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1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Physical activity and metabolic health in chronic kidney disease: a cross-sectional study 
BMC Nephrology  2016;17:187.
Background
Patients with chronic kidney disease (CKD) are at high risk of progression to end stage renal disease and cardiovascular events. Physical activity may reduce these risks by improving metabolic health. We tested associations of physical activity with central components of metabolic health among people with moderate-severe non-diabetic CKD.
Methods
We performed a cross-sectional study of 47 people with CKD (estimated GFR <60 ml/min/1.73 m2) and 29 healthy control subjects. Accelerometry was used to measured physical activity over 7 days, the hyperinsulinemic-euglycemic clamp was used to measure insulin sensitivity, and DXA was used to measured fat mass. We tested associations of physical activity with insulin sensitivity, fat mass, blood pressure, serum lipid concentrations, and serum high sensitivity C-reactive protein concentration using multivariable linear regression, adjusting for possible confounding factors.
Results
Participants with CKD were less active than participants without CKD (mean (SD) 468.1 (233.1) versus 662.3 (292.5) counts per minute) and had lower insulin sensitivity (4.1 (2.1) versus 5.2 (2.0 (mg/min)/(μU/mL)), higher fat mass (32.0 (11.4) versus 29.4 (14.8) kg), and higher triglyceride concentrations (153.2 (91.6) versus 99.6 (66.8) mg/dL). With adjustment for demographics, comorbidity, medications, and estimated GFR, each two-fold higher level of physical activity was associated with a 0.9 (mg/min)/(μU/mL) higher insulin sensitivity (95% CI 0.2, 1.5, p = 0.006), an 8.0 kg lower fat mass (−12.9, −3.1, p = 0.001), and a 37.9 mg/dL lower triglyceride concentration (−71.9, −3.9, p = 0.03). Associations of physical activity with insulin sensitivity and triglycerides did not differ significantly by CKD status (p-values for interaction >0.3).
Conclusions
Greater physical activity is associated with multiple manifestations of metabolic health among people with moderate-severe CKD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-016-0400-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-016-0400-x
PMCID: PMC5120456  PMID: 27876008
Chronic kidney disease; Physical activity; Metabolism; Insulin resistance; Obesity; Triglycerides
4.  Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association 
Diabetes Care  2015;38(9):1777-1803.
Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.
doi:10.2337/dci15-0012
PMCID: PMC4876675  PMID: 26246459
5.  Vitamin D Metabolites and Bone Mineral Density: the Multi-Ethnic Study of Atherosclerosis 
Bone  2015;78:186-193.
Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations with low bone mineral density (BMD) and fractures, motivating widespread use of vitamin D supplements for bone health. However, previous studies have been limited to predominantly White populations despite differences in the distribution and metabolism of 25(OH)D by race/ethnicity. We determined associations of serum 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH2)D3), and parathyroid hormone (PTH) with BMD among 1,773 adult participants in the Multi-Ethnic Study of Atherosclerosis (MESA) in a staggered cross-sectional study design. Vitamin D metabolites were measured using liquid chromatography-mass spectroscopy and PTH using a 2-site immunoassay from serum collected in 2000–2002. Volumetric trabecular lumbar BMD was measured from computed tomography scans performed in 2002–2005 expressed as g/cm3. We used linear regression and graphical methods to compare associations of vitamin D metabolite and PTH concentrations with BMD as the outcomes measure among White (n=714), Black (n=353), Chinese (n=249), and Hispanic (n=457) participants. Serum 25(OH)D and 24,25(OH2)D3 concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants (P-for interaction=0.054). Comparing the lowest category of 25(OH)D (<20 ng/ml) to the highest (≥30 ng/ml), the adjusted mean difference in BMD was −8.1 g/cm3 (95% CI −14.8, −1.4) for Whites; −10.2 g/cm3 (−20.4, 0.0) for Chinese vs. 8.8 g/cm3 (−2.8, 20.5) for Black and −1.1 g/cm3 (−8.3, 6.2) for Hispanic. Similar results were observed for serum 24,25(OH2)D3. Serum PTH was not associated with BMD. In a multi-ethnic population, associations of 25(OH)D with BMD were strongest among White and Chinese participants and null among Black and Hispanic participants. Further studies are needed to determine optimal biomarkers for bone health for multiple ethnic groups.
