Factor H-related protein 1 (FHR-1) is associated with atherosclerotic cardiovascular disease
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ABSTRACT:
SUBMITTER: Irmscher S
PROVIDER: S-EPMC8602345 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The complement factor H-related (FHR) proteins are hypothesized to fine-tune the regulatory role of complement factor H (FH) in the alternative pathway of the complement system. Moreover, FHR-1, FHR-2, and FHR-5 have been proposed to be dimers, which further complicates accurate analysis. As FHRs are highly similar among themselves and toward FH, obtaining specific reagents for quantification of serum levels and functional analysis is challenging. In this study, we generated antibodies and developed ELISAs to measure FHR-1, FHR-2, and FHR-5 in serum. We used both recombinant and serum-derived proteins to show that four dimers occur in human circulation: homodimers of FHR-1, FHR-2, and FHR-5, as well as FHR-1/FHR-2 heterodimers. Heterodimers containing FHR-5 were not found. In individuals with homozygous CFHR1 deletions or compound heterozygous CFHR2 missense/nonsense mutations identified in this study, the respective FHR-1 and FHR-2 homo- and heterodimers were absent. Using FRET, we found that recombinant FHR dimers exchange monomers rapidly. This was confirmed ex vivo, using FHR-1- and FHR-2-deficient sera. Of all FHR dimers, FHR-5/5 homodimers demonstrated strong binding affinity toward heparin. Specific ELISAs demonstrated that serum levels of FHR-1/1, FHR-1/2, FHR-2/2, and FHR-5/5 dimers were low compared to FH, which circulates at a 10- to 200-fold molar excess. In summary, FHR-1, FHR-2, and FHR-5 homodimerize, with FHR-1 and FHR-2 forming heterodimers as well, and equilibrate quickly in plasma.
| S-EPMC5651247 | biostudies-literature
Project description:ImportanceThere is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively.ObjectiveTo evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD.Design, setting, and participantsThis was a cross-sectional, multicenter, nationwide VA health care system-based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary care visit in the Veterans Affairs (VA) health care system from October 1, 2014, to September 30, 2015. Participants included 147 600 veteran patients with premature ASCVD, encompassing ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD).ExposuresWomen vs men with premature and extremely premature ASCVD.Main outcomes and measuresAntiplatelet use, any statin use, HIS use, and statin adherence (proportion of days covered [PDC] ≥0.8).ResultsWe identified 10 413 women and 137 187 men with premature ASCVD (age ≤55 years) and 1340 women and 8145 men with extremely premature (age ≤40 years) ASCVD. Among patients with premature and extremely premature ASCVD, women represented 7.1% and 14.1% of those groups, respectively. When compared with men, women with premature ASCVD had a higher proportion of African American patients (36.1% vs 23.8%) and lower proportions of Asian patients (0.5% vs 0.7%) and White patients (56.1% vs. 68.1%). In the extremely premature ASCVD group, women had a comparatively higher proportion of African American patients (36.8% vs 23.2%) and lower proportion of White patients (55.0% vs 67.8%) and Asian patients (1.3% vs 1.5%) than men. Among patients with premature IHD, women received less antiplatelet (adjusted odds ratio [AOR], 0.47, 95% CI, 0.45-0.50), any statin (AOR, 0.62; 95% CI, 0.59-0.66), and HIS (AOR, 0.63; 95% CI, 0.59-0.66) therapy and were less statin adherent (mean [SD] PDC, 0.68 [0.34] vs 0.73 [0.31]; β coefficient: -0.02; 95% CI, -0.03 to -0.01) compared with men. Similarly, women with premature ICVD and premature PAD received comparatively less antiplatelet agents, any statin, and HIS. Among patients with extremely premature ASCVD, women also received less antiplatelet therapy (AOR, 0.61; 95% CI, 0.53-0.70), any statin therapy (AOR,0.51; 95% CI, 0.44-0.58), and HIS therapy (AOR, 0.45; 95% CI, 0.37-0.54) than men. There were no sex-associated differences in statin adherence among patients with premature ICVD, premature PAD, or extremely premature ASCVD.Conclusions and relevanceThis cross-sectional study revealed that women veterans with premature ASCVD and extremely premature ASCVD receive less optimal secondary prevention cardiovascular care in comparison with men. Women with premature ASCVD, particularly those with IHD, were also less statin adherent. Multidisciplinary and patient-centered interventions are needed to improve these disparities in women.
