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1.  BLOOLD METHYLMICS IN RESPONSE TO ARSENIC EXPOSURE IN A LOW–EXPOSED US POPULATION 
Exposure to arsenic (As) has been associated with cancers, CVD, and neurological disorder. To explore the possible underlying epigenetic mechanisms, a genome-wide study was conducted in low exposed healthy individuals. This study was nested within a prospective study of Coronary Artery Risk Development in Young Adults (CARDIA) by randomly selecting 46 non-smoker and non-diabetic White participants with low (N=23) and high (N=23) As exposure. based on toenail total As measures at examination year 2. We conducted methylomic profiling of white blood cell DNA collected at examination year 15 using the Illumina HumanMethylation450 BeadChip. Multivariate linear regression models were fitted to evaluate the associations between As exposure status and DNA methylation levels at each CpG site. We identified 29 CpG sites with methylation levels associated with As exposure status at a nominal p-value less than 0.0001. Some genes are known to be involved in cancers, CVD, and neurological disorder. Pathway analyses further revealed several canonical pathways relevant to the etiology of As-associated diseases. We demonstrated that As exposure is prospectively associated with DNA methylation levels in a number of genes implicated in As-associated diseases. Further studies are required for elucidating the role of epigenetic alterations in the pathogenesis of these diseases.
doi:10.1038/jes.2013.89
PMCID: PMC4167014  PMID: 24368509
arsenic exposure; methylomic profiling; prospective association
2.  Left Ventricular Global Function Index By Magnetic Resonance Imaging- A Novel Marker for Assessment of Cardiac Performance for the Prediction Of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(4):770-778.
LV function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multi-ethnic population of men and women without history of cardiovascular diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance (CMR) study and were followed up for a median of 7.2 years. The LVGFI by CMR was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure (HF), hard CV events and a combined endpoint of all CV events after adjustment for established risk factors, calcium score and biomarkers. A total of 579 (11.6%) incident events were observed during the follow-up period. In adjusted models, the end points of HF, hard CV events and all events were all significantly associated with LVGFI (HF, hazard ratio [HR]= 0.64, p<0.0001; hard CV events, HR=0.79, p=0.007; all events, HR=0.79, p<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident heart failure, hard CV events and a composite endpoint including all events in this multiethnic cohort.
doi:10.1161/HYPERTENSIONAHA.111.198028
PMCID: PMC3691067  PMID: 23424238
left ventricle; ejection fraction; heart failure; LV mass; LV global function index
3.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
Köttgen, Anna | Albrecht, Eva | Teumer, Alexander | Vitart, Veronique | Krumsiek, Jan | Hundertmark, Claudia | Pistis, Giorgio | Ruggiero, Daniela | O’Seaghdha, Conall M | Haller, Toomas | Yang, Qiong | Tanaka, Toshiko | Johnson, Andrew D | Kutalik, Zoltán | Smith, Albert V | Shi, Julia | Struchalin, Maksim | Middelberg, Rita P S | Brown, Morris J | Gaffo, Angelo L | Pirastu, Nicola | Li, Guo | Hayward, Caroline | Zemunik, Tatijana | Huffman, Jennifer | Yengo, Loic | Zhao, Jing Hua | Demirkan, Ayse | Feitosa, Mary F | Liu, Xuan | Malerba, Giovanni | Lopez, Lorna M | van der Harst, Pim | Li, Xinzhong | Kleber, Marcus E | Hicks, Andrew A | Nolte, Ilja M | Johansson, Asa | Murgia, Federico | Wild, Sarah H | Bakker, Stephan J L | Peden, John F | Dehghan, Abbas | Steri, Maristella | Tenesa, Albert | Lagou, Vasiliki | Salo, Perttu | Mangino, Massimo | Rose, Lynda M | Lehtimäki, Terho | Woodward, Owen M | Okada, Yukinori | Tin, Adrienne | Müller, Christian | Oldmeadow, Christopher | Putku, Margus | Czamara, Darina | Kraft, Peter | Frogheri, Laura | Thun, Gian Andri | Grotevendt, Anne | Gislason, Gauti Kjartan | Harris, Tamara B | Launer, Lenore J | McArdle, Patrick | Shuldiner, Alan R | Boerwinkle, Eric | Coresh, Josef | Schmidt, Helena | Schallert, Michael | Martin, Nicholas G | Montgomery, Grant W | Kubo, Michiaki | Nakamura, Yusuke | Tanaka, Toshihiro | Munroe, Patricia B | Samani, Nilesh J | Jacobs, David R | Liu, Kiang | D’Adamo, Pio | Ulivi, Sheila | Rotter, Jerome I | Psaty, Bruce M | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Devuyst, Olivier | Navarro, Pau | Kolcic, Ivana | Hastie, Nicholas | Balkau, Beverley | Froguel, Philippe | Esko, Tõnu | Salumets, Andres | Khaw, Kay Tee | Langenberg, Claudia | Wareham, Nicholas J | Isaacs, Aaron | Kraja, Aldi | Zhang, Qunyuan | Wild, Philipp S | Scott, Rodney J | Holliday, Elizabeth G | Org, Elin | Viigimaa, Margus | Bandinelli, Stefania | Metter, Jeffrey E | Lupo, Antonio | Trabetti, Elisabetta | Sorice, Rossella | Döring, Angela | Lattka, Eva | Strauch, Konstantin | Theis, Fabian | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J | Bruinenberg, Marcel | Study, LifeLines Cohort | Stolk, Ronald P | Kooner, Jaspal S | Zhang, Weihua | Winkelmann, Bernhard R | Boehm, Bernhard O | Lucae, Susanne | Penninx, Brenda W | Smit, Johannes H | Curhan, Gary | Mudgal, Poorva | Plenge, Robert M | Portas, Laura | Persico, Ivana | Kirin, Mirna | Wilson, James F | Leach, Irene Mateo | van Gilst, Wiek H | Goel, Anuj | Ongen, Halit | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, Andre G | Imboden, Medea | von Eckardstein, Arnold | Cucca, Francesco | Nagaraja, Ramaiah | Piras, Maria Grazia | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Ernst, Florian | Farrington, Susan M | Theodoratou, Evropi | Prokopenko, Inga | Stumvoll, Michael | Jula, Antti | Perola, Markus | Salomaa, Veikko | Shin, So-Youn | Spector, Tim D | Sala, Cinzia | Ridker, Paul M | Kähönen, Mika | Viikari, Jorma | Hengstenberg, Christian | Nelson, Christopher P | Consortium, CARDIoGRAM | Consortium, DIAGRAM | Consortium, ICBP | Consortium, MAGIC | Meschia, James F | Nalls, Michael A | Sharma, Pankaj | Singleton, Andrew B | Kamatani, Naoyuki | Zeller, Tanja | Burnier, Michel | Attia, John | Laan, Maris | Klopp, Norman | Hillege, Hans L | Kloiber, Stefan | Choi, Hyon | Pirastu, Mario | Tore, Silvia | Probst-Hensch, Nicole M | Völzke, Henry | Gudnason, Vilmundur | Parsa, Afshin | Schmidt, Reinhold | Whitfield, John B | Fornage, Myriam | Gasparini, Paolo | Siscovick, David S | Polašek, Ozren | Campbell, Harry | Rudan, Igor | Bouatia-Naji, Nabila | Metspalu, Andres | Loos, Ruth J F | van Duijn, Cornelia M | Borecki, Ingrid B | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J | Wolffenbuttel, Bruce H R | Chambers, John C | März, Winfried | Pramstaller, Peter P | Snieder, Harold | Gyllensten, Ulf | Wright, Alan F | Navis, Gerjan | Watkins, Hugh | Witteman, Jacqueline C M | Sanna, Serena | Schipf, Sabine | Dunlop, Malcolm G | Tönjes, Anke | Ripatti, Samuli | Soranzo, Nicole | Toniolo, Daniela | Chasman, Daniel I | Raitakari, Olli | Kao, W H Linda | Ciullo, Marina | Fox, Caroline S | Caulfield, Mark | Bochud, Murielle | Gieger, Christian
Nature genetics  2012;45(2):145-154.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
doi:10.1038/ng.2500
PMCID: PMC3663712  PMID: 23263486
4.  Gene-Centric Meta-Analysis of Lipid Traits in African, East Asian and Hispanic Populations 
PLoS ONE  2012;7(12):e50198.
Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10−7 and p = 1.5×10−6 respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10−12). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
doi:10.1371/journal.pone.0050198
PMCID: PMC3517599  PMID: 23236364
5.  Genetic Ancestry-Smoking Interactions and Lung Function in African Americans: A Cohort Study 
PLoS ONE  2012;7(6):e39541.
Background
Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans.
Methodology/Principal Findings
We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV1) per pack-year of smoking (−5.7 ml FEV1/ smoking pack-year) compared with smokers with lower African ancestry (−4.6 ml in FEV1/ smoking pack-year) (interaction P value  = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV1 decline in Health ABC and independently replicated in CARDIA.
Conclusions/Significance
African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.
doi:10.1371/journal.pone.0039541
PMCID: PMC3380861  PMID: 22737244
6.  Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study 
Fox, Ervin R. | Young, J. Hunter | Li, Yali | Dreisbach, Albert W. | Keating, Brendan J. | Musani, Solomon K. | Liu, Kiang | Morrison, Alanna C. | Ganesh, Santhi | Kutlar, Abdullah | Ramachandran, Vasan S. | Polak, Josef F. | Fabsitz, Richard R. | Dries, Daniel L. | Farlow, Deborah N. | Redline, Susan | Adeyemo, Adebowale | Hirschorn, Joel N. | Sun, Yan V. | Wyatt, Sharon B. | Penman, Alan D. | Palmas, Walter | Rotter, Jerome I. | Townsend, Raymond R. | Doumatey, Ayo P. | Tayo, Bamidele O. | Mosley, Thomas H. | Lyon, Helen N. | Kang, Sun J. | Rotimi, Charles N. | Cooper, Richard S. | Franceschini, Nora | Curb, J. David | Martin, Lisa W. | Eaton, Charles B. | Kardia, Sharon L.R. | Taylor, Herman A. | Caulfield, Mark J. | Ehret, Georg B. | Johnson, Toby | Chakravarti, Aravinda | Zhu, Xiaofeng | Levy, Daniel | Munroe, Patricia B. | Rice, Kenneth M. | Bochud, Murielle | Johnson, Andrew D. | Chasman, Daniel I. | Smith, Albert V. | Tobin, Martin D. | Verwoert, Germaine C. | Hwang, Shih-Jen | Pihur, Vasyl | Vollenweider, Peter | O'Reilly, Paul F. | Amin, Najaf | Bragg-Gresham, Jennifer L. | Teumer, Alexander | Glazer, Nicole L. | Launer, Lenore | Zhao, Jing Hua | Aulchenko, Yurii | Heath, Simon | Sõber, Siim | Parsa, Afshin | Luan, Jian'an | Arora, Pankaj | Dehghan, Abbas | Zhang, Feng | Lucas, Gavin | Hicks, Andrew A. | Jackson, Anne U. | Peden, John F. | Tanaka, Toshiko | Wild, Sarah H. | Rudan, Igor | Igl, Wilmar | Milaneschi, Yuri | Parker, Alex N. | Fava, Cristiano | Chambers, John C. | Kumari, Meena | JinGo, Min | van der Harst, Pim | Kao, Wen Hong Linda | Sjögren, Marketa | Vinay, D.G. | Alexander, Myriam | Tabara, Yasuharu | Shaw-Hawkins, Sue | Whincup, Peter H. | Liu, Yongmei | Shi, Gang | Kuusisto, Johanna | Seielstad, Mark | Sim, Xueling | Nguyen, Khanh-Dung Hoang | Lehtimäki, Terho | Matullo, Giuseppe | Wu, Ying | Gaunt, Tom R. | Charlotte Onland-Moret, N. | Cooper, Matthew N. | Platou, Carl G.P. | Org, Elin | Hardy, Rebecca | Dahgam, Santosh | Palmen, Jutta | Vitart, Veronique | Braund, Peter S. | Kuznetsova, Tatiana | Uiterwaal, Cuno S.P.M. | Campbell, Harry | Ludwig, Barbara | Tomaszewski, Maciej | Tzoulaki, Ioanna | Palmer, Nicholette D. | Aspelund, Thor | Garcia, Melissa | Chang, Yen-Pei C. | O'Connell, Jeffrey R. | Steinle, Nanette I. | Grobbee, Diederick E. | Arking, Dan E. | Hernandez, Dena | Najjar, Samer | McArdle, Wendy L. | Hadley, David | Brown, Morris J. | Connell, John M. | Hingorani, Aroon D. | Day, Ian N.M. | Lawlor, Debbie A. | Beilby, John P. | Lawrence, Robert W. | Clarke, Robert | Collins, Rory | Hopewell, Jemma C. | Ongen, Halit | Bis, Joshua C. | Kähönen, Mika | Viikari, Jorma | Adair, Linda S. | Lee, Nanette R. | Chen, Ming-Huei | Olden, Matthias | Pattaro, Cristian | Hoffman Bolton, Judith A. | Köttgen, Anna | Bergmann, Sven | Mooser, Vincent | Chaturvedi, Nish | Frayling, Timothy M. | Islam, Muhammad | Jafar, Tazeen H. | Erdmann, Jeanette | Kulkarni, Smita R. | Bornstein, Stefan R. | Grässler, Jürgen | Groop, Leif | Voight, Benjamin F. | Kettunen, Johannes | Howard, Philip | Taylor, Andrew | Guarrera, Simonetta | Ricceri, Fulvio | Emilsson, Valur | Plump, Andrew | Barroso, Inês | Khaw, Kay-Tee | Weder, Alan B. | Hunt, Steven C. | Bergman, Richard N. | Collins, Francis S. | Bonnycastle, Lori L. | Scott, Laura J. | Stringham, Heather M. | Peltonen, Leena | Perola, Markus | Vartiainen, Erkki | Brand, Stefan-Martin | Staessen, Jan A. | Wang, Thomas J. | Burton, Paul R. | SolerArtigas, Maria | Dong, Yanbin | Snieder, Harold | Wang, Xiaoling | Zhu, Haidong | Lohman, Kurt K. | Rudock, Megan E. | Heckbert, Susan R. | Smith, Nicholas L. | Wiggins, Kerri L. | Shriner, Daniel | Veldre, Gudrun | Viigimaa, Margus | Kinra, Sanjay | Prabhakaran, Dorairajan | Tripathy, Vikal | Langefeld, Carl D. | Rosengren, Annika | Thelle, Dag S. | MariaCorsi, Anna | Singleton, Andrew | Forrester, Terrence | Hilton, Gina | McKenzie, Colin A. | Salako, Tunde | Iwai, Naoharu | Kita, Yoshikuni | Ogihara, Toshio | Ohkubo, Takayoshi | Okamura, Tomonori | Ueshima, Hirotsugu | Umemura, Satoshi | Eyheramendy, Susana | Meitinger, Thomas | Wichmann, H.-Erich | Cho, Yoon Shin | Kim, Hyung-Lae | Lee, Jong-Young | Scott, James | Sehmi, Joban S. | Zhang, Weihua | Hedblad, Bo | Nilsson, Peter | Smith, George Davey | Wong, Andrew | Narisu, Narisu | Stančáková, Alena | Raffel, Leslie J. | Yao, Jie | Kathiresan, Sekar | O'Donnell, Chris | Schwartz, Steven M. | Arfan Ikram, M. | Longstreth, Will T. | Seshadri, Sudha | Shrine, Nick R.G. | Wain, Louise V. | Morken, Mario A. | Swift, Amy J. | Laitinen, Jaana | Prokopenko, Inga | Zitting, Paavo | Cooper, Jackie A. | Humphries, Steve E. | Danesh, John | Rasheed, Asif | Goel, Anuj | Hamsten, Anders | Watkins, Hugh | Bakker, Stephan J.L. | van Gilst, Wiek H. | Janipalli, Charles S. | Radha Mani, K. | Yajnik, Chittaranjan S. | Hofman, Albert | Mattace-Raso, Francesco U.S. | Oostra, Ben A. | Demirkan, Ayse | Isaacs, Aaron | Rivadeneira, Fernando | Lakatta, Edward G. | Orru, Marco | Scuteri, Angelo | Ala-Korpela, Mika | Kangas, Antti J. | Lyytikäinen, Leo-Pekka | Soininen, Pasi | Tukiainen, Taru | Würz, Peter | Twee-Hee Ong, Rick | Dörr, Marcus | Kroemer, Heyo K. | Völker, Uwe | Völzke, Henry | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Zelenika, Diana | Deloukas, Panos | Mangino, Massimo | Spector, Tim D. | Zhai, Guangju | Meschia, James F. | Nalls, Michael A. | Sharma, Pankaj | Terzic, Janos | Kranthi Kumar, M.J. | Denniff, Matthew | Zukowska-Szczechowska, Ewa | Wagenknecht, Lynne E. | Fowkes, Gerald R. | Charchar, Fadi J. | Schwarz, Peter E.H. | Hayward, Caroline | Guo, Xiuqing | Bots, Michiel L. | Brand, Eva | Samani, Nilesh J. | Polasek, Ozren | Talmud, Philippa J. | Nyberg, Fredrik | Kuh, Diana | Laan, Maris | Hveem, Kristian | Palmer, Lyle J. | van der Schouw, Yvonne T. | Casas, Juan P. | Mohlke, Karen L. | Vineis, Paolo | Raitakari, Olli | Wong, Tien Y. | Shyong Tai, E. | Laakso, Markku | Rao, Dabeeru C. | Harris, Tamara B. | Morris, Richard W. | Dominiczak, Anna F. | Kivimaki, Mika | Marmot, Michael G. | Miki, Tetsuro | Saleheen, Danish | Chandak, Giriraj R. | Coresh, Josef | Navis, Gerjan | Salomaa, Veikko | Han, Bok-Ghee | Kooner, Jaspal S. | Melander, Olle | Ridker, Paul M. | Bandinelli, Stefania | Gyllensten, Ulf B. | Wright, Alan F. | Wilson, James F. | Ferrucci, Luigi | Farrall, Martin | Tuomilehto, Jaakko | Pramstaller, Peter P. | Elosua, Roberto | Soranzo, Nicole | Sijbrands, Eric J.G. | Altshuler, David | Loos, Ruth J.F. | Shuldiner, Alan R. | Gieger, Christian | Meneton, Pierre | Uitterlinden, Andre G. | Wareham, Nicholas J. | Gudnason, Vilmundur | Rettig, Rainer | Uda, Manuela | Strachan, David P. | Witteman, Jacqueline C.M. | Hartikainen, Anna-Liisa | Beckmann, Jacques S. | Boerwinkle, Eric | Boehnke, Michael | Larson, Martin G. | Järvelin, Marjo-Riitta | Psaty, Bruce M. | Abecasis, Gonçalo R. | Elliott, Paul | van Duijn , Cornelia M. | Newton-Cheh, Christopher
Human Molecular Genetics  2011;20(11):2273-2284.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
doi:10.1093/hmg/ddr092
PMCID: PMC3090190  PMID: 21378095
7.  Relation of Left Ventricular Mass at Age 23 to 35 years to Global Left Ventricular Systolic Function 20 Years Later (From the Coronary Artery Risk Development in Young Adults Study) 
The American journal of cardiology  2013;113(2):377-383.
