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BACKGROUND: Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME. METHODS: TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model. RESULTS: Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro. CONCLUSIONS: Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa.
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Próstata , Neoplasias da Próstata , Animais , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Humanos , Masculino , Camundongos , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores de Epoprostenol , Microambiente TumoralRESUMO
BACKGROUND: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. OBJECTIVE: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related coronavirus, SARS-CoV-1, and SARS-CoV-2 infections. Therefore, we investigated the very first interactions of primary human airway epithelial cells on exposure to SARS-CoV-2 in terms of complement component 3 (C3)-mediated effects. METHODS: For this, we used highly differentiated primary human 3-dimensional tissue models infected with SARS-CoV-2 patient isolates. On infection, viral load, viral infectivity, intracellular complement activation, inflammatory mechanisms, and tissue destruction were analyzed by real-time RT-PCR, high content screening, plaque assays, luminex analyses, and transepithelial electrical resistance measurements. RESULTS: Here, we show that primary normal human bronchial and small airway epithelial cells respond to SARS-CoV-2 infection by an inflated local C3 mobilization. SARS-CoV-2 infection resulted in exaggerated intracellular complement activation and destruction of the epithelial integrity in monolayer cultures of primary human airway cells and highly differentiated, pseudostratified, mucus-producing, ciliated respiratory tissue models. SARS-CoV-2-infected 3-dimensional cultures secreted significantly higher levels of C3a and the proinflammatory cytokines IL-6, monocyte chemoattractant protein 1, IL-1α, and RANTES. CONCLUSIONS: Crucially, we illustrate here for the first time that targeting the anaphylotoxin receptors C3a receptor and C5a receptor in nonimmune respiratory cells can prevent intrinsic lung inflammation and tissue damage. This opens up the exciting possibility in the treatment of COVID-19.
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Brônquios/imunologia , COVID-19/imunologia , Ativação do Complemento , Células Epiteliais/imunologia , Receptor da Anafilatoxina C5a/imunologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Brônquios/patologia , Brônquios/virologia , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Complemento C3/imunologia , Citocinas/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologiaRESUMO
The aim of present research work was to evaluate the Salvia macrosiphon Boiss. of Lamiaceae (mint family), using biochemical and biological assays. Plant's phytochemicals extraction was performed in methanol, butanol and water by mechanical shaking process. TPC and TFC were determined by Folin-Ciocalteu and aluminum chloride colorimetric procedures, respectively. The highest TPC (99.61±3.45 mg GAE/g) and TFC (234.72±7.12mg CE/g) were obtained in butanol and methanol, respectively. Regarding the antioxidant potential methanol extract showed the highest DPPH° scavenging potential (78.0±2.0%) and reducing activity (0.923±0.020 absorbance). The antibacterial activity of butanol extract against P. aeruginosa were found highest (ZOI = 23±2.00 mm). Antifungal study of methanol extract showed the ZOI (11 ±0.67mm) against F. brachygibbosum. The results revealed that the methanol stem extract of S. macrosiphon bear significant medicinal value and could be used for formulating phytomedicines and food preservers.
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Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Salvia/química , Bactérias/efeitos dos fármacos , Compostos de Bifenilo , Flavonoides/análise , Sequestradores de Radicais Livres/farmacologia , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fenóis/análise , Picratos , Folhas de PlantaRESUMO
OBJECTIVE: Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes. APPROACH AND RESULTS: This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene (LPA) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter (P<0.0001); 95.3% of patients expressed at least 1 small apo(a) isoform. Small apo(a) isoform (35.2%) carrying phenotypes were not tagged by single-nucleotide polymorphisms rs10455872 or rs3798220. CONCLUSIONS: Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.
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Apoproteína(a)/sangue , Remoção de Componentes Sanguíneos/métodos , Doenças Cardiovasculares/prevenção & controle , Hiperlipoproteinemias/terapia , Lipoproteína(a)/sangue , Idoso , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Alemanha , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/epidemiologia , Hiperlipoproteinemias/genética , Incidência , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , 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.