| S-EPMC8060887 | biostudies-literature
Project description:ObjectiveCirculating microRNAs (miRNAs) have been implicated in both heart failure and atherosclerotic disease. The aim of this study was to examine associations between heart failure specific circulating miRNAs, atherosclerotic disease and cardiovascular-related outcome in patients with heart failure.MethodsThe levels of 11 heart failure-specific circulating miRNAs were compared in plasma of 114 heart failure patients with and without different manifestations of atherosclerotic disease. We then studied these miRNAs in relation to biomarkers associated to atherosclerosis and to cardiovascular-related rehospitalizations during 18 months of follow-up.ResultsAt least one manifestation of atherosclerotic disease was found in 70 (61%) of the heart failure patients. A consistent trend was found between an increasing number of manifestations of atherosclerosis (peripheral arterial disease in specific), and lower levels of miR-18a-5p, miR-27a-3p, miR-199a-3p, miR-223-3p and miR-652-3p (all P?<?0.05). Target prediction and network analyses identified several interactions between miRNA targets and biomarkers related to inflammation, angiogenesis and endothelial dysfunction. Lower miRNA levels were associated with higher levels of these atherosclerosis-related biomarkers. In addition, lower miRNA levels were significantly associated with rehospitalizations due to cardiovascular causes within 18 months, with let-7i-5p as strongest predictor [HR 2.06 (95% CI 1.29-3.28), C-index 0.70, P?=?0.002].ConclusionsA consistent pattern of lower levels of circulating miRNAs was found in heart failure patients with atherosclerotic disease, in particular peripheral arterial disease. In addition, lower levels of miRNAs were associated with higher levels of biomarkers involved in atherosclerosis and an increased risk of a cardiovascular-related rehospitalization.
| S-EPMC5529487 | biostudies-literature
Project description:Background FGF21 (fibroblast growth factor 21), a novel hepatokine regulating lipid metabolism, has been linked to atherosclerotic disease. However, whether this relationship exists in patients without nonalcoholic fatty liver disease is unclear. We assessed the association between serum FGF21 levels and atherosclerosis in patients without nonalcoholic fatty liver disease, and investigated whether baseline FGF21 could predict incident atherosclerotic cardiovascular disease in a 7-year prospective cohort. Methods and Results Baseline serum FGF21 was measured in a cross-sectional cohort of 371 patients with type 2 diabetes mellitus without nonalcoholic fatty liver disease (determined by hepatic magnetic resonance spectroscopy), and in a population-based prospective cohort of 705 patients from the Shanghai Diabetes Study. In the cross-sectional study, FGF21 was significantly higher in patients with than in those without subclinical carotid atherosclerosis (P<0.01). The association remained significant after adjusting for demographic and traditional cardiovascular risk factors. In the prospective cohort, 80 patients developed atherosclerotic cardiovascular disease during follow-up. Baseline FGF21 was significantly higher in those who developed ischemic heart disease or cerebral infarction than in those who did not. Using a cutoff serum concentration of 232.0 pg/mL, elevated baseline FGF21 independently predicted incident total atherosclerotic cardiovascular disease events, ischemic heart disease, and cerebral infarction in a nondiabetic population (all P<0.05), and significantly improved the discriminatory and reclassifying abilities of our prediction model after adjustment for established cardiovascular risk factors. Conclusions This study provides the first evidence that FGF21 levels are elevated in patients without nonalcoholic fatty liver disease with subclinical atherosclerosis. Baseline FGF21 is an independent predictor of atherosclerotic cardiovascular disease and represents a novel biomarker for primary prevention in the general population.
| S-EPMC7428997 | biostudies-literature
Project description:CONTEXT:A large body of experimental and observational data has implicated vitamin D deficiency in the development of cardiovascular disease. However, evidence to support routine vitamin D supplementation to prevent or treat cardiovascular disease is lacking. EVIDENCE ACQUISITION:A comprehensive literature review was performed using Pubmed and other literature search engines. EVIDENCE SYNTHESIS:Mounting epidemiological evidence and data from Mendelian randomization studies support a link between vitamin D deficiency and adverse cardiovascular health outcomes, but randomized trial evidence to support vitamin D supplementation is sparse. Current public health guidelines restrict vitamin D intake recommendations to the maintenance of bone health and prevention of fractures. Two recently published large trials (VITAL and ViDA) that assessed the role of moderate-to-high dose vitamin D supplementation as primary prevention for cardiovascular outcomes in the general population had null results, and previous randomized trials have also been generally negative. These findings from general population cohorts that are largely replete in vitamin D may not be applicable to chronic kidney disease (CKD) populations, in which the use of active (1?-hydroxylated) vitamin D compounds is prevalent, or to other high-risk populations. Additionally, recent trials in the CKD population, and trials using vitamin D analogues have been limited. CONCLUSIONS:Current randomized trials of vitamin D supplementation do not support benefits for cardiovascular health, but the evidence remains inconclusive. Additional randomized trials assessing larger numbers of participants with low baseline vitamin D levels, having longer follow-up periods, and testing higher vitamin D dosages, are needed to guide clinical practice.
| S-EPMC7112191 | biostudies-literature
Project description:High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.
