PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (91)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
Document Types
1.  A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration 
de Vries, Paul S. | Chasman, Daniel I. | Sabater-Lleal, Maria | Chen, Ming-Huei | Huffman, Jennifer E. | Steri, Maristella | Tang, Weihong | Teumer, Alexander | Marioni, Riccardo E. | Grossmann, Vera | Hottenga, Jouke J. | Trompet, Stella | Müller-Nurasyid, Martina | Zhao, Jing Hua | Brody, Jennifer A. | Kleber, Marcus E. | Guo, Xiuqing | Wang, Jie Jin | Auer, Paul L. | Attia, John R. | Yanek, Lisa R. | Ahluwalia, Tarunveer S. | Lahti, Jari | Venturini, Cristina | Tanaka, Toshiko | Bielak, Lawrence F. | Joshi, Peter K. | Rocanin-Arjo, Ares | Kolcic, Ivana | Navarro, Pau | Rose, Lynda M. | Oldmeadow, Christopher | Riess, Helene | Mazur, Johanna | Basu, Saonli | Goel, Anuj | Yang, Qiong | Ghanbari, Mohsen | Willemsen, Gonneke | Rumley, Ann | Fiorillo, Edoardo | de Craen, Anton J. M. | Grotevendt, Anne | Scott, Robert | Taylor, Kent D. | Delgado, Graciela E. | Yao, Jie | Kifley, Annette | Kooperberg, Charles | Qayyum, Rehan | Lopez, Lorna M. | Berentzen, Tina L. | Räikkönen, Katri | Mangino, Massimo | Bandinelli, Stefania | Peyser, Patricia A. | Wild, Sarah | Trégouët, David-Alexandre | Wright, Alan F. | Marten, Jonathan | Zemunik, Tatijana | Morrison, Alanna C. | Sennblad, Bengt | Tofler, Geoffrey | de Maat, Moniek P. M. | de Geus, Eco J. C. | Lowe, Gordon D. | Zoledziewska, Magdalena | Sattar, Naveed | Binder, Harald | Völker, Uwe | Waldenberger, Melanie | Khaw, Kay-Tee | Mcknight, Barbara | Huang, Jie | Jenny, Nancy S. | Holliday, Elizabeth G. | Qi, Lihong | Mcevoy, Mark G. | Becker, Diane M. | Starr, John M. | Sarin, Antti-Pekka | Hysi, Pirro G. | Hernandez, Dena G. | Jhun, Min A. | Campbell, Harry | Hamsten, Anders | Rivadeneira, Fernando | Mcardle, Wendy L. | Slagboom, P. Eline | Zeller, Tanja | Koenig, Wolfgang | Psaty, Bruce M. | Haritunians, Talin | Liu, Jingmin | Palotie, Aarno | Uitterlinden, André G. | Stott, David J. | Hofman, Albert | Franco, Oscar H. | Polasek, Ozren | Rudan, Igor | Morange, Pierre-Emmanuel | Wilson, James F. | Kardia, Sharon L. R. | Ferrucci, Luigi | Spector, Tim D. | Eriksson, Johan G. | Hansen, Torben | Deary, Ian J. | Becker, Lewis C. | Scott, Rodney J. | Mitchell, Paul | März, Winfried | Wareham, Nick J. | Peters, Annette | Greinacher, Andreas | Wild, Philipp S. | Jukema, J. Wouter | Boomsma, Dorret I. | Hayward, Caroline | Cucca, Francesco | Tracy, Russell | Watkins, Hugh | Reiner, Alex P. | Folsom, Aaron R. | Ridker, Paul M. | O'Donnell, Christopher J. | Smith, Nicholas L. | Strachan, David P. | Dehghan, Abbas
Human Molecular Genetics  2015;25(2):358-370.
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
doi:10.1093/hmg/ddv454
PMCID: PMC4715256  PMID: 26561523
2.  Vitamin D deficiency and incident stroke risk in community-living black and white adults 
Background
Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals.