doi:10.1016/j.bone.2015.05.008
PMCID: PMC4466133  PMID: 25976951
Vitamin D; parathyroid hormone; quantitation of bone; general population studies; aging
6.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
7.  Fibroblast Growth Factor 23 and Sudden Versus Nonsudden Cardiac Death: The Cardiovascular Health Study 
Background
Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with greater risk of cardiovascular events and mortality, especially among people with chronic kidney disease (CKD). Since individuals with CKD are at an increased risk of sudden cardiac death (SCD), we sought to understand whether FGF-23 is a stronger risk factor for SCD versus non-SCD.
Study Design
Cohort study.
Setting & Participants
3,244 participants in the community-based Cardiovascular Health Study, aged 65 years or older.
Predictor
Plasma FGF-23 concentrations.
Outcomes
We assessed SCD and non-SCD in these analyses. SCD was rigorously adjudicated and was defined as a sudden pulseless condition of cardiac origin in a previously stable person occurring out of hospital or in emergency department.
Measurements
We estimated associations of baseline FGF-23 concentrations with SCD and non-SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, comorbidities, and kidney function. We also tested whether associations differed by CKD status.
Results
During a median follow-up of 8.1 years, there were 118 adjudicated SCD and 570 non-SCD events. After multivariable adjustment for demographics, cardiovascular risk factors, comorbidities, and parameters of kidney function, higher FGF-23 concentrations were an independent risk factor for non-SCD (HR [per doubling], 1.17; 95% CI, 1.06-1.30). Elevated FGF-23 concentrations, however, were not independently associated with SCD (HR [per doubling], 1.07; 95% CI, 0.85-1.35). In stratified analysis by CKD status (36.5% of cohort), doubling of FGF-23 concentrations was independently associated with non-SCD (adjusted HR, 1.26; 95% CI, 1.10-1.45). A similar magnitude of association was observed between FGF-23 and SCD among the CKD subgroup; however, it was not significant (HR, 1.20; 95% CI, 0.89-1.62).
Limitations
Limited power to detect moderate-sized effects between FGF-23 and SCD in both the primary and stratified analyses.
Conclusions
In this population-based study, FGF-23 elevations were independently associated with non-SCD. Among individuals with CKD, the associations between FGF-23 and SCD and non-SCD were similar.
doi:10.1053/j.ajkd.2014.10.025
PMCID: PMC4485528  PMID: 25572028
fibroblast growth factor 23 (FGF-23); chronic kidney disease (CKD); sudden cardiac death (SCD); non-SCD; cardiovascular event; cardiovascular mortality; fatal arrhythmic event; renal function; Cardiovascular Health Study (CHS); cohort study
8.  Potassium Measures and Their Associations with Glucose and Diabetes Risk: The Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2016;11(6):e0157252.
Background
Recent studies have found low-normal potassium (K) to be associated with increased diabetes risk. We sought to verify these associations in a multi-ethnic US cohort; and to determine if these associations extend to US Hispanics and Asian-Americans.
Methods
We analyzed data from Multi-Ethnic Study of Atherosclerosis (MESA) participants who were free-of-diabetes at baseline. We examined cross-sectional associations between measures of K—serum, dietary, and urine—with fasting glucose and HOMA-IR. We examined longitudinal associations between K and diabetes risk over 8 years.
Findings
In multivariable models, compared to those with higher serum K (≥4.5mmol/L), those with lower serum K (<4.0mmol/L) had significantly higher fasting glucose [1.3 mg/dL (95%CI 0.2, 2.4), P-value = 0.03]. Incident diabetes developed in 1281 of 5415 at-risk participants. In minimally-adjusted models, we found inverse associations between serum and dietary K and diabetes risk. Compared to those with higher serum K, those with lower serum K had an HR (95% CI) of incident diabetes of 1.23 (1.04, 1.47), P-value = 0.02. However, these associations were attenuated in fully-adjusted models. We found no significant interaction between potassium and ethnicity.
