RESUMO
Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)-like particle in which the apolipoprotein B component is covalently linked to apolipoprotein(a) (apo(a)). Lp(a) is a well-established independent risk factor for cardiovascular diseases. Plasma Lp(a) concentrations vary enormously between individuals and ethnic groups. Several nucleotide polymorphisms in the SLC22A3 gene associate with Lp(a) concentration in people of different ethnicities. We investigated the association of a Polynesian-specific (Maori and Pacific peoples) SLC22A3 gene coding variant p.Thr44Met) with the plasma concentration of Lp(a) in a cohort of 302 healthy Polynesian males. An apo(a)-size independent assay assessed plasma Lp(a) concentrations; all other lipid and apolipoprotein concentrations were measured using standard laboratory techniques. Quantitative real-time polymerase chain reaction was used to determine apo(a) isoforms. The range of metabolic (HbA1c, blood pressure, and blood lipids) and blood lipid variables were similar between the non-carriers and carriers in age, ethnicity and BMI adjusted models. However, rs8187715 SLC22A3 variant was significantly associated with lower Lp(a) concentrations. Median Lp(a) concentration was 10.60 nmol/L (IQR: 5.40-41.00) in non-carrier group, and was 7.60 nmol/L (IQR: 5.50-12.10) in variant carrier group (P<0.05). Lp(a) concentration inversely correlated with apo(a) isoform size. After correction for apo(a) isoform size, metabolic parameters and ethnicity, the association between the SLC22A3 variant and plasma Lp(a) concentration remained. The present study is the first to identify the association of this gene variant and low plasma Lp(a) concentrations. This provides evidence for better guidance on ethnic specific cut-offs when defining 'elevated' and 'normal' plasma Lp(a) concentrations in clinical applications.
Assuntos
Apoproteína(a) , Lipoproteína(a) , Proteínas de Transporte de Cátions Orgânicos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Apoproteína(a)/genética , Apoproteína(a)/sangue , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Proteínas de Transporte de Cátions Orgânicos/genética , População das Ilhas do Pacífico , Isoformas de Proteínas/genética , Isoformas de Proteínas/sangueRESUMO
Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competitive blockade of the αIIbß3 integrin on platelets. ApoA-IV inhibition of platelets was dependent on the N-terminal D5/D13 residues, and enhanced with absence of the C-terminus, suggesting it sterically hinders its N-terminal platelet binding site. The C-terminus is also the site of common apoA-IV polymorphisms apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). Interestingly, both are linked with an increased risk of cardiovascular disease, however, the underlying mechanism remains unclear. Here, we generated recombinant apoA-IV and found that the Q360H or T347S polymorphisms dampened its inhibition of platelet aggregation in human platelet-rich plasma and gel-filtered platelets, reduced its inhibition of platelet spreading, and its inhibition of P-selectin on activated platelets. Using an ex vivo thrombosis assay, we found that Q360H and T347S attenuated its inhibition of thrombosis at both high (1800s-1) and low (300s-1) shear rates. We then demonstrate a conserved monomer-dimer distribution among apoA-IV WT, Q360H, and T347S and use protein structure modelling software to show Q360H and T347S enhance C-terminal steric hindrance over the N-terminal platelet-binding site. These data provide critical insight into increased cardiovascular risk for individuals with Q360H or T347S polymorphisms.