Methods
We examined the association of 25(OH)D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. Using a case-cohort study design, plasma 25(OH)D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort).
Results
In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25(OH)D concentrations were associated with higher risk of stroke (25(OH)D >30 ng/mL reference; 25(OH)D concentrations 20–30 ng/mL, hazard ratio [HR] 1.33, 95% confidence interval [95%CI] 0.89,1.96; 25(OH)D <20 ng/mL, HR 1.85, 95%CI 1.17,2.93). There were no statistically significant differences in the association of lower 25(OH)D with higher risk of stroke in black vs. white participants in fully adjusted models (HR comparing lowest vs. higher 25(OH)D category 2.62, 95%CI 1.18, 5.83 in blacks vs. 1.64, 95%CI 0.83, 3.24 in whites, Pinteraction=0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25(OH)D categories.
Discussion
Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race.
doi:10.1177/1747493015607515
PMCID: PMC4920062  PMID: 26763025
stroke; vitamin D; epidemiology
3.  Physical Activity, Physical Fitness and Leukocyte Telomere Length: the Cardiovascular Health Study 
Introduction
The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL), repetitive DNA sequences that may mark biologic aging, is not well-established. Few prior studies have been conducted in older adults, these were mainly cross-sectional, and few evaluated PF.
Methods
We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (age 73±5 y at baseline) in the Cardiovascular Health Study, having serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL; and changes in cumulatively averaged PA and PF against changes in TL.
Results
Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (p-trend=0.007, 0.04 respectively). In longitudinal analyses, no significant associations were observed between baseline PA and PF with change in TL. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.
Conclusions
Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.
doi:10.1249/MSS.0000000000000720
PMCID: PMC4648672  PMID: 26083773
elderly; exercise; fitness; biological aging; DNA
4.  Vitamin D, Fibroblast Growth Factor 23 and Incident Cognitive Impairment: Findings from the REGARDS Study 
PLoS ONE  2016;11(11):e0165671.
Vitamin D protects against cognitive decline in animals but evidence in humans has been inconsistent. Fibroblast growth factor 23 (FGF23) is a hormone that inhibits vitamin D activation yet few studies examined whether FGF23 is associated with cognitive impairment. The objective of this study was to examine associations of 25(OH)D and FGF23 with incident cognitive impairment in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years old. FGF23 and 25(OH)D were measured in 474 incident impairment cases and 561 controls. In multivariable-adjusted models, there were no significant associations of FGF23 with incident cognitive impairment. In analyses using clinically-relevant categories of 25(OH)D (< 20 ng/ml, 20–29.9 ng/ml, ≥30 ng/ml), there was no statistically significant association of lower 25(OH)D concentrations with odds of incident cognitive impairment in models adjusted for demographic, clinical, and laboratory variables and season of blood draw (tertile 1 [≥30 ng/ml] reference; tertile 2 [20–29.9 ng/ml], odds ratio [OR] 0.96, 95%CI 0.67, 1.38; tertile 3 [<20 ng/ml] OR 1.26, 95%CI 0.83, 1.91). When 25(OH)D was modeled as race-specific tertiles, there were no significant associations of 25(OH)D with incident cognitive impairment in whites, whereas lower 25(OH)D was associated with higher odds in blacks (tertile 1 [>23 ng/ml] reference; tertile 2 [15–23 ng/ml], OR 2.96, 95%CI 1.48,5.94; tertile 3 [<15 ng/ml] OR 2.40, 95%CI 1.07,5.40) in the fully adjusted model. In this cohort of older adults, lower race-specific tertiles of 25(OH)D were associated with higher incidence of cognitive impairment in black individuals but not white individuals. These data suggest that treating low 25(OH)D may be a novel strategy for addressing racial disparities in neurocognitive outcomes.
doi:10.1371/journal.pone.0165671
PMCID: PMC5094718  PMID: 27812184
5.  Validating laboratory results in a national observational cohort study without field centers: The Reasons for Geographic and Racial Differences in Stroke cohort 
Clinical biochemistry  2014;47(16-17):243-246.
