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.

Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near MGAT5 (top result rs62165726, P=3.3×10-18),19 variants near chromosome 17 gene ASGR1 (rs55714927, P=1.5×10-14), and 18 variants near chromosome 11 gene ST3GAL4. These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 P=7.1×10-9) in the HLA region, and 3 variants (rs115391969 P=4.3×10-8) near the chromosome 16 gene MYLK3. Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.

Protein Phosphatase PP2C Identification in Entamoeba spp.

Entamoeba histolytica is the causative agent of amoebiasis, and Entamoeba dispar is its noninvasive morphological twin. Entamoeba invadens is a reptilian parasite. In the present study, Western blot, phosphatase activity, immunofluorescence, and bioinformatic analyses were used to identify PP2C phosphatases of E. histolytica, E. dispar, and E. invadens. PP2C was identified in trophozoites of all Entamoeba species and cysts of E. invadens. Immunoblotting using a Leishmania mexicana anti-PP2C antibody recognized a 45.2 kDa PP2C in all species. In E. histolytica and E. invadens, a high molecular weight element PP2C at 75 kDa was recognized, mainly in cysts of E. invadens. Immunofluorescence demonstrated the presence of PP2C in membrane and vesicular structures in the cytosol of all species analyzed. The ~75 kDa PP2C of Entamoeba spp. shows the conserved domain characteristic of phosphatase enzymes (according to in silico analysis). Possible PP2C participation in the encystation process was discussed.

Parasite protein phosphatases: biological function, virulence, and host immune evasion.

Protein phosphatases are enzymes that dephosphorylate tyrosine and serine/threonine amino acid residues. Although their role in cellular processes has been best characterized in higher eukaryotes, they have also been identified and studied in different pathogenic microorganisms (e.g., parasites) in the last two decades. Whereas some parasite protein phosphatases carry out functions similar to those of their homologs in yeast and mammalian cells, others have unique structural and/or functional characteristics. Thus, the latter unique phosphatases may be instrumental as targets for drug therapy or as markers for diagnosis. It is important to better understand the involvement of protein phosphatases in parasites in relation to their cell cycle, metabolism, virulence, and evasion of the host immune response. The up-to-date information about parasite phosphatases of medical and veterinarian relevance is herein reviewed.

Protein Serine/Threonine Phosphatase Type 2C of Leishmania mexicana.

Protein phosphorylation and dephosphorylation are increasingly recognized as important processes for regulating multiple physiological mechanisms. Phosphorylation is carried out by protein kinases and dephosphorylation by protein phosphatases. Phosphoprotein phosphatases (PPPs), one of three families of protein serine/threonine phosphatases, have great structural diversity and are involved in regulating many cell functions. PP2C, a type of PPP, is found in Leishmania, a dimorphic protozoan parasite and the causal agent of leishmaniasis. The aim of this study was to clone, purify, biochemically characterize and quantify the expression of PP2C in Leishmania mexicana (LmxPP2C). Recombinant LmxPP2C dephosphorylated a specific threonine (with optimal activity at pH 8) in the presence of the manganese divalent cation (Mn+2). LmxPP2C activity was inhibited by sanguinarine (a specific inhibitor) but was unaffected by protein tyrosine phosphatase inhibitors. Western blot analysis indicated that anti-LmxPP2C antibodies recognized a molecule of 45.2 kDa. Transmission electron microscopy with immunodetection localized LmxPP2C in the flagellar pocket and flagellum of promastigotes but showed poor staining in amastigotes. Interestingly, LmxPP2C belongs to the ortholog group OG6_142542, which contains only protozoa of the family Trypanosomatidae. This suggests a specific function of the enzyme in the flagellar pocket of these microorganisms.

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.

BACKGROUND: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear. OBJECTIVE: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults. METHODS: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors. RESULTS: Of 20 factors evaluated individually, only higher levels of plasmin-α2 -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP ß = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI ß = -0.55, 95% CI: -0.90 to -0.19; FXc ß = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE. CONCLUSIONS: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

C-Reactive Protein and Incident Hypertension in Black and White Americans in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Cohort Study.

