Nowy marker molekularny genu dla receptora endotelinowego typu A - brak zależności między polimorfizmem G1354C a chorobą miażdżycową tętnic u mężczyzn

Background. There is some evidence pointing toward endothelin system involvement in pathogenesis of atherosclerosis, manifested as coronary heart disease (CHD) and peripheral arterial occlusive disease (PAOD). Material and methods. In the study, 133 male patients - 46 with CHD (age 47.1 ± 4.12 years), 87 with PAOD (51.7 ± 5.31) and 87 healthy controls (46.35 ± 3.81) were genotyped by a polymerase chain reaction and restrictive fragments length polymorphism (PCR-RFLP) for a endothelin-A receptor (ENDRA) polymorphism. The allelic and genotype frequencies were compared between the groups using the χ2 test. Results. The novel single nucleotide polymorphism of the ENDRA gene (G1354C) was studied as a marker in CHD or PAOD. Genotype distribution in each of the groups did not deviate from the Hardy-Weinberg equilibrium. The allelic and genotype frequencies of the ENDRA gene did not differ between the groups. The allele G frequencies were 0.522 in CHD group, 0.506 in PAOD patients and 0.483 in controls. Conclusions. No genetic association between allelic variants of ENDRA and CHD or PAOD was found. It is unlikely that genetic variation at this ENDRA gene locus could contribute to the pathogenesis of arterial disease.Wstęp. Istnieją przesłanki wskazujące na udział układu endotelin w patogenezie miażdżycy objawiającej się klinicznie jako choroba wieńcowa (CHD) i choroba obwodowych naczyń tętniczych (PAOD). Materiał i metody. Badaniem objęto 133 chorych mężczyzn - 46 osób z CHD w wieku 47,1 ± 4,12 roku, 87 pacjentów z PAOD w wieku 51,7 ± 5,31 roku oraz grupę kontrolną 87 zdrowych mężczyzn w wieku 46,35 ± 3,81roku. Genotypowanie polimorfizmu genu dla receptora endotelinowego typu A (ENDRA) wykonano z zastosowaniem reakcji łańcuchowej polimerazy i polimorfizmu długości fragmentów restrykcyjnych (RFLP-PCR). Porównano częstości występowania alleli i genotypów pomiędzy grupami, posługując się testem χ2. Wyniki. Poszukiwano asocjacji genetycznej nowego polimorfizmu pojedynczego nukleotydu genu ENDRA (G1354) z występowaniem CHD i PAOD. We każdej z grup częstości występowania genotypów były zgodne z prawem Hardy’ego-Weinberga. Częstości alleliczne i genotypowe genu ENDRA nie różniły się istotnie w badanych grupach. Częstość występowania allelu G wynosiła 0,522 u osób z CHD; 0,506 u pacjentów z PAOD i 0,483 w grupie kontrolnej. Wnioski. Nie stwierdzono asocjacji genetycznej między wariantami allelicznymi ENDRA a CHD i PAOD. Zbadany wariant genetyczny genu dla receptora endoteliny nie wiąże się z ryzykiem miażdżycy tętnic

Increased oxidative stress in asthma - relation to inflammatory blood and lung biomarkers and airway remodeling indices

Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using recently developed real-time monitoring of the protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also investigated the relation of the systemic oxidative stress response in asthma to disease severity, lung function, airway remodeling indices (lung computed tomography and histology), and blood and bronchoalveolar lavage fluid (BAL) inflammatory biomarkers. We documented enhanced systemic oxidative stress in asthma, reflected by 35% faster and 58% higher cumulative fluorescent product generation in the CBA assay (p < 0.001 for both). The dynamics of HP generation correlated inversely with lung function but not with asthma severity or histological measures of airway remodeling. HP generation was associated positively with inflammatory indices in the blood (e.g., C-reactive protein) and BAL (e.g., interleukin [IL]-6, IL-12p70, and neutrophil count). Bronchial obstruction, thicker airway walls, increased BAL IL-6, and citrullinated histone 3 in systemic circulation independently determined increased HP formation. In conclusion, a real-time CBA assay showed increased systemic HP generation in asthma. In addition, it was associated with inflammatory biomarkers, suggesting that proper disease control can also lead to a decrease in oxidative stress