Objectives
The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective cohort of 30,239 Americans in the contiguous United States; the first of this scale to use home visits to obtain, process, and ship biologic samples to a core laboratory. Pre-analytical factors resulting from this study design may affect the results of some laboratory assays. We investigated the impact of REGARDS processing on a variety of analytes.
Design and methods
In REGARDS, blood samples were processed in the field by technicians who were trained on standardized methods for phlebotomy and sample processing. Field processing included centrifugation using varying non-uniform equipment and shipping overnight on ice to the University of Vermont, where samples were re-centrifuged for 30,000 ×g-minutes and stored at −80 °C. We assessed the effects of REGARDS sample handling by processing split samples from 20 volunteers using either ideal procedures or simulated REGARDS procedures. Assays for 19 analytes for potential study in REGARDS were then run on both samples and results compared.
Results
Spearman correlation coefficients for analytes measured in ideal versus REGARDS processed samples ranged from 0.11 to 1.0. Thirteen of 19 analytes were highly correlated (>0.75), but platelet proteins were more variable.
Conclusions
Simulation of non-optimal field processing and shipment to a central laboratory showed high variability in analytes released by platelets. The majority of other analytes produced valid results, but platelet contamination in REGARDS samples makes measurement of platelet proteins unadvisable in these samples. Future analytes considered by REGARDS or similar studies should undergo similar pilot testing.
doi:10.1016/j.clinbiochem.2014.08.003
PMCID: PMC5038129  PMID: 25130959
Quality control; Blood chemical analysis; Biological markers; Blood specimen collection; Cohort studies
6.  Lipoprotein-Associated Phospholipase A2 and Risk of Incident Cardiovascular Disease in a Multi-Ethnic Cohort: The Multi Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;241(1):176-182.
Objective
Prospective studies reporting a positive association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis.
Methods
Lp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score>0 or carotid intima-media thickness value>80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death).
Results
516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01–1.26) for Lp-PLA2 activity and 1.10 (1.01–1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis.
Conclusion
In this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media.
doi:10.1016/j.atherosclerosis.2015.05.006
PMCID: PMC4504012  PMID: 26004387
Lipoprotein-associated Phospholipase A2; Cardiovascular Disease; Inflammation; Ethnicity; Biomarker
7.  Physical activity, sedentary behaviors and the incidence of type 2 diabetes mellitus: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
The association between physical activity (PA), sedentary behavior, and incident diabetes has been assessed in whites but is less well investigated in multiethnic populations.
Objective
To assess the association between PA, sedentary behavior, and incident diabetes in the Multi-Ethnic Study of Atherosclerosis.
Research design and methods
Incident diabetes was assessed among adults without prevalent baseline diabetes (2000–2002) at 5 in-person examinations between 2002 and 2012. Baseline PA (moderate, vigorous, and exercise-specific; metabolic equivalents of task-hours/week) and sedentary behaviors (television watching, reading; hours/day) were assessed by questionnaire. HRs were estimated using Cox proportional hazard models.
Results
Among 5829 adults (mean age 61.8 years, 54% female, 42% white, 12% Chinese-American, 26% African-American, 21% Hispanic-American), there were 655 incident diabetes cases (median follow-up 11.1 years). After adjustment, diabetes risk was lower in those with brisk or striding compared with none or casual walking pace (HR 0.67; 95% CI 0.54 to 0.84), higher levels of exercise PA (HR for highest vs lowest quartile 0.79; 95% CI 0.63 to 0.98), and any compared with no vigorous PA (HR 0.79; 95% CI 0.66 to 0.95). Race/ethnicity influenced the association of walking pace, exercise PA, and any vigorous PA on diabetes risk, which was only significant among whites. Total leisure sedentary behaviors (HR for highest vs lowest quartile 1.65; 95% CI 1.26 to 2.14) and television watching (HR for highest vs lowest quartile 2.68; 95% CI 1.38 to 5.21) were significantly associated with diabetes risk in multiethnic analyses and were influenced by race/ethnicity.
