TY - JOUR T1 - Antihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis. JF - Int J Biostat Y1 - 2011 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - van der Laan, Mark J A1 - Delaney, Joseph A C A1 - Peralta, Carmen A A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Shlipak, Michael G KW - Aged KW - Antihypertensive Agents KW - Cystatin C KW - Data Interpretation, Statistical KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney KW - Longitudinal Studies KW - Male KW - Models, Statistical AB -

BACKGROUND: The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.

METHODS: Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989-1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.

RESULTS: The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m(2). In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m(2) per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (-0.13, 4.59) ml/min/1.73 m(2) per year slower decline in eGFR.

CONCLUSION: In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.

VL - 7 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22049266?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. JF - Am J Hum Genet Y1 - 2016 A1 - Liu, Ching-Ti A1 - Raghavan, Sridharan A1 - Maruthur, Nisa A1 - Kabagambe, Edmond Kato A1 - Hong, Jaeyoung A1 - Ng, Maggie C Y A1 - Hivert, Marie-France A1 - Lu, Yingchang A1 - An, Ping A1 - Bentley, Amy R A1 - Drolet, Anne M A1 - Gaulton, Kyle J A1 - Guo, Xiuqing A1 - Armstrong, Loren L A1 - Irvin, Marguerite R A1 - Li, Man A1 - Lipovich, Leonard A1 - Rybin, Denis V A1 - Taylor, Kent D A1 - Agyemang, Charles A1 - Palmer, Nicholette D A1 - Cade, Brian E A1 - Chen, Wei-Min A1 - Dauriz, Marco A1 - Delaney, Joseph A C A1 - Edwards, Todd L A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Lange, Leslie A A1 - Leong, Aaron A1 - Liu, Jingmin A1 - Liu, Yongmei A1 - Nayak, Uma A1 - Patel, Sanjay R A1 - Porneala, Bianca C A1 - Rasmussen-Torvik, Laura J A1 - Snijder, Marieke B A1 - Stallings, Sarah C A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Biggs, Mary L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Chen, Guanjie A1 - Correa, Adolfo A1 - Couper, David J A1 - Crawford, Dana C A1 - Cushman, Mary A1 - Eicher, John D A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fu, Yi-Ping A1 - Goodarzi, Mark O A1 - Gottesman, Omri A1 - Hara, Kazuo A1 - Harris, Tamara B A1 - Jensen, Richard A A1 - Johnson, Andrew D A1 - Jhun, Min A A1 - Karter, Andrew J A1 - Keller, Margaux F A1 - Kho, Abel N A1 - Kizer, Jorge R A1 - Krauss, Ronald M A1 - Langefeld, Carl D A1 - Li, Xiaohui A1 - Liang, Jingling A1 - Liu, Simin A1 - Lowe, William L A1 - Mosley, Thomas H A1 - North, Kari E A1 - Pacheco, Jennifer A A1 - Peyser, Patricia A A1 - Patrick, Alan L A1 - Rice, Kenneth M A1 - Selvin, Elizabeth A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Tajuddin, Salman M A1 - Vaidya, Dhananjay A1 - Wren, Mary P A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Julie T A1 - Zmuda, Joseph M A1 - Zonderman, Alan B A1 - Zwinderman, Aeilko H A1 - Adeyemo, Adebowale A1 - Boerwinkle, Eric A1 - Ferrucci, Luigi A1 - Hayes, M Geoffrey A1 - Kardia, Sharon L R A1 - Miljkovic, Iva A1 - Pankow, James S A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Wagenknecht, Lynne E A1 - Arnett, Donna K A1 - Chen, Yii-Der Ida A1 - Nalls, Michael A A1 - Province, Michael A A1 - Kao, W H Linda A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Loos, Ruth J F A1 - Dupuis, Josée A1 - Rich, Stephen S A1 - Florez, Jose C A1 - Rotter, Jerome I A1 - Morris, Andrew P A1 - Meigs, James B AB -

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract ER - TY - JOUR T1 - The association of prediagnosis social support with survival after heart failure in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 2020 A1 - Kaiser, Paulina A1 - Allen, Norrina A1 - Delaney, Joseph A C A1 - Hirsch, Calvin H A1 - Carnethon, Mercedes A1 - Arnold, Alice M A1 - Odden, Michelle C AB -

PURPOSE: Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure.

METHODS: We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989-1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure.

RESULTS: After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null.

CONCLUSIONS: These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.

VL - 42 ER - TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - HGG Adv Y1 - 2021 A1 - Sun, Daokun A1 - Richard, Melissa A1 - Musani, Solomon K A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Chai, Jin Fang A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Harris, Sarah E A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Roux, Ana V Diez A1 - Dörr, Marcus A1 - Faul, Jessica D A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Grabe, Hans Jörgen A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jonas, Jost Bruno A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - O'Connell, Jeff R A1 - Palmas, Walter R A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Råback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Rice, Kenneth A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Deary, Ian J A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - Weir, David R A1 - Zheng, Wei A1 - Evans, Michele K A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Sim, Xueling A1 - Bierut, Laura A1 - Rotter, Jerome I A1 - Kardia, Sharon L R A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

VL - 2 IS - 1 ER - TY - JOUR T1 - Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). JF - BMC Cardiovasc Disord Y1 - 2021 A1 - Delaney, Joseph A C A1 - Olson, Nels C A1 - Sitlani, Colleen M A1 - Fohner, Alison E A1 - Huber, Sally A A1 - Landay, Alan L A1 - Heckbert, Susan R A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Feinstein, Matt A1 - Doyle, Margaret F AB -

BACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP).

METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level.

RESULTS: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14CD16) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 T helper cell subsets with average systolic blood pressure.

CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

VL - 21 IS - 1 ER - TY - JOUR T1 - Immune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis. JF - Heart Rhythm Y1 - 2022 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Feinstein, Matthew J A1 - Olson, Nels C A1 - Heckbert, Susan R A1 - Huber, Sally A A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Delaney, Joseph A C ER - TY - JOUR T1 - Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. JF - Calcif Tissue Int Y1 - 2023 A1 - Elam, Rachel E A1 - Bůzková, Petra A1 - Delaney, Joseph A C A1 - Fink, Howard A A1 - Barzilay, Joshua I A1 - Carbone, Laura D A1 - Saha, Rick A1 - Robbins, John A A1 - Mukamal, Kenneth J A1 - Valderrábano, Rodrigo J A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Olson, Nels C A1 - Huber, Sally A A1 - Doyle, Margaret F A1 - Landay, Alan L A1 - Cauley, Jane A AB -

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

ER - TY - JOUR T1 - Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2023 A1 - Kalani, Rizwan A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Elkind, Mitchell S V A1 - Floyd, James S A1 - Gerszten, Robert E A1 - Shojaie, Ali A1 - Heckbert, Susan R A1 - Bis, Joshua C A1 - Austin, Thomas R A1 - Tirschwell, David L A1 - Delaney, Joseph A C A1 - Longstreth, W T AB -

BACKGROUND: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).

METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.

RESULTS: Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.

CONCLUSIONS: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

ER -