Plasma 25-Hydroxyvitamin D and the Longitudinal Risk of Sepsis in the REGARDS Cohort.

BACKGROUND: Low baseline plasma 25-hydroxyvitamin D (25(OH)D) is associated with increased risk of acute respiratory infections, but its association with long-term risk of sepsis remains unclear. METHODS: We performed a case-cohort analysis of participants selected from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a US cohort of 30239 adults aged ≥45 years. We measured baseline plasma 25(OH)D in 711 sepsis cases and in 992 participants randomly selected from the REGARDS cohort. We captured sepsis events by screening records with International Classification of Disease methods and then adjudicating clinical charts for significant, suspected infection and severe inflammatory response syndrome criteria on presentation. RESULTS: In the study sample, the median age of participants was 65.0 years, 41% self-identified as black, and 45% were male. Mean plasma 25(OH)D concentration was 25.8 ng/mL; for 31% of participants, it was <20 ng/mL. The adjusted risk of community-acquired sepsis was higher for each lower category of baseline 25(OH)D. Specifically, in a Cox proportional hazards model adjusting for multiple potential confounders, when compared to a baseline 25(OH)D >33.6 ng/mL, lower 25(OH)D groups were associated with higher hazards of sepsis (16.5-22.4 ng/mL; hazard ratio [HR]; 3.21; 95% confidence interval [CI], 1.98 to 5.21 and <16.5 ng/mL; HR, 6.81, 95% CI, 3.95 to 11.73). Results did not materially differ in analyses stratified by race or age. CONCLUSIONS: In the REGARDS cohort of community-dwelling US adults, low plasma 25(OH)D measured at a time of relative health was independently associated with increased risk of sepsis.

C-reactive protein and stroke risk in blacks and whites: The REasons for Geographic And Racial Differences in Stroke cohort.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker used in vascular risk prediction, though with less data in people of color. Blacks have higher stroke incidence and also higher CRP than whites. We studied the association of CRP with ischemic stroke risk in blacks and whites. METHODS: REGARDS, an observational cohort study, recruited and followed 30,239 black and white Americans 45 years and older for ischemic stroke. We calculated hazard ratios and 95% CIs of ischemic stroke by CRP category (<1, 1-3, 3-10, and ≥10 mg/L) adjusted for age, sex and stroke risk factors. RESULTS: There were 292 incident ischemic strokes among blacks and 439 in whites over 6.9 years of follow-up. In whites, the risk was elevated for CRP in the range from 3 to 10 mg/L and even higher for CRP >10 mg/L, whereas in blacks, an association was only seen for CRP >10 mg/L. Considered as a continuous variable, the risk factor-adjusted hazard ratios per SD higher lnCRP were 1.18 (95% CI 1.09-1.28) overall, 1.14 (95% CI 1.00-1.29) in blacks, and 1.22 (95% CI 1.10-1.35) in whites. Spline regression analysis visually confirmed the race difference in the association. CONCLUSIONS: CRP may not be equally useful in stroke risk assessment in blacks and whites. Confirmation, similar study for coronary heart disease, and identification of reasons for these racial differences require further study.

Association of lipoprotein-associated phospholipase A2 and risk of incident atrial fibrillation: Findings from 3 cohorts.

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity and incident AF has not been extensively evaluated. METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA2 levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data. RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13%), 2,084 (40%), and 615 (11%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA2 activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95% CI 1.06-1.20) and MESA (HR 1.24, 95% CI 1.05-1.46). Each SD increment in Lp-PLA2 mass was also associated with incident AF in MESA (HR 1.25, 95% CI 1.11-1.41). No significant associations were observed among CHS participants. CONCLUSIONS: Although higher Lp-PLA2 mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study.

OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, ß=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (ß=0.373, P=9.06×10-13) than among men (ß=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (ß=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

Vitamin K-Dependent Protein Activity and Incident Ischemic Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: Vitamin K-dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular disease has not been studied. APPROACH AND RESULTS: VKDP activity was determined by measuring circulating des-γ-carboxy prothrombin concentrations in a random sample of 709 multiethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA). Lower des-γ-carboxy prothrombin concentrations reflect greater VKDP activity. Subjects were followed up for the risk of ischemic cardiovascular disease (coronary heart disease, stroke, and fatal cardiovascular disease) for 11.0 years of follow-up. A total of 75 first ischemic CVD events occurred during follow-up. The incidence of ischemic cardiovascular disease increased progressively across des-γ-carboxy prothrombin quartiles, with event rates of 5.9 and 11.7 per 1000 person-years in the lowest and highest quartiles. In analyses adjusted for traditional cardiovascular risk factors and measures of vitamin K intake, a doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53 (95% confidence interval, 1.09-2.13; P=0.008) higher risk of incident ischemic cardiovascular disease. The association was consistent across strata of participants with diabetes mellitus, hypertension, renal impairment, and low vitamin K nutritional intake. CONCLUSIONS: In this sample of middle-aged and older adults, VKDP activity was associated with incident ischemic cardiovascular events. Further studies to understand the role of this large class of proteins in cardiovascular disease are warranted.

Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI). APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged ≥65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95% confidence interval 1.09, 1.50). CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease in a multi-ethnic cohort: The Multi-Ethnic Study of Atherosclerosis.

Prospective studies supporting a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident peripheral arterial disease (PAD) are limited. We evaluated the association of Lp-PLA2 with incident PAD in a multi-ethnic cohort without clinical cardiovascular disease. A total of 4622 participants with measurement of Lp-PLA2 mass and Lp-PLA2 activity and an ankle-brachial index (ABI) between 0.9 and 1.4 were followed for the development of PAD (median follow-up = 9.3 years), defined as an ABI ⩽0.9 and decline from baseline ⩾0.15. There were 158 incident PAD events during follow-up. In adjusted logistic regression models, each higher standard deviation of both Lp-PLA2 activity and mass did not confer an increased risk of developing PAD [odds ratios, (95% confidence intervals)]: 0.92 (0.66-1.27) for Lp-PLA2 activity and 1.06 (0.85-1.34) for mass. Additionally, no significant interaction was found according to ethnicity: p=0.43 for Lp-PLA2 activity and p=0.55 for Lp-PLA2 mass. We found no evidence of an association between Lp-PLA2 and incident PAD.

Association between Heat Shock Protein-60 and Development of Atrial Fibrillation: Results from the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: During atrial fibrillation (AF), a high rate of myocyte activation causes cellular stress and initiates the process of atrial remodeling, which further promotes persistence of AF. Although heat shock proteins (HSPs) have been shown to prevent atrial remodeling and suppress the occurrence of AF in cellular and animal experimental models, increased levels of HSP-60 have been observed in patients with postoperative AF, likely reflecting a response to cellular stress. To better understand the role of HSP-60 in relation to AF, we examined the association of HSP-60 levels in relation to the future development of AF in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: MESA is a cohort study that recruited 6,814 participants aged 45-84 years and free of known cardiovascular disease at baseline (2000-2002) from six field centers. We investigated 983 participants, selected at random from the total cohort, who had HSP-60 measured and were free of AF at baseline. We tested the association of HSP-60 levels with the incidence of AF using multivariate Cox models after adjustment for demographics, clinical characteristics, and biomarkers. RESULTS: During an average of 10.6 years of follow-up, 77 participants developed AF. We did not observe a significant association between the log-transformed HSP-60 levels and development of AF on either unadjusted or multivariate analysis (adjusted hazard ratio: 1.02 per unit difference on natural log scale, 95% confidence interval: 0.77-1.34 ln (ng/mL). CONCLUSION: Contrary to the findings from the preclinical studies, which demonstrated an important role of HSP-60 in the pathogenesis of AF, we did not observe a significant association between HSP-60 and occurrence of AF.

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 aged ≥45 years. FGF23 was measured in 615 participants who developed incident stroke (cases) and in 936 participants randomly selected from the REGARDS cohort (comparison subcohort). 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 comparing fourth with first quartile 1.19; 95% confidence interval, 0.78-1.82). In prespecified models stratified by stroke subtypes, there was a graded association of FGF23 with risk of cardioembolic stroke in fully adjusted models (quartile 1, reference; quartile 2 hazard ratio, 1.48; 95% confidence interval, 0.63-3.47; quartile 3 hazard ratio, 1.99; 95% confidence interval, 0.89-4.44; quartile 4 hazard ratio, 2.52; 95% confidence interval, 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 with other stroke subtypes in community-dwelling adults. Additional studies should delineate reasons for these findings.