Assuntos
Apolipoproteínas A , Plaquetas , Agregação Plaquetária , Trombose , Humanos , Trombose/genética , Trombose/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Polimorfismo Genético , Apoproteína(a)/genética , Apoproteína(a)/metabolismo , Apoproteína(a)/química , Selectina-P/genética , Selectina-P/metabolismoRESUMO
Lipoprotein(a) [Lp(a)] concentrations are regulated by the LPA gene mainly via the large kringle IV-type 2 (KIV-2) copy number variation and multiple causal variants. Early studies suggested an effect of long pentanucleotide repeat (PNR) alleles (10 and 11 repeats, PNR10 and PNR11) in the LPA promoter on gene transcription and found an association with lower Lp(a). Subsequent in vitro studies showed no effects on mRNA transcription, but the association with strongly decreased Lp(a) remained consistent. We investigated the isolated and combined effect of PNR10, PNR11, and the frequent splice site variant KIV-2 4925G>A on Lp(a) concentrations in the Cooperative Health Research in the Region of Augsburg F4 study by multiple quantile regression in single-SNP and joint models. Data on Lp(a), apolipoprotein(a) Western blot isoforms, and variant genotypes were available for 2,858 individuals. We found a considerable linkage disequilibrium between KIV-2 4925G>A and the alleles PNR10 and PNR11. In single-variant analysis adjusted for age, sex, and the shorter apo(a) isoform, we determined that both PNR alleles were associated with a highly significant Lp(a) decrease (PNR10: ß = -14.43 mg/dl, 95% CI: -15.84, -13.02, P = 3.33e-84; PNR11: ß = -17.21 mg/dl, 95% CI: -20.19, -14.23, P = 4.01e-29). However, a joint model, adjusting the PNR alleles additionally for 4925G>A, abolished the effect on Lp(a) (PNR10: ß = +0.44 mg/dl, 95% CI: -1.73, 2.60, P = 0.69; PNR11: ß = -1.52 mg/dl, 95% CI: -6.05, 3.00, P = 0.51). Collectively, we conclude that the previously reported Lp(a) decrease observed in pentanucleotide alleles PNR10 or PNR11 carriers results from a linkage disequilibrium with the frequent splicing mutation KIV-2 4925G>A.
Assuntos
Variações do Número de Cópias de DNA , Kringles , Humanos , Apoproteína(a)/genética , Kringles/genética , Apolipoproteínas A/genética , Lipoproteína(a)/genética , Repetições de MicrossatélitesRESUMO
High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for cardiovascular disease. Lp(a) concentrations are an enigmatic trait largely controlled by one single gene (LPA) that contains a complex interplay of several genetic elements with many surprising effects discussed in this review. A hypervariable coding copy number variation (the kringle IV type-2 repeat, KIV-2) generates >40 apolipoprotein(a) protein isoforms and determines the median Lp(a) concentrations. Carriers of small isoforms with up to 22 kringle IV domains have median Lp(a) concentrations up to 5 times higher than those with large isoforms (>22 kringle IV domains). The effect of the apo(a) isoforms are, however, modified by many functional single nucleotide polymorphisms (SNPs) distributed over the complete range of allele frequencies (<0.1% to >20%) with very pronounced effects on Lp(a) concentrations. A complex interaction is present between the apo(a) isoforms and LPA SNPs, with isoforms partially masking the effect of functional SNPs and, vice versa, SNPs lowering the Lp(a) concentrations of affected isoforms. This picture is further complicated by SNP-SNP interactions, a poorly understood role of other polymorphisms such as short tandem repeats and linkage structures that are poorly captured by common R2 values. A further layer of complexity derives from recent findings that several functional SNPs are located in the KIV-2 repeat and are thus not accessible to conventional sequencing and genotyping technologies. A critical impact of the ancestry on correlation structures and baseline Lp(a) values becomes increasingly evident. This review provides a comprehensive overview on the complex genetic architecture of the Lp(a) concentrations in plasma, a field that has made tremendous progress with the introduction of new technologies. Understanding the genetics of Lp(a) might be a key to many mysteries of Lp(a) and booster new ideas on the metabolism of Lp(a) and possible interventional targets.
Assuntos
Kringles , Lipoproteína(a) , Apolipoproteínas A/genética , Apoproteína(a)/genética , Variações do Número de Cópias de DNA , Kringles/genética , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genéticaRESUMO
Background Lp(a) (lipoprotein(a)) is the major lipoprotein carrier of oxidized phospholipids (OxPL) and this function mediates Lp(a) atherogenicity. However, the relationship between OxPL, Lp(a), and genetic and biological characteristics remains poorly understood. We assessed the relationship between Lp(a)-bound OxPL, apolipoprotein(a) (apo(a)) size, age, and family structure in 2 racial groups. Methods and Results Healthy Black and White families were recruited from the general population (age: 6-74 years, n=267). OxPL and Lp(a) levels were assayed enzymatically; apo(a) isoform, LPA allele sizes, and allele-specific Lp(a) levels were determined. Lp(a)-OxPL levels did not differ significantly by racial and age groups. Lp(a)-OxPL levels were associated with total plasma Lp(a) in all participants and in race-specific analyses. Further, OxPL levels were significantly associated with allele-specific Lp(a) levels carried by the smaller apo(a) size in all participants (ß=0.33, P=0.0003) as well as separately for Black (ß=0.50, P=0.0032) and White (ß=0.26, P=0.0181) participants. A significant association of OxPL with allele-specific Lp(a) levels for larger apo(a) sizes was seen only in Black participants (ß=0.53, P=0.0076). In this group, Lp(a)-OxPL levels were also heritable (h2=0.29, P=0.0235), resulting in a significant interracial difference in heritability between Black and White people (P=0.0352). Conclusions Lp(a)-OxPL levels were associated with allele-specific Lp(a) level carried on smaller apo(a) sizes and among Black participants also for larger apo(a) sizes. The heritability estimates for Lp(a)-bound OxPL differed by race.