Conclusions
These results confirm the importance of PA and sedentary behavior on diabetes risk in a multiethnic population and demonstrate potential variations across race/ethnic groups.
doi:10.1136/bmjdrc-2015-000185
PMCID: PMC4932325  PMID: 27403323
Type 2 Diabetes; Physical Activity Epidemiology; Sedentary Behaviors; Racial Differences
8.  Physical Activity, Physical Fitness and Leukocyte Telomere Length: the Cardiovascular Health Study. 
Introduction
The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL), repetitive DNA sequences that may mark biologic aging, is not well-established. Few prior studies have been conducted in older adults, these were mainly cross-sectional, and few evaluated PF.
Methods
We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (age 73±5 y at baseline) in the Cardiovascular Health Study, having serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL; and changes in cumulatively averaged PA and PF against changes in TL.
Results
Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (p-trend=0.007, 0.04 respectively). In longitudinal analyses, no significant associations of baseline PA and PF with change in TL were observed. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.
Conclusions
Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.
doi:10.1249/MSS.0000000000000720
PMCID: PMC4648672  PMID: 26083773
elderly; exercise; fitness; biological aging; DNA
9.  Long-term Exposure to Air Pollution and Markers of Inflammation, Coagulation, and Endothelial Activation 
Epidemiology (Cambridge, Mass.)  2015;26(3):310-320.
Background
Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation.
Methods
We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time–location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1.
Results
After controlling for confounders, 5 µg/m3 increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution.
Conclusions
These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.
doi:10.1097/EDE.0000000000000267
PMCID: PMC4455899  PMID: 25710246
10.  Fibroblast growth factor 23 and risk of incident stroke in community-living adults 
Background and Purpose
Fibroblast growth factor 23 (FGF23) is a hormone that regulates phosphorus and vitamin D metabolism. Elevated FGF23 concentrations are associated with excess risk of cardiovascular disease. Associations of FGF23 with stroke outcomes are less clear.
Methods
Using a case-cohort study design, we examined the association of baseline plasma FGF23 concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. FGF23 was measured in 615 participants who developed incident stroke (cases) and in 936 participants randomly selected from the REGARDS cohort (comparison sub-cohort).
Results
In multivariable-adjusted models, higher calcium and phosphorus concentrations, lower estimated glomerular filtration rate and higher urine albumin excretion were independently associated with higher FGF23. There was no statistically significant association of FGF23 with risk of all-cause stroke in Cox models adjusted for demographic factors and established stroke risk factors (hazard ratio [HR] comparing fourth to first quartile 1.19, 95%CI 0.78,1.82). In pre-specified models stratified by stroke subtypes, there was a graded association of FGF23 with risk of cardioembolic stroke in fully adjusted models (quartile 1 ref; quartile 2 HR 1.48, 95%CI 0.63,3.47; quartile 3 HR 1.99, 95%CI 0.89,4.44; quartile 4 HR 2.52, 95%CI 1.08,5.91). There were no statistically significant associations of FGF23 with other ischemic stroke subtypes or with hemorrhagic strokes.
Conclusions
Higher FGF23 concentrations were associated with higher risk of cardioembolic but not other stroke subtypes in community-dwelling adults. Future studies should delineate reasons for these findings.
doi:10.1161/STROKEAHA.114.007489
PMCID: PMC4308535  PMID: 25563643
cerebrovascular disease; stroke; fibroblast growth factor; embolic stroke
11.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
12.  The relationship between adiposity-associated inflammation and coronary artery and abdominal aortic calcium differs by strata of central adiposity: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score >0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association (pinteraction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association (pinteraction=0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association.
doi:10.1177/1358863X14537545
PMCID: PMC4258162  PMID: 24907349
abdominal aorta calcium (AAC); adiposity-associated inflammation; central adiposity; coronary artery calcium (CAC)
13.  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
14.  Lipoprotein-associated phospholipase A2 and Risk of Dementia in the Cardiovascular Health Study 
Atherosclerosis  2014;235(2):384-391.