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Apoproteína(a)/genética , Lipoproteína(a)/genética , Pan troglodytes/genética , África Central , Animais , Congo , Gabão , Humanos , Serra LeoaRESUMO
Lipoprotein (a) [Lp(a)] has attracted the interest of researchers and physicians due to its intriguing properties, including an intragenic multiallelic copy number variation in the LPA gene and the strong association with coronary heart disease (CHD). This review summarizes present knowledge of the structure, function, and genetics of Lp(a) with emphasis on the molecular and population genetics of the Lp(a)/LPA trait, as well as aspects of genetic epidemiology. It highlights the role of genetics in establishing Lp(a) as a risk factor for CHD, but also discusses uncertainties, controversies, and lack of knowledge on several aspects of the genetic Lp(a) trait, not least its function.
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Doenças Cardiovasculares/genética , Lipoproteína(a)/química , Lipoproteína(a)/fisiologia , Animais , Frequência do Gene , Predisposição Genética para Doença , Humanos , Polimorfismo Genético , Domínios ProteicosRESUMO
The development of single-cell omics tools has enabled scientists to study the tumor microenvironment (TME) in unprecedented detail. However, each of the different techniques may have its unique strengths and limitations. Here we directly compared two commercially available high-throughput single-cell RNA sequencing (scRNA-seq) technologies - droplet-based 10X Chromium vs. microwell-based BD Rhapsody - using paired samples from patients with localized prostate cancer (PCa) undergoing a radical prostatectomy. Although high technical consistency was observed in unraveling the whole transcriptome, the relative abundance of cell populations differed. Cells with low mRNA content such as T cells were underrepresented in the droplet-based system, at least partly due to lower RNA capture rates. In contrast, microwell-based scRNA-seq recovered less cells of epithelial origin. Moreover, we discovered platform-dependent variabilities in mRNA quantification and cell-type marker annotation. Overall, our study provides important information for selection of the appropriate scRNA-seq platform and for the interpretation of published results.
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We report the synthesis, characterization, biological evaluation and quantitative structure-activity relationship of some Schiff base esters as promising new antitumor, antioxidant and anti-inflammatory agents. The Schiff base esters were synthesized by two synthetic routes using variably substituted hydroxy benzaldehydes with para amino phenol in appreciable yields. All the newly synthesized esters have been characterized by (1)H-NMR,(.13)C-NMR, FT-IR techniques and elemental analysis. The synthesized esters were examined for antioxidant, antitumor and anti-inflammatory potentials through different bioassays and quantitative structure-activity relationship was studied. Bioassays showed encouraging results and indicated that some of these title compounds may have potential for further pharmacological investigations.
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Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Animais , Carragenina , Dano ao DNA , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Tumores de Planta/microbiologia , Relação Quantitativa Estrutura-Atividade , Ratos , Solanum tuberosum/efeitos dos fármacos , Solanum tuberosum/microbiologia , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.
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BACKGROUND: Hepatitis C virus (HCV) is an enveloped and positive-stranded RNA virus that is a major causative agent of chronic liver diseases worldwide. HCV has become the main cause of liver transplantations and there is no effective drug for all hepatitis genotypes. Elucidation of the life cycle and non-structural proteins of HCV, involved in viral replication, are attractive targets for the development of antiviral drugs.. METHODS: In this work, pharmacoinformatics approaches coupled with docking analyses were applied on HCV non-structural proteins to identify the novel potential hits and HCV drugs. Molecular docking analyses were carried out on HCV-approved drugs, followed by the ligandbased pharmacophore generation to screen the antiviral libraries for novel potential hits. RESULTS: Virtual screening technique has top-ranked five novel compounds (ZINC00607900, ZINC03635748, ZINC03875543, ZINC04097464, and ZINC12503102) along with their least binding energies (-8.0 kcal/mol, -6.1 kcal/mol, -7.5 kcal/mol, -7.4 kcal/mol, and -7.3 kcal/mol, respectively) and stability with the non-structural proteins target. CONCLUSION: These promising hits exhibited better absorption and ADMET properties as compared to the selected drug molecules. These potential compounds extracted from in silico approach may be significant in drug design and development against Hepatitis and other liver diseases.