The role of PKCzeta in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil

While immunodeficiency of immaturity of the neonate has been considered important as the basis for unusual susceptibility to infection, it has also been recognized that the ability to progress from an immature Th2 cytokine predominance to a Th1 profile has relevance in determining whether children will develop allergy, providing an opportunity for epigenetic regulation through environmental pressures. However, this notion remains relatively unexplored. Here, we present evidence that there are two major control points to explain the immunodeficiency in cord blood (CB) T-cells, a deficiency in interleukin (IL)-12 (IL-12) producing and IL-10 overproducing accessory cells, leading to a decreased interferon γ (IFNγ) synthesis and the other, an intrinsic defect in T-cell protein kinase C (PKC) ζ (PKCζ) expression. An important finding was that human CB T-cells rendered deficient in PKCζ, by shRNA knockdown, develop into low tumour necrosis factor α (TNFα) and IFNγ but increased IL-13 producing cells. Interestingly, we found that the increase in PKCζ levels in CB T-cells caused by prenatal supplementation with fish oil correlated with modifications of histone acetylation at the PKCζ gene (PRKCZ) promoter. The data demonstrate that PKCζ expression regulates the maturation of neonatal T-cells into specific functional phenotypes and that environmental influences may work via PKCζ to regulate these phenotypes and disease susceptibility.Hani Harb, James Irvine, Manori Amarasekera, Charles S. Hii, Dörthe A. Kesper, YueFang Ma, Nina D′Vaz, Harald Renz, Daniel P. Potaczek, Susan L. Prescott and Antonio Ferrant

Elements of Immunoglobulin E Network Associate with Aortic Valve Area in Patients with Acquired Aortic Stenosis

Allergic mechanisms are likely involved in atherosclerosis and its clinical presentations, such as coronary artery disease (CAD). It has been previously reported that CAD severity associates with serum levels of immunoglobulin E (IgE), the molecule that, along with its high-affinity receptor (FcԑRI), plays a central role in allergic reactions. Considering multiple pathophysiological similarities between atherosclerosis and acquired aortic (valve) stenosis (AS), we speculated that allergic pathways could also contribute to the AS mechanisms and grading. To validate this hypothesis, we first checked whether total serum IgE levels associate with echocardiographic markers of AS severity. Having found a positive correlation between serum IgE and aortic valve area (AVA), we further speculated that also total IgE-determining genetic polymorphisms in FCER1A, a locus encoding an allergen-biding FcԑRI subunit, are related to acquired AS severity. Indeed, the major allele of rs2251746 polymorphism, known to associate with higher IgE levels, turned out to correlate with larger AVA, a marker of less severe AS. Our findings surprisingly suggest a protective role of IgE pathways against AS progression. IgE-mediated protective mechanisms in AS require further investigations

Editorial of Special Issue “Molecular Mechanisms of Allergy and Asthma”

This Special Issue aggregates several high-quality original articles written by renowned researchers [...

Genetic Variability of the High-affinity IgE Receptor α Subunit (Fc ε RI α) is Related to Total Serum IgE levels in Allergic Subjects

Known susceptibility genes to atopy and asthma have been identified by linkage or associations with clinical phenotypes, including total serum IgE levels. IgE-mediated sensitivity reactions require a high-affinity IgE receptor (FcεRI), which immobilizes the immunoglobulin on the surface of the effector cells, mostly mast cells and basophils. In this mini-review, recent findings are presented on genetic variation of this receptor, as related to atopy. Transcription of FCER1A gene encoding the receptor α subunit can be initiated from two separate promoters, the proximal one and the distal one, which results in a transcript containing two novel untranslated exons (1A, 2A). Our knowledge on the role of this mechanism in allergic diseases is still at an infancy stage. Within regulatory elements of FCER1A some common single nucleotide polymorphisms have functional associations, which were recently reported and replicated in different ethnical groups. Interestingly, these associations do not confer susceptibility to allergic diseases, but rather modulate serum concentrations of IgE. Similarly to the previously investigated β subunit of the receptor, FCER1A is a good candidate for a quantitative trait locus (QTL) in allergic diseases, and appears to participate in the systemic regulation of IgE levels