Objective
To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.
Methods
Analysis were completed on 3,320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥ 65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.
Results
Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR:1.11 per SD, 95% CI:1.00-1.24 for mass; HR:1.12 per SD, 95% CI:1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR:1.98, 95% CI:1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR:2.21, 95% CI:1.12-4.373).
Interpretation
These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.
doi:10.1016/j.atherosclerosis.2014.04.032
PMCID: PMC4096578  PMID: 24929287
Lp-PLA2; dementia; Alzheimer’s disease; cardiovascular risk factors
15.  THE ASSOCIATIONS OF ADIPOKINES WITH SELECTED MARKERS OF THE RENIN-ANGIOTENSINOGEN-ALDOSTERONE SYSTEM: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Journal of human hypertension  2014;29(2):127-133.
Among obese individuals, increased sympathetic nervous system activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the reninangiotensinogen-aldosterone system (RAAS). The sample was 1,970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (SD) PRA and aldosterone were 1.45 (0.56) ng/ml and 150.1 (130.5) pg/ml, respectively. After multivariable adjustment, a 1-SD increment of leptin was associated with a 0.55 ng/ml higher PRA and 8.4 pg/ml higher aldosterone (p < 0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (−5.5 pg/ml, p = 0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking anti-hypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (p < 0.01). The findings suggest that both adiponectin and leptin may relevant to blood pressure regulation via the RAAS, that the associations appear to be robust to anti-hypertension medication use and that the associations are likely different by ethnicity.
doi:10.1038/jhh.2014.40
PMCID: PMC4265023  PMID: 24919752
Adipokines; Renin; Aldosterone; Ethnicity
16.  Metabolic Syndrome, C-Reactive Protein, and Mortality in U.S. Blacks and Whites: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Diabetes Care  2014;37(8):2284-2290.
OBJECTIVE
We evaluate associations of metabolic syndrome (MetS), C-reactive protein (CRP), and a CRP-incorporated definition of MetS (CRPMetS) with risk of all-cause mortality in a biracial population.
RESEARCH DESIGN AND METHODS
We studied 23,998 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of black and white adults ≥45 years old across the U.S. Elevated CRP was defined as ≥3 mg/L and MetS by the revised Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III; ATP III) criteria (three of five components). CRPMetS was defined as presence of three out of six components, with elevated CRP added to ATP III criteria as a sixth component. Cox models were used to calculate hazard ratios (HRs) for all-cause mortality, and population attributable risk (PAR) was calculated. Stratified analyses based on race and diabetes status were performed.
RESULTS
There were 9,741 participants (41%) with MetS and 12,179 (51%) with CRPMetS at baseline. Over 4.8 years of follow-up, 2,050 participants died. After adjustment for multiple confounders, MetS, elevated CRP, and CRPMetS were each significantly associated with increased mortality risk (HRs 1.26 [95% CI 1.15–1.38], 1.55 [1.41–1.70], and 1.34 [1.22–1.48], respectively). The PAR was 9.5% for MetS, 18.1% for CRP, and 14.7% for CRPMetS. Associations of elevated CRP and of CRPMetS with mortality were significantly greater in whites than blacks, while no differences in associations were observed based on diabetes status.
CONCLUSIONS
By definition, CRPMetS identifies more people at risk than MetS but still maintains a similar mortality risk. Incorporating CRP into the definition for MetS may be useful in identifying additional high-risk populations to target for prevention.
doi:10.2337/dc13-2059
PMCID: PMC4113170  PMID: 24879838
17.  Incident Physical Disability in People with Lower Extremity Peripheral Arterial Disease: The Role of Cardiovascular Disease 
Objective
To evaluate the risk of incident physical disability and the decline in gait speed over a six year follow-up associated with a low ankle-arm index (AAI) in older adults.
Design
Observational cohort study.
Setting
Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; or Allegheny County, Pennsylvania.
Participants
4705 older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study were included.