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Hepacivirus , Hepatite C , Animais , Antivirais/química , Hepatite C/tratamento farmacológico , Ligantes , Simulação de Acoplamento Molecular , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
Ertapenem is a member of carbapenem antibiotics used for the treatment of moderate-to-severe intra-abdominal, urinary tract, acute pelvic, and post-surgical gynecologic infections. The antibacterial activity of ertapenem is mediated through binding to penicillin-binding proteins which results in inhibiting the cross-linking of the peptidoglycan layer of the bacterial cell wall. Therefore, ertapenem can be labeled with technetium-99m (99mTc), a gamma emitter radionuclide, for the diagnosis of deep-seated bacterial infections, such as urinary tract, intra-abdominal, osteomyelitis, and post-surgical gynecologic infections. The labeling procedure was carried out by varying the reaction conditions, such as the amount of the ligand and reducing agent, pH, reaction time and temperature, and radioactivity. At optimized reaction conditions more than 93% 99mTc-ertapenem radioconjugate was obtained. 99mTc-ertapenem was found 90% intact in saline medium up to 6 h, while 88% intact in human blood serum up to 3 h. Biodistribution study showed target-to-non-target ratios of 2.91 ± 0.19, 2.39 ± 0.31, and 1.23 ± 0.22 in S. aureus, E. coli, and turpentine oil-infected rat models, respectively. The SPECT scintigraphy showed high uptake of 99mTc-ertapenem in bacterial-infected abscesses, and low counts were recorded in normal and turpentine oil-inflamed tissues. In conclusion, 99mTc-ertapenem can be a potent infection-imaging agent, which can diagnosis deep-seated bacterial infections at early stage but need further pre-clinical evaluation in variety of infection models.
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The aim of this study was to investigate the phytochemicals using reverse-phase high pressure liquid chromatography (RP-HPLC), antioxidant, antifungal and antibacterial activities of Seriphidium oliverianum stem extracts. The extraction was carried out by conventional shaking process (CSP) and ultrasonic assisted process (UAP). The highest total phenolic contents (97.85 ± 0.735 mg gallic acid equivalent (GAE)/g sample) and flavonoid contents (188.15 ± 0.53 mg catechin equivalent (CE)/g sample) were found in methanol extract obtained by CSP. Antioxidant activity was investigated using DPPH° scavenging assay and reducing power assay. Methanol extract using UAP showed the highest DPPH° scavenging activity (79.95% ± 1.80%) followed by methanol and butanol extracts obtained through CSP. Moreover, methanol extracts using CSP showed highest reducing activity (1.032 ± 0.0205 absorbance). In-vitro antimicrobial activity was studied using most common infection causing fungal and bacterial strains. Anti-fungal activity of methanol extract using CSP showed the highest zone of inhibition (10.5 mm) against F. avenaceum fungal strain, while aqueous extracts obtained through showed the highest antibacterial activity (22 ± 1.32 mm zone of inhibition) against S. aureus. The results showed that the methanol stem extract of S. oliverianum is a valued candidate for further screening and could be processed for in-vivo infection induced animal trials.
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Since long-term corticosteroid treatment is associated with emerging opportunistic fungal infections causing high morbidity and mortality in immune-suppressed individuals, here we characterized the impact of dexamethasone (Dex) treatment on Aspergillus fumigatus-related immune modulation. We found by high content screening and flow cytometric analyses that during monocyte-to-macrophage differentiation, as little as 0.1 µg/mL Dex resulted in a shift in macrophage polarization from M1 to M2-like macrophages. This macrophage repolarization mediated via Dex was characterized by significant upregulation of the M2 marker CD163 and downmodulation of M1 markers CD40 and CD86 as well as changes in phenotypic properties and adherence. These Dex-mediated phenotypic alterations were furthermore associated with a metabolic switch in macrophages orchestrated via PKM2. Such treated macrophages lost their ability to prevent Aspergillus fumigatus germination, which was correlated with accelerated fungal growth, destruction of macrophages, and induction of an anti-inflammatory cytokine profile. Taken together, repolarization of macrophages following corticosteroid treatment and concomitant switch to an anti-inflammatory phenotype might play a prominent role in triggering invasive aspergillosis (IA) due to suppression of innate immunological responses necessary to combat extensive fungal outgrowth.