Left ventricular (LV) mass and LV ejection fraction (EF) are major independent predictors of future cardiovascular disease. The association of LV mass with future LVEF in younger populations has not been studied. We investigated the relation of LV mass index (LVMI) at age 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study that enrolled young adults in 1985–1986. We included participants with echocardiographic examinations at both years-5 and -25. LVMI and LVEF were assessed using M-mode echocardiography at year-5 and using both M-mode and 2-dimensional images at year-25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters both cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year-25 was 62%. Although there was no cross-sectional correlation between LVMI and LVEF at year-5, there was a small, but statistically significant negative correlation between LVMI at year-5 and LVEF 20 years later (r = −0.10, p < 0.0001); this inverse association persisted for LVMI in the multivariable model. High LVMI was an independent predictor of systolic dysfunction (LVEF < 50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, we have shown that LVMI in young adulthood in association with chronic risk exposure impacts systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
doi:10.1016/j.amjcard.2013.08.052
PMCID: PMC3901209  PMID: 24176073
left ventricular mass; left ventricular ejection fraction; echocardiography; left ventricular remodeling
8.  Longitudinal Effects of a Decade of Aging on Carotid Artery Stiffness: The Multi-Ethnic Study of Atherosclerosis 
Background and Purpose
Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multi-ethnic, longitudinal study.
Methods
Distensibility coefficient and Young’s elastic modulus of the right common carotid artery were calculated at baseline and after a mean (standard deviation) of 9.4 (0.5) years in 2,650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and analysis of covariance models.
Results
At baseline, participants were 59.9 (9.4) years old (53% female; 25% Black, 22% Hispanic, 14% Chinese). Young’s elastic modulus increased from 1,581 (927) to 1,749 (1,306) mmHg (p<0.0001) and distensibility coefficient decreased from 3.1 (1.3) to 2.7 (1.1) x 10−3 mmHg−1 (p<0.001), indicating progressive arterial stiffening. Young’s elastic modulus increased more among participants who were >75 years old at baseline (p<0.0001). In multivariable analyses, older age and less education independently predicted worsening Young’s elastic modulus and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of Young’s elastic modulus (β=360.2 mmHg, p=0.008). Starting antihypertensive medication after exam 1 was predictive of improvements in distensibility coefficient (β =1.1 x 10−4, mmHg−1; p=0.024).
Conclusions
Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in Young’s elastic modulus than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.
doi:10.1161/STROKEAHA.113.002649
PMCID: PMC3888489  PMID: 24253542
Aging; Carotid arteries; Elasticity; Hypertension; Cardiovascular disease risk factors
9.  No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects 
Baumert, Jens | Huang, Jie | McKnight, Barbara | Sabater-Lleal, Maria | Steri, Maristella | Chu, Audrey Y. | Trompet, Stella | Lopez, Lorna M. | Fornage, Myriam | Teumer, Alexander | Tang, Weihong | Rudnicka, Alicja R. | Mälarstig, Anders | Hottenga, Jouke-Jan | Kavousi, Maryam | Lahti, Jari | Tanaka, Toshiko | Hayward, Caroline | Huffman, Jennifer E. | Morange, Pierre-Emmanuel | Rose, Lynda M. | Basu, Saonli | Rumley, Ann | Stott, David J. | Buckley, Brendan M. | de Craen, Anton J. M. | Sanna, Serena | Masala, Marco | Biffar, Reiner | Homuth, Georg | Silveira, Angela | Sennblad, Bengt | Goel, Anuj | Watkins, Hugh | Müller-Nurasyid, Martina | Rückerl, Regina | Taylor, Kent | Chen, Ming-Huei | de Geus, Eco J. C. | Hofman, Albert | Witteman, Jacqueline C. M. | de Maat, Moniek P. M. | Palotie, Aarno | Davies, Gail | Siscovick, David S. | Kolcic, Ivana | Wild, Sarah H. | Song, Jaejoon | McArdle, Wendy L. | Ford, Ian | Sattar, Naveed | Schlessinger, David | Grotevendt, Anne | Franzosi, Maria Grazia | Illig, Thomas | Waldenberger, Melanie | Lumley, Thomas | Tofler, Geoffrey H. | Willemsen, Gonneke | Uitterlinden, André G. | Rivadeneira, Fernando | Räikkönen, Katri | Chasman, Daniel I. | Folsom, Aaron R. | Lowe, Gordon D. | Westendorp, Rudi G. J. | Slagboom, P. Eline | Cucca, Francesco | Wallaschofski, Henri | Strawbridge, Rona J. | Seedorf, Udo | Koenig, Wolfgang | Bis, Joshua C. | Mukamal, Kenneth J. | van Dongen, Jenny | Widen, Elisabeth | Franco, Oscar H. | Starr, John M. | Liu, Kiang | Ferrucci, Luigi | Polasek, Ozren | Wilson, James F. | Oudot-Mellakh, Tiphaine | Campbell, Harry | Navarro, Pau | Bandinelli, Stefania | Eriksson, Johan | Boomsma, Dorret I. | Dehghan, Abbas | Clarke, Robert | Hamsten, Anders | Boerwinkle, Eric | Jukema, J. Wouter | Naitza, Silvia | Ridker, Paul M. | Völzke, Henry | Deary, Ian J. | Reiner, Alexander P. | Trégouët, David-Alexandre | O'Donnell, Christopher J. | Strachan, David P. | Peters, Annette | Smith, Nicholas L.