Measurements
The AAI was measured in 1992–93 (baseline). Self-reported mobility disability, activities of daily living (ADL) and instrumental activities of daily living (IADL) disability and gait speed were recorded at baseline and at 1 year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking ½ mile and ADL/IADL disability was defined as any difficulty with 11 specific ADL/IADL tasks. Individuals with mobility and/or ADL/IADL disability at baseline were excluded from the respective incident disability analyses.
Results
Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. These associations were partially explained by clinical cardiovascular disease (CVD), diabetes and interim CVD events for mobility disability and by clinical CVD and diabetes for ADL/IADL disability. Individuals with AAI < 0.90 had on average a mean decrease in gait speed of 0.02 m/s/year or a decline of 0.12 m/s over the 6 year follow-up. This decrease was partly explained by prevalent CVD but not further attenuated by interim CVD events.
Conclusions
Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.
doi:10.1111/j.1532-5415.2008.01719.x
PMCID: PMC4509641  PMID: 18384579
Peripheral arterial disease; disability; cardiovascular disease
18.  Cardiac Micro-Injury Measured by Troponin T Predicts Collagen Metabolism in Adults Aged ≥ 65 Years with Heart Failure 
Circulation. Heart failure  2012;5(4):406-413.
Background
Repeated myocardial micro-injuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition.
Methods and Results
Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N-353; mean age=74±6 years, 52% women) at baseline and at three years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I (PIP), carboxyterminal telopeptide of type I collagen (CITP); and aminoterminal propeptide of procollagen III (PIIINP). Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up, adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of CITP (β=0.22, p<0.001) and PIIINP (β=0.12, p=0.035) at follow-up when adjusting for demographic, clinical and biochemical covariates including baseline cTnT. These associations were stronger in heart failure patients than in controls.
Conclusions
Increases in myocardial micro-injury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.
doi:10.1161/CIRCHEARTFAILURE.111.965327
PMCID: PMC4479498  PMID: 22685114
collagen metabolism; fibrosis; myocardial micro-injury; troponin T; heart failure; risk factors
19.  Associations of Pentraxin 3 with Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
Pentraxin 3 (PTX3) is likely a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
2838 participants free of prevalent CVD with measurements of PTX3 were included in the present study. Adjusting for age, sex and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP) and carotid intima media thickness (all p<0.045). A one standard deviation increase in PTX3 (1.62 ng/ml) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk; 95% confidence interval 1.05; 1-01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio; 95% confidence interval 1.51; 1.16-1.97), combined CVD events (1.23; 1.05-1.45) and combined CHD events (1.33; 1.10-1.60) but not stroke, CVD-related mortality or all cause death.
Conclusions
In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independent of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP and may provide additional insight into the development and progression of atherosclerosis.
doi:10.1111/jth.12557
PMCID: PMC4055511  PMID: 24628740
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
20.  Association of Renin and Aldosterone With Ethnicity and Blood Pressure: The Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2014;27(6):801-810.
BACKGROUND
Although variations in plasma renin activity (PRA) and aldosterone have been examined in whites and blacks, the association of these hormones with blood pressure in multiethnic populations has not been described.
METHODS
We measured PRA and aldosterone in 1,021 participants in the Multi-Ethnic Study of Atherosclerosis not taking antihypertensives and examined the association between ethnicity and PRA/aldosterone and the association between PRA/aldosterone with systolic blood pressure (SBP).
RESULTS
Average age was 62 (SD = 9) years, and 49% of participants were women. Median PRA was 0.51 (interquartile range (IQR) = 0.29–0.87) ng/ml/hour, and median aldosterone was 12.6 (IQR = 9.1–17.1) ng/dl. After age and sex adjustment, compared with whites, blacks had 28% lower PRA and 17.4% lower aldosterone, and Hispanics had 20.1% higher PRA but similar aldosterone levels. After multivariable adjustment, compared with whites, only Hispanic ethnicity independently associated with higher PRA (0.18ng/ml/hour; 95% confidence interval (CI) = 0.06–0.31). Blacks had lower aldosterone (−1.7ng/dl; 95% CI = −3.2 to −0.2) compared with whites. After multivariable adjustment, PRA was associated with lower SBP in whites (−3.2mm Hg; 95% CI = −5.2 to −1.2 per standardized unit PRA), Chinese (−3.5mm Hg; 95% CI = −6.2 to −0.80 per standardized unit), and Hispanics (−2.3mm Hg; 95% CI = −4.1 to −0.6 per standardized unit) but not blacks. Aldosterone was associated with higher SBP only in Hispanics (2.5mm Hg; 95% CI = 0.4–4.5 per SD).