BACKGROUND: More inflammation is associated with greater risk incident hypertension, and Black United States (US) adults have excess burden of hypertension. We investigated whether increased inflammation as quantified by higher C-reactive protein (CRP) explains the excess incidence in hypertension experienced by Black US adults. METHODS: We included 6,548 Black and White REasons for Geographic and Racial Differences in Stroke (REGARDS) participants without hypertension at baseline (2003-2007) who attended a second visit (2013-2016). Sex-stratified risk ratios (RRs) for incident hypertension at the second exam in Black compared to White individuals were estimated using Poisson regression adjusted for groups of factors known to partially explain the Black-White differences in incident hypertension. We calculated the percent mediation by CRP of the racial difference in hypertension. RESULTS: Baseline CRP was higher in Black participants. The Black-White RR for incident hypertension in the minimally adjusted model was 1.33 (95% confidence interval 1.22, 1.44) for males and 1.15 (1.04, 1.27) for females. CRP mediated 6.6% (95% confidence interval 2.7, 11.3%) of this association in females and 19.7% (9.8, 33.2%) in males. In females, CRP no longer mediated the Black-White RR in a model including waist circumference and body mass index, while in males the Black-White difference was fully attenuated in models including income, education and dietary patterns. CONCLUSIONS: Elevated CRP attenuated a portion of the unadjusted excess risk of hypertension in Black adults, but this excess risk was attenuated when controlling for measures of obesity in females and diet and socioeconomic factors in males. Inflammation related to these risk factors might explain part of the Black-White disparity in hypertension.

C-reactive protein and risk of cognitive decline: The REGARDS study.

Markers of systemic inflammation are associated with increased risk of cognitive impairment, but it is unclear if they are associated with a faster rate of cognitive decline and whether this relationship differs by race. Our objective was to examine the association of baseline C-reaction protein (CRP) with cognitive decline among a large racially diverse cohort of older adults. Participants included 21,782 adults aged 45 and older (36% were Black, Mean age at baseline 64) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. CRP was measured at baseline and used as a continuous variable or a dichotomous grouping based on race-specific 90th percentile cutoffs. Cognitive measures of memory and verbal fluency were administered every 2 years for up to 12 years. Latent growth curve models evaluated the association of CRP on cognitive trajectories, adjusting for relevant demographic and health factors. We found that higher CRP was associated with worse memory (B = -.039, 95% CI [-.065,-.014]) and verbal fluency at baseline (B = -.195, 95% CI [-.219,-.170]), but not with rate of cognitive decline. After covariate adjustment, the association of CRP on memory was attenuated (B = -.005, 95% CI [-.031,-.021]). The association with verbal fluency at baseline, but not over time, remained (B = -.042, 95% CI [-.067,-.017]). Race did not modify the association between CRP and cognition. Findings suggest that levels of CRP at age 45+, are a marker of cognitive impairment but may not be suitable for risk prediction for cognitive decline.

Relation of Plasma Renin Activity to Subclinical Peripheral and Coronary Artery Disease (from the Multiethnic Study of Atherosclerosis).

Experimental studies support a link between activation of the renin-angiotensin-aldosterone system and cardiovascular disease (CVD). The relationship with subclinical atherosclerosis is uncertain. Among 1,699 individuals without prevalent CVD from the Multiethnic Study of Atherosclerosis, we measured plasma renin activity (PRA) and aldosterone. Using multivariable logistic regression with restricted cubic splines, we assessed continuous log-transformed PRA and aldosterone associations with the ankle-brachial index (ABI) and coronary artery calcium (CAC) scores (Agatston) with adjustment for cardiovascular disease (CVD) risk factors, kidney function, and inflammatory biomarkers. In fully adjusted models mutually adjusting for PRA and aldosterone, higher PRA was associated with an ABI <1.0 (p overall <0.001, p nonlinear = 0.02) and CAC Agatston score >300 (p overall = 0.02, p nonlinear = 0.22), while aldosterone was not associated with either outcome. For example, compared to the 10th percentile (0.16 ng/ml/hr) of PRA, the 90th percentile (2.68 ng/ml/hr) had 3.6 times (OR 3.62; 95% CI: 2.13 to 6.13) and 1.7 times higher odds (odds ratio 1.67; 95% confidence interval: 1.13 to 2.48) of ABI <1.0 and CAC >300, respectively. These associations persisted after adjustment for levels of C-reactive protein, Interleukin-6, and Tumor Necrosis Factor-alpha. There were no significant differences in these associations by race/ethnicity or antihypertensive medication status. In conclusion, in a multiethnic cohort of community-living adults without prevalent clinical CVD, PRA was associated with greater burden of subclinical peripheral artery and coronary artery disease. These findings provide additional evidence that PRA may have deleterious effects on cardiovascular health through an atherosclerotic pathway.

Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study.

BACKGROUND: The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation. METHODS: We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined. RESULTS: The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95% CI: -0. 37, -0.03; p = .02), compared to no change in men (ß = 0.07; 95% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4. CONCLUSIONS: We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

Transitions to family caregiving: enrolling incident caregivers and matched non-caregiving controls from a population-based study.

BACKGROUND AND AIM: Providing care to an older adult with a disability has been associated with increased risk to the caregiver's health, but most previous studies of caregiving and health compare persons who are already caregivers with poorly matched non-caregiving controls and are often based on convenience samples. In this report, we describe the enrollment of persons who transitioned into a family caregiving role while participating in a national epidemiological study. METHODS: Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were asked on two occasions 9-14 years apart if they were providing care on an ongoing basis to a family member with a chronic illness or disability. Those who answered "no" and "yes", respectively, to this caregiving question and reported sufficient caregiving responsibilities after their transitions were enrolled in the present study as incident caregivers (N = 251). Participants matched on multiple demographic and health history variables and who reported no history of caregiving were enrolled as non-caregiving controls (N = 251). RESULTS: Among eligible participants, 84% agreed to participate, and 47% of caregivers reported caring for a person with dementia. Descriptive analyses confirmed the success of the matching procedures for balancing the groups on multiple demographic and pre-caregiving health variables. Depressive symptoms and perceived stress increased significantly after the transition to caregiving. CONCLUSION: Comparable, population-based samples of incident caregivers and matched non-caregivers have been enrolled. Future analyses will examine within-person changes in health and circulating biomarkers as a function of the transition to caregiving.

Endothelin-1, cardiac morphology, and heart failure: the MESA angiogenesis study.

BACKGROUND: Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. METHODS AND RESULTS: ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. CONCLUSIONS: These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

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.

Biomarkers of mineral metabolism and progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Previous research has implicated dysregulation of phosphate metabolism and calcium-phosphate solubilization in cardiovascular calcification, but epidemiologic studies evaluating longitudinal associations with valvular or annular calcification by computed tomography (CT), a highly sensitive imaging modality, are lacking. Our primary aim was to investigate the associations of mineral biomarkers with incidence and progression of aortic valve calcification (AVC) and mitral annular calcification (MAC). METHODS: We evaluated the associations of serum FGF-23 (n = 6547 participants), phosphate (n = 6547), and fetuin-A (n = 2550) measured at baseline in the community-based Multi-Ethnic Study of Atherosclerosis with AVC and MAC on CT performed at baseline and at a median of 2.4 (1.6, 3.1) years later. We used linear mixed-effects models to account simultaneously for prevalence, incidence and progression of AVC and MAC. RESULTS: After adjustment for demographic and clinical characteristics, a significant association was documented for FGF-23 with accelerated annual progression of MAC (2.83 Agatston units (AU), 95% CI = 0.49, 5.17 AU, per standard deviation (18.46 pg/mL) of FGF-23), but this was not seen for phosphate or fetuin-A. None of these biomarkers was associated with accelerated annual progression of AVC. CONCLUSIONS: This study provides evidence relating serum FGF-23 to accelerated annual MAC progression. Whether this mineral regulator is a risk marker or is involved in pathogenesis merits further investigation.

Inflammatory cytokines and ischemic stroke risk: The REGARDS cohort.