PLoS ONE  2014;9(12):e111156.
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
doi:10.1371/journal.pone.0111156
PMCID: PMC4281156  PMID: 25551457
10.  Prognostic Value of Frontal QRS-T Angle in Patients without Clinical Evidence of Cardiovascular Disease (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;112(12):10.1016/j.amjcard.2013.08.017.
Abnormal frontal QRS-T angle on a 12 lead electrocardiogram (ECG) is associated with incident coronary heart disease and total mortality in a biracial cohort but there have been no studies to date examining QRS-T angle’s prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62) from MESA; a multi-ethnic cohort aged 45–84 free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead ECG’s. Frontal QRS-T axis was defined as normal (<75th percentile), borderline (75–95th percentile) or abnormal (≥ 95th percentile) and participants were followed for the composite endpoint of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris or heart failure. After 7.6 years of follow up there were 444 total events. Borderline ((HR 1.37 95% Confidence Interval (CI) (1.10,1.70)) and abnormal QRS-T angle (HR 2.2 95% CI (1.63, 2.97)) was associated with incident CVD events in multivariable-adjusted models. However, after adjusting for T wave abnormalities there was no statistically significant association of either borderline (HR 1.12 95% CI (0.90, 1.41)) or abnormal (HR 1.31 95% CI (0.93, 1.84)) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population and this increased risk is primarily mediated through T wave abnormalities. QRS-T angle provides an easily interpretable, continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction.
doi:10.1016/j.amjcard.2013.08.017
PMCID: PMC3863114  PMID: 24063831
Electrocardiography; risk assessment; cardiovascular disease
11.  Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: Objectives, Methods, and Cohort Description 
Clinical cardiology  2013;36(12):713-720.
Background
South Asians (individuals from India, Pakistani, Bangladesh, Nepal, and Sri Lanka) have high rates of cardiovascular disease which cannot be explained by traditional risk factors. There are no prospective cohort studies investigating antecedents of cardiovascular disease in South Asians.
Methods
The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is investigating the prevalence, correlates and outcomes associated with subclinical cardiovascular disease (CVD) in a population-based sample of South Asian men and women between ages 40 – 79 years from two U.S. clinical field centers. This cohort is similar in methods and measures to the Multi-Ethnic Study of Atherosclerosis to allow for efficient cross-ethnic comparisons. Measurements obtained at the baseline examination include sociodemographic information, lifestyle and psychosocial factors, standard CVD risk factors, oral glucose tolerance testing, electrocardiogram, assessment of microalbuminuria, ankle and brachial blood pressures, carotid intima media wall thickness using ultrasonagraphy, coronary artery calcium measurement and abdominal visceral fat using computed tomography. Blood samples will be assayed for biochemical risk factors.
Results
Between October 2010 and March 2013 we enrolled 906 South Asians with mean age of 55±9 years, 46% women, 98% immigrants who have lived 27±11 years in the US.
Conclusions
The sociodemographic characteristics of this cohort are representative of US South Asians. Participants are being followed with annual telephone calls for identification of CVD events including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, therapeutic interventions for CVD, and mortality.
doi:10.1002/clc.22219
PMCID: PMC3947423  PMID: 24194499
12.  Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age 
JAMA  2013;310(3):280-288.
IMPORTANCE
Younger individuals are experiencing a greater cumulative exposure to excess adiposity over their lifetime. However, few studies have determined the consequences of long-term obesity.
OBJECTIVE
To examine whether the duration of overall and abdominal obesity was associated with the presence and 10-year progression of coronary artery calcification (CAC), a subclinical predictor of coronary heart disease.
DESIGN, SETTING, AND PARTICIPANTS
Prospective study of 3275 white and black adults aged 18 to 30 years at baseline in 1985–1986 who did not initially have overall obesity (body mass index [BMI] ≥30) or abdominal obesity (men: waist circumference [WC] >102 cm; women: >88 cm) in the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants completed computed tomography scanning for the presence of CAC during the 15-, 20-, or 25-year follow-up examinations. Duration of overall and abdominal obesity was calculated using repeat measurements of BMI and WC, respectively, performed 2, 5, 7, 10, 15, 20, and 25 years after baseline.
MAIN OUTCOMES AND MEASURES
Presence of CAC was measured by computed tomography at the year 15 (2000–2001), year 20 (2005–2006), or year 25 (2010–2011) follow-up examinations. Ten-year progression of CAC (2000–2001 to 2010–2011) was defined as incident CAC in 2010–2011 or an increase in CAC score of 20 Agatston units or greater.
RESULTS
During follow-up, 40.4% and 41.0% developed overall and abdominal obesity, respectively. Rates of CAC per 1000 person-years were higher for those who experienced more than 20 years vs 0 years of overall obesity (16.0 vs 11.0, respectively) and abdominal obesity (16.7 vs 11.0). Approximately 25.2% and 27.7% of those with more than 20 years of overall and abdominal obesity, respectively, experienced progression of CAC vs 20.2% and 19.5% of those with 0 years. After adjustment for BMI or WC and potential confounders, the hazard ratios for CAC for each additional year of overall or abdominal obesity were 1.02 (95% CI, 1.01–1.03) and 1.03 (95% CI, 1.02–1.05), respectively. The adjusted odds ratios for CAC progression were 1.04 (95% CI, 1.01–1.06) and 1.04 (95% CI, 1.01–1.07), respectively. Associations were attenuated but largely persisted following additional adjustment for potential intermediate metabolic factors during follow-up.