Conclusions
In this multi-ethnic cohort, we found a significant inverse association between serum K and fasting glucose but no significant association with longer-term diabetes risk. This inverse association between potassium and glucose must be studied further to understand the physiology and its potential impact on chronic health.
doi:10.1371/journal.pone.0157252
PMCID: PMC4900670  PMID: 27280455
9.  Creatinine Clearance and Walking Speed and Muscle Atrophy: A Cohort Study 
Background
Chronic kidney disease (CKD) is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney function with muscle composition and longitudinal measures of physical performance are unknown.
Study Design
Prospective cohort study.
Setting & Participants
We evaluated 826 community-dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study free of baseline stroke or activities of daily living disability.
Predictor
Baseline creatinine clearance (Clcr) based on a 24-hour urine collection.
Outcomes
Cross-sectional and longitudinal trajectories of physical performance measured by 7-meter usual gait speed, 400-meter fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative CT.
Results
Mean age of participants was 74 ± 7 (SD) years with 183 having Clcr < 60ml/min/1.73m2. After adjustment each 10ml/min/1.73m2 decrement in Clcr was associated with 0.01 (95% CI, 0.004–0.017) m/s slower 7-meter usual walking speed and 0.008 (95% CI, 0.002–0.014) m/s slower 400-meter walking speed. Each 10 ml/min/1.73m2 decrement in Clcr was associated with 28mm2 (95% CI, 0.8–55) lower muscle area and 0.15mg/cm3 (95% CI, 0.04–0.26) lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-meter (P=0.005) and 400-meter (P=0.02) walk and knee extension strength (P=0.001) over the course of follow-up. Over a mean follow-up of 7.1 ±2.5 years, each 10 ml/min/1.73m2 lower baseline Clcr was associated with 0.024 (95% CI, 0.01–0.037) kg/year greater decline in knee strength.
Limitations
Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to non-differential misclassification and attenuation of estimates. Conclusions: Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed and more rapid declines in lower extremity strength over time.
doi:10.1053/j.ajkd.2014.10.016
PMCID: PMC4414665  PMID: 25542415
physical performance; skeletal muscle composition; muscle strength; mobility impairment; muscle atrophy; longitudinal trajectory; creatinine clearance (Clcr); renal function; chronic kidney disease (CKD)
10.  Effects of Serum Creatinine Calibration on Estimated Renal Function in African Americans: the Jackson Heart Study 
Background
The calibration to Isotope Dilution Mass Spectroscopy (IDMS) traceable creatinine is essential for valid use of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (GFR).
Methods
For 5,210 participants in the Jackson Heart Study (JHS), serum creatinine was measured with a multipoint enzymatic spectrophotometric assay at the baseline visit (2000–2004) and re-measured using the Roche enzymatic method, traceable to IDMS in a subset of 206 subjects. The 200 eligible samples (6 were excluded, 1 for failure of the re-measurement and 5 for outliers) were divided into three disjoint sets - training, validation, and test - to select a calibration model, estimate true errors, and assess performance of the final calibration equation. The calibration equation was applied to serum creatinine measurements of 5,210 participants to estimate GFR and the prevalence of CKD.
Results
The selected Deming regression model provided a slope of 0.968 (95% Confidence Interval (CI), 0.904 to 1.053) and intercept of −0.0248 (95% CI, −0.0862 to 0.0366) with R squared 0.9527. Calibrated serum creatinine showed high agreement with actual measurements when applying to the unused test set (concordance correlation coefficient 0.934, 95% CI, 0.894 to 0.960). The baseline prevalence of CKD in the JHS (2000–2004) was 6.30% using calibrated values, compared with 8.29% using non-calibrated serum creatinine with the CKD-EPI equation (P < 0.001).