OBJECTIVE: We studied circulating interleukin (IL)-6, IL-8, and IL-10 concentrations and incident ischemic stroke risk in a biracial cohort, and determined if these cytokines mediated the racial disparity in stroke incidence affecting the black population. METHODS: The Reasons for Geographic and Racial Differences in Stroke study enrolled 30,237 black and white men and women age ≥45 in 2003-2007. We measured baseline IL-6, IL-8, and IL-10 in a case-cohort study of 557 participants with incident stroke over 5.4 years and 951 participants in a cohort sample. RESULTS: IL-6, but not IL-8 or IL-10, was higher in cases compared to the cohort sample (mean 4.5 vs 3.7 ng/mL; p < 0.001). Only IL-6 was associated with stroke risk factors. Adjusting for age, sex, and race, the hazard ratio (HR; 95% confidence interval) for incident stroke for the highest vs lowest quartile of IL-6 was 2.4 (1.6-3.4). HRs for the highest vs lowest quartiles of IL-8 and IL-10 were 1.5 (1.0-2.1) and 1.4 (1.0-1.9), respectively. After additional adjustment for stroke risk factors, only higher IL-6 remained associated with stroke risk (HR 2.0; 1.2-3.1). Associations did not differ by race. Mediation analyses showed that IL-6 mediated the black-white disparity in stroke risk, but mediation was via IL-6 associations with stroke risk factors. CONCLUSIONS: In this biracial population-based sample, IL-6 was strongly associated with risk of incident stroke and mediated the racial disparity in stroke via inflammatory effects of risk factors. Further study on the clinical utility of IL-6 measurement in stroke risk assessment would be helpful.

Is Family Caregiving Associated With Inflammation or Compromised Immunity? A Meta-Analysis.

BACKGROUND AND OBJECTIVES: Family caregiving stress has been widely reported to have negative effects on circulating biomarkers of immune system function and inflammation. Our goals were to systematically review this literature and conduct a meta-analysis on the extracted effects. RESEARCH DESIGN AND METHODS: A systematic search of published studies comparing caregivers and noncaregivers on biomarkers measured from blood samples was conducted in the PubMed, Embase, and Cochrane databases. This search identified 2,582 articles and abstracts. After removing duplicative papers and studies not meeting inclusion criteria, 30 articles were identified that reported analyses on 86 relevant biomarkers from 1,848 caregivers and 3,640 noncaregivers. RESULTS: Random-effects models revealed an overall effect size across all biomarkers of 0.164 SD units (d). A slightly larger overall effect (d = 0.188) was found for dementia caregivers only. Immune system comparisons yielded somewhat larger differences than inflammation comparisons. Most studies used small convenience samples, and effect sizes were larger for studies with moderate or high bias ratings than for studies with low bias ratings. No significant associations were found in studies that used population-based samples. DISCUSSION AND IMPLICATIONS: Caregivers had small but significantly reduced immune system functioning and greater inflammation than noncaregivers, but associations were generally weak and of questionable clinical significance. The absence of clear associations from low bias studies and population-based studies underscores concerns with possible selection biases in many of the convenience samples. Population-based studies that assess biomarkers before and after the onset of caregiving might add much clarity to this literature.

Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans.

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in Fucosyltransferase 6 (FUT6; rs17855739,p.Glu274Lys, P = 9.02 × 10-24) with higher soluble E-selectin levels. This variant is considerably more common in populations of African ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women's Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an electronic medical record-based phenome-wide association scan of over 9000 AAs.

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.

Lp-PLA2, scavenger receptor class B type I gene (SCARB1) rs10846744 variant, and cardiovascular disease.

BACKGROUND: We previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis. METHODS: We first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies. RESULTS: SCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52. SUMMARY: SCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

Selected occupational characteristics and change in leukocyte telomere length over 10 years: The Multi-Ethnic Study of Atherosclerosis (MESA).

Telomere length (TL) is considered as a marker of cell senescence, but factors influencing the rate of TL attrition are not well understood. While one previous study reported the association of occupation and TL, many subsequent studies have failed to find the association. This may be due to heterogeneity within the samples and cross-sectional designs. This longitudinal study examines two occupational characteristics, occupational complexity and hazardous conditions, as predictors of TL attrition in gender- and race/ethnicity-stratified analysis. Leukocyte TL (expressed as T/S ratio) was measured twice over a 10-year period in a multi-racial sample (n = 914). Linear mixed effect models were used to estimate TL attrition associated with occupational complexity and hazardous conditions. Analysis was stratified by gender and race/ethnicity (white, African American, and Latino) and controlled for baseline age, baseline TL, and time since baseline. Higher occupational complexity was associated with slower rates of TL attrition only among white men. Hazardous conditions were not associated with TL attrition for any gender-and-race/ethnicity stratified group. Occupational complexity may influence TL attrition, but the different findings for white men and other groups suggest that a more comprehensive framework is needed to better understand the potential link between occupational characteristics and biological aging.