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Lung immunity and susceptibility to infections is subject to interactions between the epithelial layer and immune cells residing in the pulmonary space. Aspergillus (A.) fumigatus, the most prevalent pathogenic fungus, affects both upper and lower respiratory tracts of immunocompromised hosts. Several reports implicate corticosteroids as a major risk factor due to their anti-inflammatory and immunosuppressive effects, which are exacerbated by long-term treatment regimens. Here we demonstrate for the first time the influence of dexamethasone when it comes to germination and hyphae formation of A. fumigatus in the presence of macrophages within a highly differentiated air-liquid interphase (ALI) epithelial/immune lung model. We illustrate suppressed mucus production within the highly differentiated 3D respiratory model as well as significantly decreased cilia beat frequencies by dexamethasone treatment. This goes along with corticosteroid-mediated macrophage M2 polarization within the epithelial/immune microenvironment. Therefore, we here showed that corticosteroids promote enhanced fungal growth and invasion A. fumigatus by creating a suppressive environment affecting both epithelial as well as immune cells.
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Amazingly little sequence variation is reported for the kringle IV 2 copy number variation (KIV 2 CNV) in the human LPA gene. Apart from whole genome sequencing projects, this region has only been analyzed in some detail in samples of European populations. We have performed a systematic resequencing study of the exonic and flanking intron regions within the KIV 2 CNV in 90 alleles from Asian, European, and four different African populations. Alleles have been separated according to their CNV length by pulsed field gel electrophoresis prior to unbiased specific PCR amplification of the target regions. These amplicons covered all KIV 2 copies of an individual allele simultaneously. In addition, cloned amplicons from genomic DNA of an African individual were sequenced. Our data suggest that sequence variation in this genomic region may be higher than previously appreciated. Detection probability of variants appeared to depend on the KIV 2 copy number of the analyzed DNA and on the proportion of copies carrying the variant. Asians had a high frequency of so-called KIV 2 type B and type C (together 70% of alleles), which differ by three or two synonymous substitutions respectively from the reference type A. This is most likely explained by the strong bottleneck suggested to have occurred when modern humans migrated to East Asia. A higher frequency of variable sites was detected in the Africans. In particular, two previously unreported splice site variants were found. One was associated with non-detectable Lp(a). The other was observed at high population frequencies (10% to 40%). Like the KIV 2 type B and C variants, this latter variant was also found in a high proportion of KIV 2 repeats in the affected alleles and in alleles differing in copy numbers. Our findings may have implications for the interpretation of SNP analyses in other repetitive loci of the human genome.
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Variações do Número de Cópias de DNA , Variação Genética , Lipoproteína(a)/genética , Povo Asiático/genética , Sequência de Bases , População Negra/genética , Clonagem Molecular , Etnicidade/genética , Éxons , Feminino , Frequência do Gene , Humanos , Íntrons , Kringles/genética , Masculino , População Branca/genéticaRESUMO
OBJECTIVE: The variant allele of rs3798220 in the apolipoprotein(a) gene (LPA) is used to assess the risk for coronary artery disease (CAD) in Europeans, where it is associated with short alleles of the Kringle IV-2 (KIV-2) copy number variation (CNV) and high lipoprotein(a) (Lp(a)) concentrations. No association of rs3798220 with CAD was detected in a GWAS of East Asians. Our study investigated the association of rs3798220 with Lp(a) concentrations and KIV-2 CNV size in non-European populations to explain the missing association of the variant with CAD in Asians. METHODS: We screened three populations from Africa and seven from Asia by TaqMan Assay for rs3798220 and determined KIV-2 CNV sizes of LPA alleles by pulsed-field gel electrophoresis (PFGE). Additionally, CAD cases from India were analysed. To investigate the phylogenetic origin of rs3798220, 40 LPA alleles from Chinese individuals were separated by PFGE and haplotyped for further SNPs. RESULTS: The variant was not found in Africans. Allele frequencies in East and Southeast Asians ranged from 2.9% to 11.6%, and were very low (0.15%) in CAD cases and controls from India. The variant was neither associated with short KIV-2 CNV alleles nor elevated Lp(a) concentrations in Asians. CONCLUSION: Our study shows that rs3798220 is no marker for short KIV-2 CNV alleles and high Lp(a) in East and Southeast Asians, although the haplotype background is shared with Europeans. It appears unlikely that this SNP confers atherogenic potential on its own. Furthermore, this SNP does not explain Lp(a) attributed risk for CAD in Asian Indians.