Assuntos
População Negra/genética , Lipoproteína(a) , Fosfolipídeos , População Branca/genética , Adolescente , Adulto , Idoso , Apoproteína(a)/genética , Criança , Humanos , Lipoproteína(a)/genética , Pessoa de Meia-Idade , Oxirredução , Adulto JovemRESUMO
BACKGROUND AND AIMS: Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a) thresholds, but the prevalence of LPA genetic variants and their effect on efficacy of these ASOs are not well described. METHODS: We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a). RESULTS: The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied. CONCLUSIONS: In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.
Assuntos
Apolipoproteínas A , Lipoproteína(a) , Apoproteína(a)/genética , Humanos , Lipoproteína(a)/genética , Prevalência , Isoformas de Proteínas/genéticaRESUMO
Lipoprotein(a) (Lp(a)) is an independent risk factor in the development of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve disease (CAVD). Lp(a) is an LDL-like particle to which apolipoprotein (a) (apo(a)) is covalently bound. Apo(a) contains a variable number of kringle IV repeats, a kringle V and a protease domain. Serum/plasma Lp(a) concentrations are traditionally expressed as total particle mass in mg/L. Concern has arisen lately as flawed Lp(a) mass tests have masked its clinical utility. The determinants of variability in Lp(a) composition were investigated, including the apo(a) size polymorphism, post-translational modifications -N- and O-glycosylation- and the lipid:protein ratio. Depending on the number of kringle IV-2 repeats, the theoretical protein content of the Lp(a) particle varies between 30 and 46 (w/w) %, which inescapably confounds Lp(a) mass measurements. The authors advocate that reporting of Lp(a) particle concentrations in mass units is metrologically inappropriate and should be abandoned, as it results in systematically biased Lp(a) results. Enabling technology, such as mass spectrometry, allows unequivocal molecular characterization of the apo(a) measurand(s) and accurate quantitation of apo(a) in molar units, unaffected by apo(a) size polymorphism. To guarantee that Lp(a)/apo(a) tests are fit-for-clinical-purpose, basic metrology principles should be implemented upfront during test development.
Assuntos
Apolipoproteínas A , Medicina de Precisão , Apolipoproteínas A/genética , Apoproteína(a)/genética , Humanos , Kringles , Lipoproteína(a)/genéticaRESUMO
BACKGROUND: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts. METHODS: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline. RESULTS: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R2 = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping. CONCLUSIONS: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.
Assuntos
Alelos , Apoproteína(a)/genética , Códon sem Sentido , Genética Populacional , Idoso , Povo Asiático/genética , Biomarcadores , Feminino , Estudos de Associação Genética , Genética Populacional/métodos , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único , Sítios de Splice de RNA , População Branca/genéticaRESUMO
AIMS: Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a). METHODS AND RESULTS: Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C). CONCLUSION: Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).
