, Trudy; Waldenberger, Melanie; Wennberg, Patrik; Wilson, Gregory; Xiang, Yong-Bing; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; de Faire, Ulf; Deary, Ian J; Elliott, Paul; Esko, Tõnu; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Kato, Norihiro; Laakso, Markku; Lakka, Timo A; Lehtimäki, Terho; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Samani, Nilesh J; Shu, Xiao-Ou; van der Harst, Pim; Van Vliet-Ostaptchouk, Jana V; Vollenweider, Peter; Wagenknecht, Lynne E; Wang, Ya X; Wareham, Nicholas J; Weir, David R; Wu, Tangchun; Zheng, Wei; Zhu, Xiaofeng; Evans, Michele K; Franks, Paul W; Gudnason, Vilmundur; Hayward, Caroline; Horta, Bernardo L; Kelly, Tanika N; Liu, Yongmei; North, Kari E; Pereira, Alexandre C; Ridker, Paul M; Tai, E Shyong; van Dam, Rob M; Fox, Ervin R; Kardia, Sharon L R; Liu, Ching-Ti; Mook-Kanamori, Dennis O; Province, Michael A; Redline, Susan; van Duijn, Cornelia M; Rotter, Jerome I; Kooperberg, Charles B; Gauderman, W James; Psaty, Bruce M; Rice, Kenneth; Munroe, Patricia B; Fornage, Myriam; Cupples, L Adrienne; Rotimi, Charles N; Morrison, Alanna C; Rao, Dabeeru C; Loos, Ruth J F
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
PMCID:6342931
PMID: 30670697
ISSN: 2041-1723
CID: 4318842
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
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
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
Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score
Onengut-Gumuscu, Suna; Chen, Wei-Min; Robertson, Catherine C; Bonnie, Jessica K; Farber, Emily; Zhu, Zhennan; Oksenberg, Jorge R; Brant, Steven R; Bridges, S Louis; Edberg, Jeffrey C; Kimberly, Robert P; Gregersen, Peter K; Rewers, Marian J; Steck, Andrea K; Black, Mary H; Dabelea, Dana; Pihoker, Catherine; Atkinson, Mark A; Wagenknecht, Lynne E; Divers, Jasmin; Bell, Ronny A; Erlich, Henry A; Concannon, Patrick; Rich, Stephen S
OBJECTIVE:Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS/METHODS:). RESULTS:*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS:Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.
PMID: 30659077
ISSN: 1935-5548
CID: 3682642
Genetic Architecture of Primary Open Angle Glaucoma in Individuals of African Descent: The African Descent & Glaucoma Evaluation Study (ADAGES) III
Taylor, Kent D; Guo, Xiuqing; Zangwill, Linda M; Liebmann, Jeffrey M; Girkin, Christopher A; Feldman, Robert M; Dubiner, Harvey; Hai, Yang; Samuels, Brian C; Panarelli, Joseph F; Mitchell, John P; Al-Aswad, Lama A; Park, Sung Chul; Tello, Celso; Cotliar, Jeremy; Bansal, Rajendra; Sidoti, Paul A; Cioffi, George A; Blumberg, Dana; Ritch, Robert; Bell, Nicholas P; Blieden, Lauren S; Davis, Garvin; Medeiros, Felipe A; Das, Swapan K; Divers, Jasmin; Langefeld, Carl D; Palmer, Nicholette D; Freedman, Barry I; Bowden, Donald W; Ng, Maggie C Y; Ida Chen, Yii-Der; Ayyagari, Radha; Rotter, Jerome I; Weinreb, Robert N
OBJECTIVE:Find genetic contributions to glaucoma in African Americans. DESIGN/METHODS:Cross-sectional, case-control study. PARTICIPANTS/METHODS:1875 POAG cases and 1709 controls, self-identified as African Descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGESIII) and Wake Forest School of Medicine. METHODS:MegaChip genotypes were imputed to Thousand Genomes data. Association of SNPs with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by Receiver Operator Characteristics (ROC-AUC). MAIN OUTCOME/RESULTS:POAG defined by visual field loss without other non-ocular conditions (N=1875). Advanced POAG was defined by age-based mean deviation of visual field (N=946). RESULTS:) was observed, not in LD with the previously reported ED SNP. Additional previously identified loci associated with POAG in AD were: 8q22, AFAP1, TMCO1. An AUC of 0.62 was observed with an unweighted genetic risk score composed of 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC=0.74 and AUC=0.94, respectively. CONCLUSIONS:A novel association with advanced POAG in the ENO4 locus was putatively identified in subjects of African descent. In addition to this finding, this GWAS in AD POAG subjects contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine-mapping of regions due to shorter average linkage disequilibrium (FNDC3B). While not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.
PMID: 30352225
ISSN: 1549-4713
CID: 3384612
The African Descent and Glaucoma Evaluation Study (ADAGES) III: Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data
Zangwill, Linda M; Ayyagari, Radha; Liebmann, Jeffrey M; Girkin, Christopher A; Feldman, Robert; Dubiner, Harvey; Dirkes, Keri A; Holmann, Matthew; Williams-Steppe, Eunice; Hammel, Naama; Saunders, Luke J; Vega, Suzanne; Sandow, Kevin; Roll, Kathryn; Slight, Rigby; Auerbach, Daniel; Samuels, Brian C; Panarelli, Joseph F; Mitchell, John P; Al-Aswad, Lama A; Park, Sung Chul; Tello, Celso; Cotliar, Jeremy; Bansal, Rajendra; Sidoti, Paul A; Cioffi, George A; Blumberg, Dana; Ritch, Robert; Bell, Nicholas P; Blieden, Lauren S; Davis, Garvin; Medeiros, Felipe A; Ng, Maggie C Y; Das, Swapan K; Palmer, Nicholette D; Divers, Jasmin; Langefeld, Carl D; Freedman, Barry I; Bowden, Donald W; Christopher, Mark A; Chen, Yii-der I; Guo, Xiuqing; Taylor, Kent D; Rotter, Jerome I; Weinreb, Robert N
PURPOSE/OBJECTIVE:To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN/METHODS:Cross-sectional, case-control study. PARTICIPANTS/METHODS:Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS:Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES/METHODS:Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS:The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS:With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES IIIÂ genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.
PMCID:6050158
PMID: 29361356
ISSN: 1549-4713
CID: 2988612
FGF23 Concentration and APOL1 Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes
Chan, Gary C; Divers, Jasmin; Russell, Gregory B; Langefeld, Carl D; Wagenknecht, Lynne E; Hsu, Fang-Chi; Xu, Jianzhao; Smith, S Carrie; Palmer, Nicholette D; Hicks, Pamela J; Bowden, Donald W; Register, Thomas C; Ma, Lijun; Carr, J Jeffrey; Freedman, Barry I
OBJECTIVE:Cardiovascular and renal complications contribute to higher mortality in patients with diabetes. We assessed novel and conventional predictors of mortality in African American-Diabetes Heart Study (AA-DHS) participants. RESEARCH DESIGN AND METHODS:) were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models. RESULTS:renal-risk genotypes (HR 0.07 [95% CI 0.01-0.69]) as the strongest predictors of mortality. CONCLUSIONS:non-renal-risk genotypes associated with higher mortality in African Americans with diabetes. These data add to growing evidence supporting FGF23 association with mortality; mechanisms whereby these novel predictors impact survival remain to be determined.
PMID: 29113983
ISSN: 1935-5548
CID: 4318642
