Genetic Predictor to Identify Individuals With High Lipoprotein(a) Concentrations.
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ABSTRACT:
SUBMITTER: Dron JS
PROVIDER: S-EPMC7887018 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionLipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease (CAD). To the best of our knowledge, this is the first study addressing the relationship between Lp(a) and platelet reactivity in primary and secondary prevention.MethodsLp(a) was evaluated in 396 individuals with (82.3%) and without (17.7%) obstructive CAD. The population was divided into two groups according to Lp(a) concentrations with a cutoff value of 50 mg/dL. The primary objective was to evaluate the association between Lp(a) and adenosine diphosphate (ADP)-induced platelet reactivity using the VerifyNow™ P2Y12 assay. Platelet reactivity was also induced by arachidonic acid and collagen-epinephrine (C-EPI) and assessed by Multiplate™, platelet function analyzer™ 100 (PFA-100), and light transmission aggregometry (LTA) assays. Secondary objectives included the assessment of the primary endpoint in individuals with or without CAD.ResultsOverall, 294 (74.2%) individuals had Lp(a) < 50 mg/dL [median (IQR) 13.2 (5.8-27.9) mg/dL] and 102 (25.8%) had Lp(a) ≥ 50 mg/dL [82.5 (67.6-114.5) mg/dL], P < 0.001. Univariate analysis in the entire population revealed no differences in ADP-induced platelet reactivity between individuals with Lp(a) ≥ 50 mg/dL (249.4 ± 43.8 PRU) versus Lp(a) < 50 mg/dL (243.1 ± 52.2 PRU), P = 0.277. Similar findings were present in individuals with (P = 0.228) and without (P = 0.669) CAD, and regardless of the agonist used or method of analysis (all P > 0.05). Finally, multivariable analysis did not show a significant association between ADP-induced platelet reactivity and Lp(a) ≥ 50 mg/dL [adjusted OR = 1.00 [(95% CI 0.99-1.01), P = 0.590].ConclusionIn individuals with or without CAD, Lp(a) ≥ 50 mg/dL was not associated with higher platelet reactivity.
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Project description:The need to identify and effectively treat COVID-19 cases at highest risk for severe disease remains critical. We identified five common genetic loci (two novel) that modulate both COVID-19 susceptibility and severity, implicating TMPRSS2, IFNAR2, CCHCR1, TCF19 and SLC6A20 as potential targets. A high genetic burden was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known clinical risk factors.
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Project description:There is extensive evidence demonstrating that there is a clear inverse correlation between plasma high density lipoprotein cholesterol (HDL-C) concentration and cardiovascular disease (CVD). On the other hand, there is also extensive evidence that HDL functionality plays a very important role in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for the metabolism and adequate function of HDL, may positively or negatively affect the HDL-C levels and/or HDL functionality and subsequently either provide protection or predispose to atherosclerotic disease. This review aims to describe certain genetic disorders associated with either low or high plasma HDL-C and discuss their clinical features, associated risk for cardiovascular events, and treatment options.
| S-EPMC6135231 | biostudies-literature
Project description:The concentration of high-density lipoprotein-cholesterol (HDL-C) in humans is partially determined by genetic factors; however, the role of these factors is incompletely understood. The aim of this study was to examine the prevalence and characteristics of CETP, LIPC, and SCARB1 variants in Korean individuals with extremely high HDL-C levels. We also analysed associations between these variants and cholesterol efflux capacity (CEC), reactive oxygen species (ROS) generation, and vascular cell adhesion molecule-1 (VCAM-1) expression. Of 13,545 participants in the cardiovascular genome cohort, 42 subjects with HDL-C levels >100 mg/dL were analysed. The three target genes were sequenced by targeted next-generation sequencing, the functional effects of detected variants were predicted, and CEC was assessed using a radioisotope and apolipoprotein B-depleted sera. We observed two rare variants of CETP in 13 individuals (rare variant c.A1196G [p.D399G] of CETP was discovered in 12 subjects) and one rare variant of SCARB1 in one individual. Furthermore, all subjects had at least one of four common variants (one CETP and three LIPC variants). Two additional novel CETP variants of unknown frequency were found in two subjects. However, the identified variants did not show significant associations with CEC, ROS generation, or VCAM-1 expression. Our study provides additional insights into the role of genetics in individuals with extremely high HDL-C.
| S-EPMC6662756 | biostudies-literature
Project description:PurposeWe aimed to assess the prognostic value of pretreatment high density lipoprotein cholesterol (HDL-C) levels in patients with nasopharyngeal carcinoma (NPC) and investigate the possible biological effects of these lipoproteins on NPC cells in vitro.Experimental designWe examined the prognostic value of pretreatment HDL-C levels in 2443 patients with non-metastatic NPC from three independent institutions. The Cox proportional hazard model and log-rank test were used to analyze the correlation between HDL-C levels and overall survival (OS). Cell growth, colony formation, and apoptotic assays were used to determine the biological functions of HDL on NPC cells in vitro. All of the statistical tests were two-sided.ResultsOS was decreased in patients with high pretreatment HDL-C levels compared with those with low HDL-C levels (P < 0.05). Similarly, a decreased OS was noted in advanced stage (stage III-IV), NPC patients with high pretreatment HDL-C levels (P < 0.01). Multivariate analyses indicated that HDL-C was an independent prognostic factor associated with shorter OS in training cohorts. These findings were confirmed in both independent validation cohorts (P < 0.01). In vitro experiments demonstrated that HDL could increase cell proliferation, invasion, and colony formation, which were largely dependent on the expression of its receptor SR-B1. Finally, HDL could enhance chemoresistance by protecting cancer cells from apoptosis.ConclusionsPretreatment HDL-C is a poor prognostic factor for patients with NPC. This effect may be associated with the ability of HDL to enhance proliferation, colony formation, migration, and chemoresistance in NPC cells.