Assuntos
Lipoproteína(a) , Monócitos , Apoproteína(a)/genética , Humanos , Oligonucleotídeos , Pró-Proteína Convertase 9/genéticaRESUMO
KEY MESSAGE: Even a point mutation in the psaA gene mediates chlorophyll deficiency. The role of the plastid signal may perform the redox state of the compounds on the acceptor-side of PSI. Two extranuclear variegated mutants of sunflower, Var1 and Var33, were investigated. The yellow sectors of both mutants were characterized by an extremely low chlorophyll and carotenoid content, as well as poorly developed, unstacked thylakoid membranes. A full-genome sequencing of the cpDNA revealed mutations in the psaA gene in both Var1 and Var33. The cpDNA from the yellow sectors of Var1 differs from those in the wild type by only a single, non-synonymous substitution (Gly734Glu) in the psaA gene, which encodes a subunit of photosystem (PS) I. In the cpDNA from the yellow sectors of Var33, the single-nucleotide insertion in the psaA gene was revealed, leading to frameshift at the 580 amino acid position. Analysis of the photosynthetic electron transport demonstrated an inhibition of the PSI and PSII activities in the yellow tissues of the mutant plants. It has been suggested that mutations in the psaA gene of both Var1 and Var33 led to the disruption of PSI. Due to the non-functional PSI, photosynthetic electron transport is blocked, which, in turn, leads to photodamage of PSII. These data are confirmed by immunoblotting analysis, which showed a significant reduction in PsbA in the yellow leaf sectors, but not PsaA. The expression of chloroplast and nuclear genes encoding the PSI subunits (psaA, psaB, and PSAN), the PSII subunits (psbA, psbB, and PSBW), the antenna proteins (LHCA1, LHCB1, and LHCB4), the ribulose 1.5-bisphosphate carboxylase subunits (rbcL and RbcS), and enzymes of chlorophyll biosynthesis were down-regulated in the yellow leaf tissue. The extremely reduced transcriptional activity of the two protochlorophyllide oxidoreductase (POR) genes involved in chlorophyll biosynthesis is noteworthy. The disruption of NADPH synthesis, due to the non-functional PSI, probably led to a significant reduction in NADPH-protochlorophyllide oxidoreductase in the yellow sectors of Var1 and Var33. A dramatic decrease in chlorophyllide was shown in the yellow sectors. A reduction in NADPH-protochlorophyllide oxidoreductase, along with photodegradation, has been suggested as a result of chlorophyll deficiency.
Assuntos
Apoproteína(a)/genética , Clorofila A/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , Helianthus/genética , Complexo de Proteína do Fotossistema I/metabolismo , Mutação Puntual , Clorofila A/química , DNA de Plantas , Genoma de Planta , Fenótipo , Complexo de Proteína do Fotossistema I/genética , PigmentaçãoRESUMO
Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.
Assuntos
Apoproteína(a)/genética , Lipoproteína(a)/genética , Plasminogênio/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Alelos , Linhagem Celular Tumoral , Estudos de Coortes , Humanos , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Plasminogênio/deficiênciaRESUMO
Ðim. Comparative assessment of respiratory indicators according to multifunctional monitoring (PFM) with the recommended standard for a complete polysomnographic study and an assessment of the effect of blood pressure (BP) measurements in PFM on sleep quality. Triаls on the аssociаtion of Lp(а) and cаrotid аtherosclerosis аre limited. The аim of the study wаs to investigаte the аssociаtion of Lp(а), аpolipoprotein(а) [apo(а)] polymorphism аnd аutoаntibodies to Lp(а) with stenotic (≥50%) cаrotid аtherosclerosis in dependence on CHD presence. Materials and methods. The study included 785 pаtients аt the аge from 21 to 92 with dаtа of instrumentаl exаmination of coronаry, cаrotid аnd lower limbs аrteries. Stenotic cаrotid аtherosclerosis wаs diаgnosed in 447 pаtients who were divided into two groups depending on presence (n=344) or аbsence (n=103) of CHD. The control group comprised of 338 pаtients without stenotic аtherosclerosis of coronаry, cаrotid аnd lower limbs аrteries. In the blood serum of pаtients levels of Lp(а), аutoаntibodies to Lp(а) were determined аnd аlso аpo(а) phenotyping wаs conducted. Results. There were more mаles, higher аverаge аge аnd frequency of hypertension, type 2 diаbetes mellitus, smoking, Lp(а) concentrаtion (mediаn [interquаrtile rаnge]): 30 [11; 63] vs. 14 [5; 30] mg/dl, p<0.01) in the group with stenotic cаrotid аtherosclerosis in compаrison with control group. Besides, Lp(а) level wаs higher in CHD subgroup thаn in pаtients with stenotic cаrotid аtherosclerosis without CHD: 32 [12; 72] vs. 24 [8; 50] mg/dl, respectively, p=0.01. Elevаted (≥30 mg/dl) Lp(а) level, low moleculаr weight аpolipoprotein(а) [(LMW аpo(а)] phenotype were аssociаted with stenotic cаrotid аtherosclerosis (odds rаtio (OR) 2.9; 95% confidence intervаl (CI) 2.1-4.0, p<0.01 аnd OR 2.3; 95% CI 1.6-3.4, p<0.01, respectively). Logistic regression аnаlysis showed independent аssociаtion of elevаted Lp(а) level аnd LMW аpo(а) phenotype with stenotic cаrotid аtherosclerosis both in the presence аnd absence of CHD. The level of IgM аutoаntibodies to Lp(а) wаs higher in control group thаn in pаtients with stenotic cаrotid аtherosclerosis, p=0.02. Conclusion The level of Lp(a) ≥30 mg/dl and low molecular weight phenotype of aprotein(a) are predictors of stenotic atherosclerosis CA, regardless of the presence of coronary heart disease and other risk factors, while a reverse relationship was found between the level of autoantibodies of the IgM class against Lp(a) and the severity of atherosclerosis CA.