Conclusions
A Deming regression model was chosen to optimally calibrate baseline serum creatinine measurements in the JHS and the calibrated values provide a lower CKD prevalence estimate.
doi:10.1097/MAJ.0000000000000446
PMCID: PMC4414728  PMID: 25806862
Calibration; Chronic Kidney Disease; CKD-EPI equation; Deming regression; Serum Creatinine
12.  Potassium and Glucose Measures in Older Adults: The Cardiovascular Health Study 
Background.
We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.
Methods.
Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.
Results.
Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of −0.18 (−0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of −0.61 (−0.94, −0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.
Conclusions.
Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.
doi:10.1093/gerona/glu071
PMCID: PMC4366599  PMID: 24895271
Potassium; Glucose metabolism; Older adults.
13.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d'Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H. | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Mägi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita P. S. | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L. R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O'Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, W. H. Linda | Fox, Caroline S.
Nature Communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
14.  Effect of Extended Release Niacin on Cardiovascular Events and Kidney Function in Chronic Kidney Disease: A Post-Hoc Analysis of the AIM-HIGH Trial 
Kidney international  2015;87(6):1250-1257.
Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post-hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared to placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dL, and high density lipoprotein-cholesterol significantly increased by a mean of 11.3 mg/dL over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality.
doi:10.1038/ki.2014.383
PMCID: PMC4449803  PMID: 25651367
chronic kidney disease; cardiovascular disease; lipids
15.  Association of fibroblast growth factor-23 with arterial stiffness in the Multi-Ethnic Study of Atherosclerosis 
Nephrology Dialysis Transplantation  2014;29(11):2099-2105.
Background
Serum fibroblast growth factor-23 (FGF-23) is associated with cardiovascular disease (CVD), yet the mechanisms remain uncertain. Our objective was to determine whether higher FGF-23 concentrations are associated with arterial stiffness.
Methods
In this cross-sectional study, serum FGF-23 concentrations were measured in 5977 participants without known CVD in the Multi-Ethnic Study of Atherosclerosis. The primary outcomes of interest were large (LAE) and small artery elasticity (SAE), pulse pressure and ankle-brachial index (ABI) > 1.30. LAE and SAE were measured by pulse contour analysis of the radial artery. Pulse pressure was measured with an automated sphygmomanometer using the average of two resting blood pressure measurements. ABI was calculated as the ratio of the ankle and brachial systolic blood pressures.
Results
Serum FGF-23 concentrations were not significantly associated with LAE [relative difference (RD) per doubling: 0%; 95% confidence interval (CI): −2–1%], SAE (RD per doubling: 0%; 95% CI: −3–2%), pulse pressure (β per doubling: 0.44; 95% CI: −0.31–1.19), or a high ABI (odds ratio per doubling: 1.14; 95% CI: 0.84–1.55). Findings were similar irrespective of chronic kidney disease status.
Conclusions
Higher serum FGF-23 concentrations are not associated with arterial stiffness, as measured by pulse pressure, LAE, SAE or high ABI, in a community-based population without CVD.