| S-EPMC6245940 | biostudies-literature
Project description:Dysregulation of the complement alternative pathway (AP) is a major pathogenic mechanism in atypical hemolytic-uremic syndrome (aHUS). Genetic or acquired defects in factor H (FH), the main AP regulator, are major aHUS drivers that associate with a poor prognosis. FH activity has been suggested to be downregulated by homologous FH-related (FHR) proteins, including FHR-3 and FHR-1. Hence, their relative levels in plasma could be disease-relevant. The genes coding for FH, FHR-3, and FHR-1 (CFH, CFHR3, and CFHR1, respectively) are polymorphic and located adjacent to each other on human chromosome 1q31.3. We have previously shown that haplotype CFH(H3)-CFHR3*B-CFHR1*B associates with aHUS and reduced FH levels. In this study, we used a specific enzyme-linked immunosorbent assay to quantify FHR-3 in plasma samples from controls and patients with aHUS genotyped for the three known CFHR3 alleles (CFHR3*A, CFHR3*B, and CFHR3*Del). In the 218 patients carrying at least one copy of CFHR3, significant differences between CFHR3 genotype groups were found, with CFHR3*A/Del patients having the lowest FHR-3 concentration (0.684-1.032?µg/mL), CFHR3*B/Del and CFHR3*A/A patients presenting intermediate levels (1.437-2.201?µg/mL), and CFHR3*A/B and CFHR3*B/B patients showing the highest concentration (2.330-4.056?µg/mL) (p?<?0.001). These data indicate that CFHR3*A is a low-expression allele, whereas CFHR3*B, associated with increased risk of aHUS, is a high-expression allele. Our study reveals that the aHUS-risk haplotype CFH(H3)-CFHR3*B-CFHR1*B generates twofold more FHR-3 than the non-risk CFH(H1)-CFHR3*A-CFHR1*A haplotype. In addition, FHR-3 levels were higher in patients with aHUS than in control individuals with the same CFHR3 genotype. These data suggest that increased plasma levels of FHR-3, altering the balance between FH and FHR-3, likely impact the FH regulatory functions and contribute to the development of aHUS.
| S-EPMC5928496 | biostudies-literature
Project description:BackgroundCardiovascular disease is the leading cause of noncancer mortality for breast cancer survivors. Data are limited regarding patient-level atherosclerotic cardiovascular disease (ASCVD) risk estimation and preventive medication use. This study aimed to characterize ASCVD risk and longitudinal preventive medication use for a cohort of patients with nonmetastatic breast cancer.Patients and methodsThis retrospective cohort study included 326 patients at an academic medical center in Boston, Massachusetts diagnosed with nonmetastatic breast cancer or ductal carcinoma in situ from January 2009 through December 2015. Patient demographics, clinical characteristics, laboratory studies, medication exposure, and incident cardiovascular outcomes were collected. Estimated 10-year ASCVD risk was calculated for all patients from nonlaboratory clinical parameters.ResultsMedian follow up time was 6.5 years (IQR 5.0, 8.1). At cancer diagnosis, 23 patients (7.1%) had established ASCVD. Among those without ASCVD, 10-year estimated ASCVD risk was ≥20% for 77 patients (25.4%) and 7.5% to <20% for 114 patients (37.6%). Two-hundred and sixteen patients (66.3%) had an indication for lipid-lowering therapy at cancer diagnosis, 123 of whom (57.0%) received a statin during the study. Among 100 patients with ASCVD or estimated 10-year ASCVD risk ≥20%, 92 (92.0%) received an antihypertensive medication during the study. Clinic blood pressure >140/90 mmHg was observed in 33.0% to 55.6% of these patients at each follow up assessment.ConclusionA majority of patients in this breast cancer cohort had an elevated risk of ASCVD at the time of cancer diagnosis. Modifiable ASCVD risk factors were frequently untreated or uncontrolled in the years following cancer treatment.
| S-EPMC10872238 | biostudies-literature
Project description:Here we performed a metagenome-wide association study (MWAS) on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls.
| PRJEB21528 | ENA
Project description:The gut microbiota has been linked to cardiovascular diseases. However, the composition and functional capacity of the gut microbiome in relation to cardiovascular diseases have not been systematically examined. Here, we perform a metagenome-wide association study on stools from 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 healthy controls. The ACVD gut microbiome deviates from the healthy status by increased abundance of Enterobacteriaceae and Streptococcus spp. and, functionally, in the potential for metabolism or transport of several molecules important for cardiovascular health. Although drug treatment represents a confounding factor, ACVD status, and not current drug use, is the major distinguishing feature in this cohort. We identify common themes by comparison with gut microbiome data associated with other cardiometabolic diseases (obesity and type 2 diabetes), with liver cirrhosis, and rheumatoid arthritis. Our data represent a comprehensive resource for further investigations on the role of the gut microbiome in promoting or preventing ACVD as well as other related diseases.The gut microbiota may play a role in cardiovascular diseases. Here, the authors perform a metagenome-wide association study on stools from individuals with atherosclerotic cardiovascular disease and healthy controls, identifying microbial strains and functions associated with the disease.
| S-EPMC5635030 | biostudies-literature