Assuntos
Apoproteína(a)/genética , Aterosclerose/genética , Doenças das Artérias Carótidas , Diabetes Mellitus Tipo 2 , Lipoproteína(a)/genética , Aterosclerose/embriologia , Autoanticorpos , Doenças das Artérias Carótidas/genética , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6-74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair was higher than that corresponding to the larger LPA allele (0.91 vs. 0.59, P = 0.017). Although not statistically different, heritability for both apo(a) isoforms (0.90 vs. 0.70) and LPA alleles (0.98 vs. 0.82) was higher for the smaller versus larger sizes. Heritability was generally lower in African-Americans versus Caucasians with a 4-fold difference for the larger LPA allele (0.25 vs. 0.94, P = 0.001). In Caucasians, an overall higher heritability pattern was noted for the older (≥47 years) versus younger (<47 years) families. In conclusion, Lp(a) level and traits associated with the smaller LPA alleles were strongly determined by genetics, although with a varying ethnic influence. Ethnic differences in heritability of the larger LPA allele warrant further investigations.
Assuntos
Apoproteína(a)/genética , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Alelos , Criança , Feminino , Variação Genética/genética , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , População Branca , Adulto JovemAssuntos
Endometriose/metabolismo , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Antígenos de Neoplasias/genética , Apoproteína(a)/genética , Proteínas de Transporte/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas dos Microfilamentos , Mutação de Sentido Incorreto/genética , Proteínas Nucleares/genética , Pró-Proteína Convertase 5/genética , Proteínas de Ligação a RNA , Cistatinas Salivares/genética , Ubiquitina-Proteína Ligases/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Lipoprotein(a) [Lp(a)] levels are primarily genetically determined, but their natural variability is not well known. OBJECTIVE: The aim of the study was to evaluate the short-term temporal variability in Lp(a) in 3 placebo groups from the IONIS-APO(a)Rx and IONIS-APO(a)-LRx trials. METHODS: The placebo groups comprised 3 studies: Study 1 with 10 subjects with any Lp(a) concentration; Study 2 with 13 subjects with Lp(a) ≥75 nmol/L (â¼30 mg/dL); and Study 3 with 29 patients with Lp(a) ≥125 nmol/L (≥â¼50 mg/dL). Lp(a) was measured in serial blood samples (range 7-12 samples up to 190 days of follow-up) and analyzed as absolute change and mean percent change from baseline. Outliers were defined as having a > ±25% difference in Lp(a) from baseline at any future time point. RESULTS: No significant temporal differences in mean absolute Lp(a) levels were present in any group. However, among individuals, the mean change in absolute Lp(a) levels at any time point ranged from -16.2 to +7.0 nmol/L in Study 1, -15.8 to +9.8 nmol/L in Study 2, and -60.2 to +16.6 nmol/L in Study 3. The mean percent change from baseline ranged from -9.4% to +21.6% for Study 1, -13.1% to 2.8% for Study 2, and -12.1% to +4.9% in Study 3. A total of 21 of 52 subjects (40.4%) were outliers, with 13 (62%) >25% up and 8 (38%) >25% down. Significant variability was also noted in other lipid parameters, but no outliers were noted with serum albumin. CONCLUSION: In subjects randomized to placebo in Lp(a) lowering trials, modest intra-individual temporal variability of mean Lp(a) levels was present. Significant number of subjects had > ±25% variation in Lp(a) in at least 1 time point. Although Lp(a) levels are primarily genetically determined, further study is required to define additional factors mediating short-term variability.