doi:10.1093/ndt/gfu101
PMCID: PMC4209876  PMID: 24782533
ABI; arterial elasticity; arterial stiffness; FGF-23; pulse pressure
16.  Genome-wide association study of kidney function decline in individuals of European descent 
Gorski, Mathias | Tin, Adrienne | Garnaas, Maija | McMahon, Gearoid M. | Chu, Audrey Y. | Tayo, Bamidele O. | Pattaro, Cristian | Teumer, Alexander | Chasman, Daniel I. | Chalmers, John | Hamet, Pavel | Tremblay, Johanne | Woodward, Marc | Aspelund, Thor | Eiriksdottir, Gudny | Gudnason, Vilmundur | Harris, Tammara B. | Launer, Lenore J. | Smith, Albert V. | Mitchell, Braxton D. | O'Connell, Jeffrey R. | Shuldiner, Alan R. | Coresh, Josef | Li, Man | Freudenberger, Paul | Hofer, Edith | Schmidt, Helena | Schmidt, Reinhold | Holliday, Elizabeth G. | Mitchell, Paul | Wang, Jie Jin | de Boer, Ian H. | Li, Guo | Siscovick, David S. | Kutalik, Zoltan | Corre, Tanguy | Vollenweider, Peter | Waeber, Gérard | Gupta, Jayanta | Kanetsky, Peter A. | Hwang, Shih-Jen | Olden, Matthias | Yang, Qiong | de Andrade, Mariza | Atkinson, Elizabeth J. | Kardia, Sharon L.R. | Turner, Stephen T. | Stafford, Jeanette M. | Ding, Jingzhong | Liu, Yongmei | Barlassina, Cristina | Cusi, Daniele | Salvi, Erika | Staessen, Jan A | Ridker, Paul M | Grallert, Harald | Meisinger, Christa | Müller-Nurasyid, Martina | Krämer, Bernhard K. | Kramer, Holly | Rosas, Sylvia E. | Nolte, Ilja M. | Penninx, Brenda W. | Snieder, Harold | Del Greco, Fabiola | Franke, Andre | Nöthlings, Ute | Lieb, Wolfgang | Bakker, Stephan J.L. | Gansevoort, Ron T. | van der Harst, Pim | Dehghan, Abbas | Franco, Oscar H. | Hofman, Albert | Rivadeneira, Fernando | Sedaghat, Sanaz | Uitterlinden, André G. | Coassin, Stefan | Haun, Margot | Kollerits, Barbara | Kronenberg, Florian | Paulweber, Bernhard | Aumann, Nicole | Endlich, Karlhans | Pietzner, Mike | Völker, Uwe | Rettig, Rainer | Chouraki, Vincent | Helmer, Catherine | Lambert, Jean-Charles | Metzger, Marie | Stengel, Benedicte | Lehtimäki, Terho | Lyytikäinen, Leo-Pekka | Raitakari, Olli | Johnson, Andrew | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Goessling, Wolfram | Köttgen, Anna | Kao, H. Linda | Fox, Caroline S. | Böger, Carsten A.
Kidney international  2014;87(5):1017-1029.
Genome wide association studies (GWAS) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, SNPs at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1 and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11 and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
doi:10.1038/ki.2014.361
PMCID: PMC4425568  PMID: 25493955
chronic kidney disease; kidney development
17.  Associations of Circulating Lymphocyte Subpopulations with Type 2 Diabetes: Cross-Sectional Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2015;10(10):e0139962.
Objective
Distinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies.
Methods
Circulating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4+ naive, CD4+ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models.
Results
Each standard deviation (SD) higher CD4+ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1–47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4–36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4+ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin.
Conclusions
A higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4+ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.
doi:10.1371/journal.pone.0139962
PMCID: PMC4601795  PMID: 26458065
18.  Plasma vitamin D is associated with fasting insulin and HOMA-IR in young adult males, but not females, of the Jerusalem Perinatal Study 
Public health nutrition  2014;18(7):1324-1331.
Objective
To examine cross-sectional relationships between plasma vitamin D and Cardiometabolic Risk Factors in young adults.
Design
Data were collected from interviews, physical examinations, and biomarker measurements. Total plasma 25-hydroxyvitamin D (25[OH]D) was measured using liquid chromatography-tandem mass spectrometry. Associations between 25[OH]D and CMR were modeled using weighted linear regression with robust standard error estimates.
Setting
Individuals born in Jerusalem during 1974-1976.
Subjects
Participants of the Jerusalem Perinatal Study (n = 1,204) interviewed and examined at age 32 years. Participants were oversampled for low and high birthweight and for maternal pre-pregnancy obesity.
Results
Mean total 25[OH]D concentration among participants was 21.7 ng/mL (SD 8.9). Among males, 25[OH]D was associated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (natural log-transformed, β = -0.011, p = 0.004) after adjustment for body mass index. However, these associations were not present among females (p for sex interaction = 0.005).