CONCLUSIONS
Compared with whites, blacks have lower aldosterone and Hispanics have higher PRA. Aldosterone had significant associations with higher SBP in Hispanics compared with other groups, a finding that may suggest a different mechanism of hypertension.
doi:10.1093/ajh/hpt276
PMCID: PMC4017931  PMID: 24436325
black; blood pressure; Chinese; cross-sectional analysis; Hispanic; hypertension; white.
21.  N-terminal pro-B-type natriuretic peptide and stroke risk: the REasons for Geographic And Racial Differences in Stroke cohort 
Background and Purpose
Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30,239 black and white participants of the REasons for Geographic And Racial Differences in Stroke cohort.
Methods
With 5.4 years follow-up after enrollment in 2003–7, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke.
Results
NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation and lower low-density lipoprotein cholesterol. Adjusting for age, race, sex, income, education and traditional stroke risk factors there was an increased risk of stroke across quartiles of NT-proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% CI 1.9–4.5). There was no impact of added adjustment for kidney function and heart failure. Among etiologic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% CI 2.9–29.2). Associations did not differ by age, sex or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors (p<0.001).
Conclusion
NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, clinical use of NT-proBNP measurement in primary prevention settings should be considered.
doi:10.1161/STROKEAHA.114.004712
PMCID: PMC4142424  PMID: 24757103
stroke; risk factor; natriuretic peptides
22.  Associations between γ-glutamyltransferase (GGT) and Biomarkers of Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2014;233(2):387-393.
OBJECTIVE
To evaluate associations between total serum γ-glutamyltransferase activity (GGT) and biomarkers of arteriosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), including 6,783 participants from four ethnic subgroups, i.e., White, Chinese, Black and Hispanic.
METHODS
Associations between fasting total serum GGT activity and oxidized low-density lipoproteins (oxLDL), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed. Following evaluation of linear trends between GGT and biomarkers of interest, multivariable linear regression models were serially adjusted for age, gender, site, ethnicity (M1); M1+lifestyle variables (M2); M2+traditional cardiovascular risk factors plus medications (M3); and M3+metabolic status (M4). Interactions were evaluated between GGT and age and ethnicity in all models.
RESULTS
Linear trends were positive and significant between GGT and oxLDL, IL-6, CRP and sICAM-1 in crude models, and trends remained significant in all ethnic subgroups for CRP (p<0.0001) and sICAM-1 (p<0.001), and for IL-6 except in the Chinese. Trends between GGT and oxLDL were significant in the entire cohort and the White subgroup (p<0.0001), but not in other ethnic subgroups. Multivariable models demonstrated continuous strong, positive associations between GGT and CRP, IL-6 and sICAM-1. Associations between GGT and oxLDL were attenuated upon adjustment for LDL-C and other traditional risk factors. All models were attenuated with adjustment for metabolic status. No age interactions were evident.
CONCLUSIONS
Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis.
doi:10.1016/j.atherosclerosis.2014.01.010
PMCID: PMC4000064  PMID: 24530768
GGT; oxidative stress; oxidized LDL; sICAM; CRP; endothelial dysfunction
23.  Multi-Ancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Background
C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
Methods and Results
We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40,473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected p<3.1×10−3 for replication, p<2.0×10−4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (p=2.0×10−6) and rs646776 (p=3.1×10−5).