Assuntos
Acetilgalactosamina/química , Doenças Cardiovasculares/tratamento farmacológico , Lipoproteína(a)/sangue , Oligonucleotídeos Antissenso/uso terapêutico , Apoproteína(a)/antagonistas & inibidores , Apoproteína(a)/genética , Apoproteína(a)/metabolismo , LDL-Colesterol/sangue , Estudos de Coortes , Método Duplo-Cego , Humanos , Oligonucleotídeos Antissenso/química , Efeito Placebo , Resultado do TratamentoRESUMO
Elevated Lipoprotein(a) (Lp(a)) plasma concentrations are a risk factor for cardiovascular disease in humans, largely controlled by the LPA gene encoding apolipoprotein(a) (apo(a)). Lp(a) is composed of low-density lipoprotein (LDL) and apo(a) and restricted to Catarrhini. A variable number of kringle IV (KIV) domains in LPA lead to a size polymorphism of apo(a) that is inversely correlated with Lp(a) concentrations. Smaller apo(a) isoforms and higher Lp(a) levels in central chimpanzees (Pan troglodytes troglodytes [PTT]) compared to humans from Europe had been reported. We studied apo(a) isoforms and Lp(a) concentrations in 75 western (Pan troglodytes verus [PTV]) and 112 central chimpanzees, and 12 bonobos (Pan paniscus [PPA]), all wild born and living in sanctuaries in Sierra Leone, Republic of the Congo, and DR Congo, respectively, and 116 humans from Gabon. Lp(a) levels were severalfold higher in western than in central chimpanzees (181.0 ± 6.7 mg/dl vs. 56.5 ± 4.3 mg/dl), whereas bonobos showed intermediate levels (134.8 ± 33.4 mg/dl). Apo(a) isoform sizes differed significantly between subspecies (means 20.9 ± 2.2, 22.9 ± 4.4, and 23.8 ± 3.8 KIV repeats in PTV, PTT, and PPA, respectively). However, far higher isoform-associated Lp(a) concentrations for all isoform sizes in western chimpanzees offered the main explanation for the higher overall Lp(a) levels in this subspecies. Human Lp(a) concentrations (mean 47.9 ± 2.8 mg/dl) were similar to those in central chimpanzees despite larger isoforms (mean 27.1 ± 4.9 KIV). Lp(a) and LDL, apoB-100, and total cholesterol levels only correlated in PTV. This remarkable differentiation between chimpanzees from different African habitats and the trait's similarity in humans and chimpanzees from Central Africa poses the question of a possible impact of an environmental factor that has shaped the genetic architecture of LPA. Overall, studies on the cholesterol-containing particles of Lp(a) and LDL in chimpanzees should consider differentiation between subspecies.