Conclusions
We found evidence for inverse associations of 25[OH]D with markers of insulin resistance among males, but not females, in a health, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex specific effects of vitamin D on CMR are warranted.
doi:10.1017/S1368980014001475
PMCID: PMC4592940  PMID: 25145881
20.  Diabetic Kidney Disease: A Report From an ADA Consensus Conference 
Diabetes Care  2014;37(10):2864-2883.
The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
doi:10.2337/dc14-1296
PMCID: PMC4170131  PMID: 25249672
21.  Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.
Study Design
Retrospective cohort study.
Setting & Participants
6380 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73m2 using the CKD-EPI (CKD Epidemiology Collaboration) creatinine–cystatin C equation.
Predictors
Serum bicarbonate concentrations.
Outcomes
Rapid kidney function decline (eGFR decline >5% per year) and incident reduced eGFR (eGFR<60 mL/min/1.73 m2 with minimum rate of eGFR loss of 1 mL/min/1.73 m2 per year).
Results
The average bicarbonate concentration was 23.2 ± 1.8 mEq/L. 1730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%–20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03–1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate <21mEq/L relative to 23–24 mEq/L was 1.35 (95% CI, 1.05–1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83–1.62) for incident reduced eGFR.
Limitations
Etiology of metabolic acidosis cannot be determined in this study.
Conclusions
Lower serum bicarbonate concentrations are independently associated with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with a baseline eGFR >60 mL/min/1.73 m2. If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria, or may have a causal role in the development of an eGFR <60 mL/min/1.73 m2.
doi:10.1053/j.ajkd.2014.05.008
PMCID: PMC4177290  PMID: 24953891
serum bicarbonate; metabolic acidosis; chronic kidney disease (CKD); kidney function; renal disease; disease progression; kidney disease trajectory
22.  Estimated GFR and Circulating 24,25-Dihydroxyvitamin D3 Concentration: A Participant-Level Analysis of 5 Cohort Studies and Clinical Trials 
Background
Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25(OH)D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFR.
Study Design
Cross-sectional study.
Setting & Participants
9596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1193), Multi-Ethnic Study of Atherosclerosis (N=6470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).
Predictor
eGFR.
Outcome
Circulating 24,25(OH)2D3 concentration.
Measurements
GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.
Results
Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64–0.88). This correlation was weaker with lower eGFR. Moreover, the increment in 24,25(OH)2D3 associated with higher 25(OH)D3 (“slope”) was lower with lower eGFR: 2.06 (95% CI, 2.01–2.10), 1.77 (95% CI, 1.74–1.81), 1.55 (95% CI, 1.48–1.62), 1.17 (95% CI, 1.05–1.29), 0.92 (95% CI, 0.74–1.10), 0.61 (95% CI, 0.22–1.00), and 0.37 (95% CI, 0.35–0.39) ng/mL 24,25(OH)2D3 per 10 ng/mL 25(OH)D3 for eGFR ≥90, 60–89, 45–59, 30–44, 15–29, and <15 mL/min/1.73 m2 and ESRD treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentration was 2.92 (95% CI, 2.87–2.96), 2.68 (95% CI, 2.64–2.72), 2.35 (95% CI, 2.26–2.45), 1.92 (95% CI, 1.74–2.10), 1.69 (95% CI, 1.43–1.95), 1.14 (95% CI, 0.62–1.66), and 1.04 (95% CI,1.02–1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and the circulating concentrations of parathyroid hormone and fibroblast growth factor 23 more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.
Limitations
Lack of direct pharmacokinetic measurements of vitamin D catabolism.
Conclusions
Lower eGFR is strongly associated with reduced vitamin D catabolism as measured by circulating 24,25(OH)2D3 concentration.
doi:10.1053/j.ajkd.2014.02.015
PMCID: PMC4111986  PMID: 24703961
decreased renal function; low estimated glomerular filtration rate; vitamin D catabolism; 1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D3; active vitamin D; chronic kidney disease (CKD); biomarker
23.  Fibroblast Growth Factor-23 and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) 
Circulation  2014;130(4):298-307.