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 (REGARDS) cohort. METHODS: During 5.4 years of follow-up after enrollment in 2003 to 2007, 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% confidence interval, 1.9-4.5). There was no impact of added adjustment for kidney function and heart failure. Among pathogenetic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% confidence interval, 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). CONCLUSIONS: NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, the clinical use of NT-proBNP measurement in primary prevention settings should be considered.

Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes. METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults. CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

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 (p interaction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association (p interaction=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.

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels.

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

Fetuin-A is inversely associated with coronary artery calcification in community-living persons: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Fetuin-A is a hepatic secretory protein that inhibits arterial calcification in vitro. The association of fetuin-A with coronary arterial calcification (CAC) in the general population is uncertain. METHODS: Among 2457 community-living individuals without cardiovascular disease (CVD), we measured serum fetuin-A concentrations by ELISA and evaluated the cross-sectional association of fetuin-A with CAC prevalence (any vs none) and severity; on follow-up 3.2 years (median) later, we evaluated the association of fetuin-A with CAC incidence and progression. RESULTS: The mean age was 62 (SD 10) years, and the mean fetuin-A concentration was 0.48 (0.10) g/L. At baseline, 1200 individuals (49%) had CAC, and 272 individuals developed CAC during follow-up. At baseline, there was a threshold effect at the lowest fetuin-A quartile with CAC prevalence. In models adjusted for demographics, traditional cardiovascular disease (CVD) risk factors and kidney function, the lowest fetuin-A quartile had 7% (95% CI 1%-13%; P = 0.04) greater CAC prevalence compared with quartiles 2-4. Similar associations were observed with CAC severity at baseline, but the association was more linear. Each SD (0.10 g/L) lower fetuin-A was associated with a 12% (95% CI 3%-21%; P = 0.01) greater CAC severity in adjusted models. There was no significant association of fetuin-A with CAC incidence or progression. CONCLUSIONS: Fetuin-A is inversely associated with CAC severity among community-living individuals without CVD. Whether fetuin-A concentrations are associated with incident CVD event in the general population requires future study.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators.

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10(-323)). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10(-13)). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immunoflow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications.

Inflammation biomarkers and risk of all-cause mortality in the Reasons for Geographic And Racial Differences in Stroke cohort.

Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003-2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 × 10(9) cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (P(trend) < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers.

Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.

Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype.

Dietary micronutrient intakes are associated with markers of inflammation but not with markers of subclinical atherosclerosis.

Few studies have examined associations of dietary micronutrients with markers of inflammation and subclinical atherosclerosis. The present study investigated associations of heme iron, nonheme iron, zinc (Zn), magnesium (Mg), ß-carotene, vitamin C, and vitamin E with C-reactive protein (CRP), IL-6, total homocysteine (tHcy), fibrinogen, coronary artery calcium, and common and internal carotid artery intima media thickness. Micronutrient intakes and markers of inflammation and subclinical atherosclerosis were studied in 5,181 participants from the Multi-Ethnic Study of Atherosclerosis who were aged 45-84 y and free of diabetes and cardiovascular disease. Models were adjusted for energy intake, demographics, lifestyle characteristics, and BMI. Dietary nonheme iron and Mg intakes were inversely associated with tHcy concentrations (mean tHcy: 9.11, 8.86, 8.74, 8.71, and 8.50 µmol/L, and 9.20, 9.00, 8.65, 8.76, and 8.33 µmol/L across increasing quintiles of nonheme iron and Mg, respectively; P-trend < 0.001 for both). However, dietary Zn and heme iron were positively associated with CRP [mean: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L across increasing quintiles of Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L across increasing quintiles of heme iron (P-trend = 0.002 and 0.01, respectively). Other tested micronutrient-marker associations were not significant. In conclusion, of the 49 tested associations, only 7 were significant. Although this study does not provide strong support for associations between the micronutrients and markers of inflammation and subclinical atherosclerosis, the results are consistent with dietary guidelines that advocate for a balanced diet that includes a variety of plant foods containing Mg, Zn, and nonheme iron.