Assuntos
Apoproteína(a)/genética , Lipoproteína(a)/genética , Pan troglodytes/genética , África Central , Animais , Congo , Gabão , Humanos , Serra LeoaRESUMO
Essentials Elevated lipoproteinp(a) is an independent and causal risk factor for atherothrombotic diseases. rs3798220 (Ile/Met substitution in apo(a) protease-like domain) is associated with disease risk. Recombinant I4399M apo(a) altered clot structure to accelerate coagulation/delay fibrinolysis. Evidence was found for increased solvent exposure and oxidation of Met residue. SUMMARY: Background Lipoprotein(a) (Lp[a]) is a causal risk factor for a variety of cardiovascular diseases. Apolipoprotein(a) (apo[a]), the distinguishing component of Lp(a), is homologous with plasminogen, suggesting that Lp(a) can interfere with the normal fibrinolytic functions of plasminogen. This has implications for the persistence of fibrin clots in the vasculature and hence for atherothrombotic diseases. A single-nucleotide polymorphism (SNP) (rs3798220) in the gene encoding apo(a) has been reported that results in an IleâMet substitution in the protease-like domain (I4399M variant). In population studies, the I4399M variant has been correlated with elevated plasma Lp(a) levels and higher coronary heart disease risk, and carriers of the SNP had increased cardiovascular benefit from aspirin therapy. In vitro studies suggested an antifibrinolytic role for Lp(a) containing this variant. Objectives We performed a series of experiments to assess the effect of the IleâMet substitution on fibrin clot formation and lysis, and on the architecture of the clots. Results We found that the Met variant decreased coagulation time and increased fibrin clot lysis time as compared with wild-type apo(a). Furthermore, we observed that the presence of the Met variant significantly increased fibrin fiber width in plasma clots formed ex vivo, while having no effect on fiber density. Mass spectrometry analysis of a recombinant apo(a) species containing the Met variant revealed sulfoxide modification of the Met residue. Conclusions Our data suggest that the I4399M variant differs structurally from wild-type apo(a), which may underlie key differences related to its effects on fibrin clot architecture and fibrinolysis.
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Apoproteína(a)/sangue , Apoproteína(a)/genética , Coagulação Sanguínea/genética , Fibrinólise/genética , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único , Trombose/sangue , Trombose/genética , Adulto , Apoproteína(a)/química , Feminino , Fibrina/química , Fibrina/metabolismo , Predisposição Genética para Doença , Células HEK293 , Homozigoto , Humanos , Lipoproteína(a)/química , Masculino , Metionina , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Oxirredução , Fenótipo , Conformação Proteica , Proteínas Recombinantes/sangue , Relação Estrutura-Atividade , TransfecçãoRESUMO
BACKGROUND: The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. METHODS: In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17â503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60â801 patients with coronary heart disease and 123â504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. FINDINGS: The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60â801 patients with coronary heart disease and 123â504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS. INTERPRETATION: Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. FUNDING: British Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer.
Assuntos
Apoproteína(a)/sangue , Biomarcadores/sangue , Doença das Coronárias/sangue , Lipoproteína(a)/sangue , Análise da Randomização Mendeliana/métodos , Infarto do Miocárdio/sangue , Polimorfismo de Nucleotídeo Único , Apoproteína(a)/genética , Estudos de Casos e Controles , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Incidência , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Paquistão/epidemiologia , Fenótipo , Isoformas de Proteínas , Fatores de RiscoRESUMO
OBJECTIVE: In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)-related elevated cardiovascular disease risk remain unclear. APPROACH AND RESULTS: The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima-media thickness. CONCLUSIONS: Lp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.
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Alelos , Apoproteína(a)/sangue , Apoproteína(a)/genética , Doenças das Artérias Carótidas/etiologia , Artéria Carótida Primitiva/diagnóstico por imagem , Espessura Intima-Media Carotídea , Infecções por HIV/complicações , Adulto , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/genética , Estudos de Casos e Controles , Feminino , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/genética , Humanos , Modelos Lineares , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto JovemRESUMO
Lipoprotein(a)[Lp(a)] is a risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Vitamin C is responsible for maintaining the catalytic activity of a group of iron and 2-oxoglutarate (2OG)-dependent dioxygenases and induces the generation of 5-hydroxymethylcytosine (5hmC) via Ten-eleven translocation (Tet) dioxygenases. In addition, It has been reported vitamin C deficiency induces atherosclerosis and increases Lp(a) and apo(a) plasma levels in Lp(a)+ mice. However, the mechanism is still unclear. In this study, we investigated the effects of vitamin C on apo(a) expression and the possible molecular mechanism of vitamin C that influences apolipoprotein(a) [apo(a)] biosynthesis in HepG2 cells. Results showed that vitamin C significantly inhibited the expression and secretion levels of apo(a). Vitamin C can also increase ELK1 expression and hydroxymethylation of ELK1 promoter and the globle DNA in HepG2 cells. In addition, the effects of vitamin C inhibiting the apo(a) expression were attenuated by ELK1siRNA and Tet2siRNA. These results suggested vitamin C down-regulate apo(a) expression via Tet2-dependent DNA demethylation in HepG2 cells.