Background
Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.
Methods and Results
We tested associations of circulating FGF-23 concentration with incident AF among 6,398 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 1,350 participants in the Cardiovascular Health Study (CHS), all free of clinical cardiovascular disease at baseline. Over 7.7 and 8.0 years median follow-up, we observed 291 and 229 incident AF events in MESA and CHS, respectively. In multivariable Cox proportional hazards models, each two-fold higher FGF-23 concentration was associated with a 41% higher risk of incident AF in MESA (HR 1.41 [95% CI 1.13-1.76], p=0.003) and a 30% higher risk of incident AF in CHS (HR 1.30 [95% CI 1.05-1.61], p=0.016), adjusting for potential confounding characteristics including kidney disease. Serum phosphate concentration was significantly associated with incident AF in MESA (HR 1.15 per 0.5 mg/dL [CI 1.02-1.31], p-value=0.023) but not CHS. In MESA, an association of low estimated glomerular filtration rate with incident AF was partially attenuated by adjusting for FGF-23.
Conclusions
Higher circulating FGF-23 concentration is associated with incident AF and may, in part, explain the link between chronic kidney disease and AF.
doi:10.1161/CIRCULATIONAHA.113.005499
PMCID: PMC4108550  PMID: 24920722
atrial fibrillation; fibroblast growth factor; mineral; chronic kidney disease
24.  25-hydroxyvitamin D and Parathyroid Hormone Levels do not Predict Changes in Carotid Arterial Stiffness: The Multi-Ethnic Study of Atherosclerosis 
Objective
To evaluate the impacts of vitamin D and parathyroid hormone (PTH) on longitudinal changes in arterial stiffness.
Approach and Results
Distensibility coefficient (DC) and Young’s elastic modulus (YEM) of the right common carotid artery were evaluated at baseline and after a mean (standard deviation) of 9.4 (0.5) years in 2,580 MESA participants. Cross-sectional and longitudinal associations were evaluated using multivariable linear regression and analysis of covariance. At baseline, participants were 60.1 (9.4) years old (54% female; 26% Black, 20% Hispanic, 14% Chinese). Mean annualized 25(OH)D was <20 ng/dL in 816 and PTH was >65 pg/dL in 285 participants. In cross-sectional analyses, low 25(OH)D (<20 ng/ml) was not associated with stiffer arteries after adjustment for cardiovascular disease (CVD) risk factors (p>0.4). PTH >65 pg/ml was associated with stiffer arteries after adjustment for CVD risk factors, other than systolic blood pressure (SBP) (DC: β=−2.4×10−4 mmHg−1, p=0.003; YEM: β=166 mmHg, p=0.01), but after adjustment for SBP, these associations no longer were statistically significant. Longitudinal arterial stiffening was associated with older age (p<0.0001), higher SBP (p<0.008), and use of antihypertensive medications (p<0.006), but not with 25(OH)D or PTH (p>0.1).
Conclusions
Carotid arterial stiffness is not associated with low 25(OH)D concentrations. Cross-sectional associations between arterial stiffness and high PTH were attenuated by SBP. After nearly a decade of follow-up, neither baseline PTH nor 25(OH)D concentrations were associated with progression of carotid arterial stiffness.
doi:10.1161/ATVBAHA.113.302605
PMCID: PMC4008121  PMID: 24700125
Arterial stiffness; Cardiovascular disease; Carotid arteries; Parathyroid hormone; Vitamin D; Young’s elastic modulus
25.  Fibroblast Growth Factor-23 and Cardiovascular Disease in the General Population: The Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2014;7(3):409-417.
Background
Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
Methods and Results
We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
Conclusions
Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
doi:10.1161/CIRCHEARTFAILURE.113.000952
PMCID: PMC4031265  PMID: 24668259
Fibroblast growth factor-23; FGF-23; left ventricular mass; left ventricular hypertrophy; coronary artery calcium; carotid intima-media thickness; heart failure; coronary heart disease; stroke; cardiovascular disease

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