| S-EPMC5190001 | biostudies-literature
Project description:A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.
| S-EPMC3063776 | biostudies-literature
Project description:Common variants in the hepatic lipase (LIPC) gene have been shown to be associated with plasma lipid levels; however, the distribution and functional features of rare and regulatory LIPC variants contributing to the extreme lipid phenotypes are not well known. This study was aimed to catalogue LIPC variants by resequencing the entire LIPC gene in 95 non-Hispanic Whites (NHWs) and 95 African blacks (ABs) with extreme HDL-C levels followed by in silico functional analyses. A total of 412 variants, including 43 novel variants were identified; 56 were unique to NHWs and 234 were unique to ABs. Seventy-eight variants in NHWs and 89 variants in ABs were present either in high HDL-C group or low HDL-C group. Two non-synonymous variants (p.S289F, p.T405M), found in NHWs with high HDL-C group were predicted to have damaging effect on LIPC protein by SIFT, MT2 and PP2. We also found several non-coding variants that possibly reside in the circRNA and lncRNA binding sites and may have regulatory potential, as identified in rSNPbase and RegulomeDB databases. Our results shed light on the regulatory nature of rare and non-coding LIPC variants as well as suggest their important contributions in affecting the extreme HDL-C phenotypes.
| S-EPMC7743991 | biostudies-literature
Project description:OBJECTIVE:Lp(a) (lipoprotein(a)) concentrations are widely genetically determined by the LPA isoforms and show 5-fold interpopulation differences. Two- to 3-fold differences have been reported even within Europe. Finns represent a distinctive population isolate within Europe and have been repeatedly reported to present lower Lp(a) concentrations than Central Europeans. The significance of this finding was unclear for a long time because of the difficult comparability of Lp(a) assays. Recently, a large standardized study in >50?000 individuals from 7 European populations confirmed this observation but could not provide insights into the causes. APPROACH AND RESULTS:We investigated Lp(a) concentrations, LPA isoforms, and genotypes of established genetic variants affecting Lp(a) concentrations (LPA variants, APOE isoforms, and PCSK9 R46L) in the Finnish YFS (Cardiovascular Risk in Young Finns Study) population (n=2281) and 3 Non-Finnish Central European populations (n=10?003). We observed ?50% lower Lp(a) concentrations in Finns. The isoform distribution was shifted toward longer isoforms, and the percentage of low-molecular-weight isoform carriers was reduced. Most interestingly, however, Lp(a) was reduced in each single-isoform group. In contrast to the known inverse relationship between LPA isoforms and Lp(a) concentrations, especially very short isoforms presented unexpectedly low Lp(a) concentrations in Finns. The investigated genetic variants, as well as age, sex, and renal function, explained 71.8% of the observed population differences. CONCLUSIONS:The population differences in Lp(a) concentrations between Finnish and Central European populations originate not only from a different LPA isoform distribution but suggest the existence of novel functional variation in the small-isoform range.
| S-EPMC5943067 | biostudies-literature
Project description:In the United States, approximately 9% of the measles cases reported from 2012 to 2014 occurred in vaccinated individuals. Laboratory confirmation of measles in vaccinated individuals is challenging since IgM assays can give inconclusive results. Although a positive reverse transcription (RT)-PCR assay result from an appropriately timed specimen can provide confirmation, negative results may not rule out a highly suspicious case. Detection of high-avidity measles IgG in serum samples provides laboratory evidence of a past immunologic response to measles from natural infection or immunization. High concentrations of measles neutralizing antibody have been observed by plaque reduction neutralization (PRN) assays among confirmed measles cases with high-avidity IgG, referred to here as reinfection cases (RICs). In this study, we evaluated the utility of measuring levels of measles neutralizing antibody to distinguish RICs from noncases by receiver operating characteristic curve analysis. Single and paired serum samples with high-avidity measles IgG from suspected measles cases submitted to the CDC for routine surveillance were used for the analysis. The RICs were confirmed by a 4-fold rise in PRN titer or by RT-quantitative PCR (RT-qPCR) assay, while the noncases were negative by both assays. Discrimination accuracy was high with serum samples collected ?3 days after rash onset (area under the curve, 0.953; 95% confidence interval [CI], 0.854 to 0.993). Measles neutralizing antibody concentrations of ?40,000 mIU/ml identified RICs with 90% sensitivity (95% CI, 74 to 98%) and 100% specificity (95% CI, 82 to 100%). Therefore, when serological or RT-qPCR results are unavailable or inconclusive, suspected measles cases with high-avidity measles IgG can be confirmed as RICs by measles neutralizing antibody concentrations of ?40,000 mIU/ml.
| S-EPMC4979181 | biostudies-literature
Project description:BackgroundMixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM.MethodsThe previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women).ResultsAlirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed.ConclusionsAlirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.
| S-EPMC7007683 | biostudies-literature