CONCLUSIONS AND RELEVANCE
Longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. Preventing or at least delaying the onset of obesity in young adulthood may lower the risk of developing atherosclerosis through middle age.
doi:10.1001/jama.2013.7833
PMCID: PMC4226407  PMID: 23860986
13.  PROGENITOR CELL RELEASE PLUS EXERCISE TO IMPROVE FUNCTIONAL PERFORMANCE IN PERIPHERAL ARTERY DISEASE: THE PROPEL STUDY 
Contemporary clinical trials  2013;36(2):502-509.
Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.
doi:10.1016/j.cct.2013.09.011
PMCID: PMC3939047  PMID: 24080099
14.  Association between Anxiety Levels and Weight Change in the Multiethnic Study of Atherosclerosis 
Journal of Obesity  2014;2014:894627.
Objective. To examine the association between anxiety and weight change in a multiethnic cohort followed for approximately 10 years. Methods. The study population consisted of participants of the multiethnic study of atherosclerosis who met specified inclusion criteria (n = 5,799). Weight was measured at baseline and four subsequent follow-up exams. Anxiety was analyzed as sex-specific anxiety quartiles (QANX). The relationship between anxiety level and weight change was examined using a mixed-effect model with weight as the dependent variable, anxiety and time as the independent variables, and adjusted for covariates. Results. Average annual weight change (range) was −0.17 kg (−6.04 to 4.38 kg) for QANX 1 (lowest anxiety), −0.16 kg (−10.71 to 4.45 kg) for QANX 2, −0.15 kg (−8.69 to 6.39 kg) for QANX 3, and −0.20 kg (−7.12 to 3.95 kg) for QANX 4 (highest anxiety). No significant association was noted between QANX and weight change. However, the highest QANX was associated with a −2.48 kg (95% CI = −3.65, −1.31) lower baseline weight compared to the lowest QANX after adjustment for all covariates. Conclusions. Among adults, age 45–84, higher levels of anxiety, defined by the STPI trait anxiety scale, are associated with lower average baseline weight but not with weight change.
doi:10.1155/2014/894627
PMCID: PMC4206924  PMID: 25374677
15.  Incidence of Type 2 Diabetes by Place of Birth in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Incidence of diabetes among US foreign-born individuals is not well studied. Data were from the Multi Ethnic Study of Atherosclerosis. Cox proportional hazards regression was used to examine diabetes risk by race/ethnicity, place of birth, and duration of residence among foreign-born. Foreign-born Latinos had a higher risk of incident diabetes compared to US-born Latinos (hazard ratio (HR) 1.79 [95 % confidence interval (CI) 1.00–3.21]). Latinos born in Mexico (HR, 2.26 [95 % CI, 1.18–4.33]) had higher risk of incident diabetes compared to US-born Latinos. Foreign-born living in the US ≥20 years had a higher adjusted risk of incident diabetes compared to those in the US for <20 years (HR, 1.60 [95 % CI, 1.05–2.55]). Incident diabetes may be higher among foreign-born compared to native born; incident diabetes may also be higher among those immigrants who have lived in the US for longer periods of time. Future studies should characterize individuals by race/ethnicity and place of birth to account for differences in biology and time spent in the US.
doi:10.1007/s10903-012-9683-6
PMCID: PMC4039384  PMID: 22833256
Immigrant; Foreign-born; Diabetes incidence; Latino; Chinese
16.  Antiphospholipid antibodies and sub-clinical atherosclerosis in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort 
Objective and design
Antiphospholipid antibodies (APA) have been associated with clinical cardiovascular disease, but it remains unclear whether APA are associated with sub-clinical atherosclerosis. This study examined the relationship between APA and sub-clinical atherosclerosis, measured as coronary artery calcification (CAC), in participants from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Subjects and method
2,203 black and white participants with sera available from the CARDIA year 7 examination and CAC measured by computed tomography at years 15 or 20 were selected.
Results
Anti-β2-glycoprotein I (anti-β2-GPI) immunoglobulin (Ig) M, IgG, and IgA were positive in 7.0, 1.4, and 1.8 % of participants, respectively; anti-cardiolipin (aCL) IgM and IgG were positive in 1.5 and 1.0 %, respectively. 9.5 % of participants had CAC score >0 at year 15. Anti-β2-GPI IgM, IgG, IgA, and aCL IgG positivity were associated with CAC >0 at year 15 after adjustment for traditional cardiovascular risk factors; [odds ratios (95 % confidence intervals) were 1.7 (1.0, 3.1), 6.4 (2.4, 16.8), 5.6 (2.3, 13.2), and 5.1 (1.4, 18.6), respectively]. Anti-β2-GPI IgG was associated with year 20 CAC >0, and anti-β2-GPI IgA and aCL IgG were marginally associated.
Conclusions
These findings indicate that APA positivity during young adulthood is a risk factor for subsequent sub-clinical atherosclerosis and might play a role in the pathogenesis of atherosclerosis.
doi:10.1007/s00011-013-0652-x
PMCID: PMC4122510  PMID: 23959159
Antiphospholipid antibodies; Cardiovascular disease; Coronary atherosclerosis; Coronary artery calcification; EBCT; MDCT
17.  Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis 
Background
Data on the relations of different types of fish meals and long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) with measures of atherosclerosis are sparse.
Objective
We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis.
Design
A cross-sectional study was conducted in 5,488 multiethnic adults aged 45–84 years and free of clinical cardiovascular disease. Diet was assessed using self-administered food frequency questionnaires. Subclinical atherosclerosis was determined by common carotid intima-media thickness (cCIMT, >80th percentile), internal CIMT (iCIMT, >80th percentile), coronary artery calcium score (CAC, >0) or ankle-brachial index (ABI, <0.90), respectively.