Conclusions
We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and LDL cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups, and of looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
doi:10.1161/CIRCGENETICS.113.000173
PMCID: PMC4104750  PMID: 24622110
genetic epidemiology; inflammation; C-reactive protein; race and ethnicity; single nucleotide polymorphism; pleiotropy
24.  Associations of Fibroblast Growth Factor-23 with Markers of Inflammation, Insulin Resistance and Obesity in Adults 
PLoS ONE  2015;10(3):e0122885.
Introduction
Elevated fibroblast growth factor-23 (FGF23) is an established marker of cardiovascular disease. The underlying reason(s) for the rise accompanying cardiovascular health decline are unclear. Prior studies have shown that FGF23 concentrations are associated with markers of inflammation and insulin resistance but they have been limited by a focus on persons with chronic kidney disease (CKD) and lack of race and sex diversity. The objective of this study was to examine the associations of FGF23 and markers of inflammation, insulin resistance, and anthropometrics in a large cohort of community-dwelling adults.
Methods
Associations of FGF23 with markers of inflammation [interleukin-6 (IL-6), IL-10, high sensitivity-CRP (hsCRP)], insulin utilization [resistin, adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR)] and anthropometrics [BMI and waist circumference (WC)] were examined cross-sectionally in a 1,040 participants randomly selected from the Reason for Geographic and Racial Differences in Stroke (REGARDS) Study, a national study of black and white adults ≥45 years. Effect modification by race and CKD status was tested, and stratified models were analyzed accordingly.
Results
Median FGF23 concentration was 69.6 RU/ml (IQR: 53.2, 102.7). Higher quartiles of FGF23 were associated with higher mean concentrations of IL-6, IL-10, hsCRP and resistin (Ptrend<0.001 for all). There were no significant differences in HOMA-IR, adiponectin concentrations, BMI, or WC across FGF23 quartiles in the crude analyses. CKD significantly modified the relationships between FGF23 and inflammatory markers, HOMA-IR, BMI and WC (P ≤ 0.01 for all). In linear regression models adjusted for sociodemographic and clinical variables, FGF23 was positively associated with IL-6, hsCRP, IL-10, HOMA-IR, BMI and WC in individuals without CKD, but not among individuals with CKD. Additionally, FGF23 was positively associated with resistin irrespective of CKD status.
Conclusions
Elevated FGF23 concentrations may be considered a biomarker for decline in metabolic function among individuals with normal kidney function.
doi:10.1371/journal.pone.0122885
PMCID: PMC4374938  PMID: 25811862
25.  Association Between Resting Heart Rate and Inflammatory Biomarkers (High-Sensitivity C-Reactive Protein, Interleukin-6, and Fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;113(4):644-649.
Heart rate (HR) at rest is associated with adverse cardiovascular events; however, the biologic mechanism for the relation is unclear. We hypothesized a strong association between HR at rest and subclinical inflammation, given their common interrelation with the autonomic nervous system. HR at rest was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis, a cohort of 4 racial or ethnic groups without cardiovascular disease at baseline and then divided into quintiles. Subclinical inflammation was measured using high-sensitivity C-reactive protein, interleukin-6, and fibrinogen. We used progressively adjusted regression models with terms for physical activity and atrioventricular nodal blocking agents in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables using the clinical cut point of ≥3 mg/L for high-sensitivity C-reactive protein and the upper quartiles of fibrinogen (≥389 mg/dl) and interleukin-6 (≥1.89 pg/ml). Participants had a mean age of 62 years (SD 9.7), mean resting heart rate of 63 beats/min (SD 9.6) and were 47% men. Increased HR at rest was significantly associated with higher levels of all 3 inflammatory markers in both continuous (p for trend <0.001) and categorical (p for trend <0.001) models. Results were similar among all 3 inflammatory markers, and there was no significant difference in the association among the 4 racial or ethnic groups. In conclusion, an increased HR at rest was associated with a higher level of inflammation among an ethnically diverse group of subjects without known cardiovascular disease.
doi:10.1016/j.amjcard.2013.11.009
PMCID: PMC4280910  PMID: 24393259

Results 1-25 (91)