Results
After adjustment for potential confounders, intakes of long-chain n-3 PUFAs and non-fried (broiled, steamed, baked or raw) fish were inversely related to subclinical atherosclerosis determined by cCIMT but not iCIMT, CAC or ABI. The multivariable odds ratio comparing the highest to the lowest quartile of dietary exposures in relation to subclinical atherosclerosis determined by cCIMT was 0.69 (95% CI: 0.55, 0.86; p for trend<0.01) for n-3 PUFA intake, 0.80 (95% CI: 0.64, 1.01; p=0.054) for non-fried fish and 0.90 (95% CI: 0.73, 1.10; p=0.33) for fried fish consumption.
Conclusions
This study indicates that dietary intake of long-chain n-3 PUFAs or non-fried fish is associated with lower prevalence of subclinical atherosclerosis classified by cCIMT although significant changes in iCIMT, CAC and ABI were not observed. Our findings also suggest that the association of fish and atherosclerosis may vary depending on the type of fish meal consumed and the measures of atherosclerosis.
PMCID: PMC4151325  PMID: 18842801
long-chain n-3 polyunsaturated fatty acids; fish; fish oil; biomarker; subclinical atherosclerosis; multi-ethnicities
18.  Longitudinal Determinants of Left Ventricular Mass and Geometry: The CARDIA Study 
Circulation. Cardiovascular imaging  2013;6(5):10.1161/CIRCIMAGING.112.000450.
Background
The purpose of this study was to identify determinants of 20 year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the CARDIA Study.
Methods and Results
We studied 2426 black and white men and women (54.7% Caucasian) aged 43-55 years with cardiovascular (CV) risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, gender, race, body mass index (BMI), change in BMI, mean arterial blood pressure, change in mean blood pressure, heart rate (HR), change in HR, tobacco use, presence of diabetes, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased while prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m2.7 were year 5 LVM, year 5 and change in BMI, year 5 and change in mean arterial pressure, year 5 and change in HR, baseline diabetes, and year 5 tobacco and/or alcohol use (overall r2 = 0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in BMI, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes. (overall r2 = 0.11).
Conclusions
Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult CV risk traits and change in these traits predicted change in LV mass/geometry.
doi:10.1161/CIRCIMAGING.112.000450
PMCID: PMC3873157  PMID: 23922005
echocardiography; left ventricular mass; blood pressure; obesity; risk assessment
19.  Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis 
Background
Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events.
Methods and Results
We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression.
Conclusions
Progression of CAC is associated with an increased risk for future hard and total CHD events.
doi:10.1016/j.jacc.2012.12.035
PMCID: PMC4148074  PMID: 23500326
coronary calcification; atherosclerosis; imaging; coronary heart disease
20.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
21.  Relation of Short-Term Heart Rate Variability to Incident Heart Failure (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(4):533-540.
Whether autonomic dysfunction predates the development of symptomatic heart failure (HF), or is simply a consequence of severe HF, is unknown. We hypothesized that reduced heart rate variability (HRV, a marker of abnormal autonomic function) at baseline is associated with incident HF in individuals free of clinically recognized cardiovascular disease. In the Multi- Ethnic Study of Atherosclerosis (MESA), a community-based study of subclinical cardiovascular disease in adults age 45–84 years, we measured HRV using a standard 30-second 12-lead electrocardiogram to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in R-R intervals (RMSSD). During a median follow-up of 7.6 years, 95 participants developed HF (incidence rate, 2.7/1000 person-years). After adjusting for age, sex, and ethnicity, hazard ratios for incident HF by RMSSD tertile were 2.4 (95% confidence interval [CI] 1.4–4.2) for the lowest tertile and 1.7 (95% CI 1.0–3.2) for the middle tertile (highest tertile = referent group; P for trend<0.001). The inverse association between RMSSD and incident HF persisted after adjustment for additional covariates, including diabetes, systolic blood pressure, heart rate, subclinical atherosclerosis, left ventricular endsystolic volume, interim myocardial infarction, and high sensitivity C-reactive protein (P for trend=0.009). A similarly significant inverse association was also observed for SDNN. In conclusion, baseline autonomic dysfunction is risk factor for the development of HF in a multiethnic cohort. These population-based findings implicate autonomic dysfunction in the pathogenesis of HF, and decreased short-term HRV may be a novel form of Stage B (asymptomatic) HF.
doi:10.1016/j.amjcard.2013.04.018
PMCID: PMC3735865  PMID: 23683953
autonomic nervous system; heart rate variability; heart failure; epidemiology
22.  Chicago Healthy Aging Study: Objectives and Design 
American Journal of Epidemiology  2013;178(4):635-644.
Investigators in the Chicago Healthy Aging Study (CHAS) reexamined 1,395 surviving participants aged 65–84 years (28% women) from the Chicago Heart Association Detection Project in Industry (CHA) 1967–1973 cohort whose cardiovascular disease (CVD) risk profiles were originally ascertained at ages 25–44 years. CHAS investigators reexamined 421 participants who were low-risk (LR) at baseline and 974 participants who were non-LR at baseline. LR was defined as having favorable levels of 4 major CVD risk factors: serum total cholesterol level <200 mg/dL and no use of cholesterol-lowering medication; blood pressure 120/≤80 mm Hg and no use of antihypertensive medication; no current smoking; and no history of diabetes or heart attack. While the potential of LR status in overcoming the CVD epidemic is being recognized, the long-term association of LR with objectively measured health in older age has not been examined. It is hypothesized that persons who were LR in 1967–1973 and have survived to older age will have less clinical and subclinical CVD, lower levels of inflammatory markers, and better physical performance/functioning and sleep quality. Here we describe the rationale, objectives, design, and implementation of this longitudinal epidemiologic study, compare baseline and follow-up characteristics of participants and nonparticipants, and highlight the feasibility of reexamining study participants after an extended period postbaseline with minimal interim contact.
doi:10.1093/aje/kwt020
PMCID: PMC3816341  PMID: 23669655
cardiovascular disease; epidemiologic studies; follow-up examination; risk factors
23.  Regional Left Ventricular Myocardial Dysfunction as a Predictor of Incident Cardiovascular Events 
Objectives
We sought to examine the prognostic value of subclinical left ventricular (LV) regional myocardial dysfunction (RMD) measured by magnetic resonance imaging (MRI) among asymptomatic individuals.
Background
LV RMD, defined as segmental impairment in systolic wall thickening, predicts adverse events in patients with established cardiovascular disease. MRI is highly accurate for detecting subtle RMD, of which the prognostic significance in a large multiethnic asymptomatic population is not known.
Methods
We used MRI to evaluate baseline regional LV myocardial function and prospectively followed a multiethnic (African American, Caucasian, Chinese, and Hispanic) population-based sample of 4,510 men and women without cardiovascular disease for a mean of 4.6 years. Regional myocardial dysfunction was defined as the presence of impaired systolic wall thickening (<10th percentile of segment-specific population distribution) in ≥2 contiguous LV segments within any given coronary artery territory.
Results
Baseline prevalence of RMD was 25.6%. Heart failure developed in 34 (1.0%) and 30 (2.6%) participants without and with RMD, respectively (p < 0.001). After adjustment for demographics and traditional risk factors, RMD remained independently associated with incident heart failure (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.56 to 4.39; p < 0.001). The relationship persisted after further adjustment for biomarkers of reported association with cardiovascular disease and indexes of global LV systolic dysfunction and hypertrophy (HR: 1.80; 95% CI: 1.02 to 3.20; p = 0.044). Similarly, RMD independently conferred an increased risk for hard coronary events (myocardial infarction or death from coronary heart disease; HR: 1.75; 95% CI: 1.06 to 2.89; p = 0.029), the composite of hard coronary events and stroke (HR: 1.72; 95% CI: 1.16 to 2.56; p = 0.005), and all atherosclerotic cardiovascular events (HR: 1.50; 95% CI: 1.09 to 2.07; p = 0.012).
Conclusions
Among an asymptomatic multiethnic American cohort, RMD is an independent predictor beyond traditional risk factors and global LV assessment for incident heart failure and atherosclerotic cardiovascular events. The clinical utility of early recognition of this subclinical phenotype deserves further investigation.
doi:10.1016/j.jacc.2010.10.060
PMCID: PMC4124734  PMID: 21511109
epidemiology; heart failure; magnetic resonance imaging; myocardial dysfunction; prognosis
24.  Blood Pressure Trajectories in Early Adulthood and Subclinical Atherosclerosis in Middle Age 
Importance
Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their impact on CVD risk are poorly characterized.
Objective
To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age.
Design
We used data from the CARDIA study from baseline in 1985-1986 through 25 years of follow-up (2010-2011).
Setting
Prospective cohort study
Participants
CARDIA participants were Black and White men and women aged 18-30 years at baseline.
Exposures
We examined systolic BP, diastolic BP, and mid-BP [calculated as (SBP+DBP)/2 and an important marker of CHD risk among younger populations] at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in SBP, DBP and mid-BP over time.
Main Outcome Measure
Coronary artery calcification greater than or equal to Agatston score of 100 Agatston units at year 25.
Results
Among 4,681 participants, we identified 5 distinct mid-BP trajectories: Low-Stable (22% [95% CI 19.9-23.7], n=987), Moderate-Stable (42% [40.3-44.3], n=2,085), Moderate-Increasing (12% [10.4-14.0], n=489), Elevated-Stable (19% [17.1-20.0], n=903) and Elevated-Increasing (5% [4.0-5.5], n=217). As compared to the Low-Stable group, trajectories with elevated BP levels had greater odds of having CAC >100. Adjusted odds ratios (95% CI) were 1.44 (0.83-2.49) for Moderate-Stable, 1.86 (0.91-3.82) for Moderate-Increasing, 2.28 (1.24-3.70) for Elevated-Stable, and 3.70 (1.66-8.20) for Elevated-Increasing groups. The adjusted prevalence of CAC ≥ 100 was 5.8% in the Low-Stable group. These ORs represent an absolute increase of 2.7%, 5%, 6.3% and 12.9% for the prevalence of CAC ≥100 for the Moderate-Stable, Moderate-Increasing, Elevated Stable and Elevated Increasing groups respectively as compared to the Low-Stable Group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories, but were attenuated for diastolic BP trajectories.
Conclusions and Relevance
BP trajectories throughout young adulthood vary and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
doi:10.1001/jama.2013.285122
PMCID: PMC4122296  PMID: 24496536
blood pressure; calcium; epidemiology; risk factors
25.  Physical Activity and High-Sensitivity C-Reactive Protein 
Background
Previous studies have suggested an inverse relationship between physical activity and markers of inflammation such as high-sensitivity C-reactive protein (hs-CRP). However, these were inconsistent, and few examined whether race and gender influenced the relationship. This study determined a cross-sectional association between physical activity and hs-CRP level in 6142 middle-aged white, Chinese, black, and Hispanic participants enrolled in the Multi Ethnic Study of Atherosclerosis in 2000–2002.
Methods
Combined moderate and vigorous physical activity was measured by self-reported leisure, conditioning, occupational, and household activities. ANCOVA was used to assess the association between moderate/vigorous physical activity and hs-CRP by gender and race.
Results
Hs-CRP was higher in women. Blacks had the highest hs-CRP, and Chinese participants had the lowest. Hs-CRP decreased across tertiles of moderate/vigorous physical activity in Hispanic men in models adjusted for age, education, study site, and physical activity questionnaire mode of administration (p=0.005) and further adjusted for smoking, infection, and aspirin use (p=0.020). The trend remained significant after further adjustment for BMI; blood pressure; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; diabetes; and the use of antihypertensive, statin, and diabetes medication (p=0.044). There was a downward trend in hs-CRP across tertiles of physical activity in black and white men, but the association was weaker. No clear trend was observed in any female racial/ethnic groups.
Conclusions
These findings suggest that the association between moderate/vigorous physical activity and hs-CRP differs by race and gender. Further studies are needed to confirm this and to examine the mechanisms for these race and gender differences.
doi:10.1016/j.amepre.2008.09.031
PMCID: PMC4122519  PMID: 19013748

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