Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype.

Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart

Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects

Zolotareva O, Saik OV, Königs C, et al. Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects. Scientific Reports. 2019;9(1): 16302.Asthma and hypertension are complex diseases coinciding more frequently than expected by chance. Unraveling the mechanisms of comorbidity of asthma and hypertension is necessary for choosing the most appropriate treatment plan for patients with this comorbidity. Since both diseases have a strong genetic component in this article we aimed to find and study genes simultaneously associated with asthma and hypertension. We identified 330 shared genes and found that they form six modules on the interaction network. A strong overlap between genes associated with asthma and hypertension was found on the level of eQTL regulated genes and between targets of drugs relevant for asthma and hypertension. This suggests that the phenomenon of comorbidity of asthma and hypertension may be explained by altered genetic regulation or result from drug side effects. In this work we also demonstrate that not only drug indications but also contraindications provide an important source of molecular evidence helpful to uncover disease mechanisms. These findings give a clue to the possible mechanisms of comorbidity and highlight the direction for future research

Genetic outline of the hermeneutics of the diseases connection phenomenon in human

The structure of diseases in humans is heterogeneous, which is manifested by various combinations of diseases, including comorbidities associated with a common pathogenetic mechanism, as well as diseases that rarely manifest together. Recently, there has been a growing interest in studying the patterns of development of not individual diseases, but entire families associated with common pathogenetic mechanisms and common genes involved in their development. Studies of this problem make it possible to isolate an essential genetic component that controls the formation of disease conglomerates in a complex way through functionally interacting modules of individual genes in gene networks. An analytical review of studies on the problems of various aspects of the combination of diseases is the purpose of this study. The review uses the metaphor of a hermeneutic circle to understand the structure of regular relationships between diseases, and provides a conceptual framework related to the study of multiple diseases in an individual. The existing terminology is considered in relation to them, including multimorbidity, polypathies, comorbidity, conglomerates, families, “second diseases”, syntropy and others. Here we summarize the key results that are extremely useful, primarily for describing the genetic architecture of diseases of a multifactorial nature. Summaries of the research problem of the disease connection phenomenon allow us to approach the systematization and natural classification of diseases. From practical healthcare perspective, the description of the disease connection phenomenon is crucial for expanding the clinician’s interpretive horizon and moving beyond narrow, disease-specific therapeutic decisions

THE ROLES OF CARDIOVASCULAR DISEASE AND DEPRESSION IN THE RELATIONSHIP BETWEEN RESPIRATORY DISEASE AND NEUROPSYCHOLOGICAL FUNCTIONING IN OLDER ADULTS

The pathophysiology of severe respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), supports the theory that oxygen deprivation to the brain may impact the brain’s execution of cognitive functions. Imaging studies also suggest that neuroanatomical changes in areas of the brain responsible for cognitive processes may be associated with respiratory diseases. Research in this area has failed to conclude definitively, especially in an older adult population, which is more likely to experience comorbid depression and cardiovascular disease, universally acknowledged predictors of poorer cognitive performance, the extent of the relationship between respiratory illness and cognitive functioning. The current study investigated the association between respiratory disease with cognitive performance in older adults, also considering the relative impact of cardiovascular disease and depression. Functioning was examined globally and in the individual domains of psychomotor functioning and verbal ability. Physiological measures of disease were also explored for potential relationships with cognition. Results suggest that depression was consistently associated with poorer performance across cognitive domains, whereas cardiovascular disease was primarily associated with reduced functioning in psychomotor tasks. After accounting for these effects, no additional association between respiratory disease and cognitive functioning was identified, with the possible exception of COPD relating to enhanced verbal ability. None of the physiological measures obtained were found to correlate with cognition in this research. Explanations and implications of these findings are discussed

Analysis of haplotypes of CAT, TLR4, and IL10 genes in bronchial asthma patients comorbid with arterial hypertension

Co-occurrence of cardiovascular diseases is significantly common among patients with bronchial asthma. Genetic factors can have a significant effect on the development of hypertension in patients with asthma. Objective of the study was to investigate the associations of polymorphic variants relating to quantitative changes in the expression profile (eQTL) of the CAT, TLR4, and IL10 genes with the development of bronchial asthma co-morbid with arterial hypertension.Material and methods. Genotyping of 48 eQTL SNPs of the CAT, TLR4, and IL10 genes was performed using MALDI-TOF mass spectrometry in patients with «isolated» asthma (n = 145) and arterial hypertension (n = 144) and their combination (n = 146), as well as in the control group of healthy individuals (n = 152). Using logistic regression, an analysis of the associations of haplotypes with the studied diseases was carried out.Results. An association of bronchial asthma in combination with arterial hypertension with haplotypes formed by eQTL SNPs of the CAT and TLR4 genes was established. The spectrum of haplotypes associated with comorbidity of asthma and hypertension differs from the haplotypes associated with “isolated” asthma.Conclusion. The molecular base of asthma and hypertension comorbidity can be associated with variants that control the expression of TLR4 and CAT genes

Chronic disease in the elderly: back to the future of internal medicine.

Elderly people are often affected by two or more chronic diseases, more frequently cardiovascular diseases, chronic respiratory diseases, metabolic syndrome and cancer. Thesemost frequent chronic diseases share largely preventable risk factors, the most important being smoking and obesity, and may be linked to chronic systemic inflammation. Coexistingchronic diseases affect the course of the primary disease and alter the efficacyand safety of its management. Current clinical practice is dominated by the "singledisease"approach, which has major limitations, and there is increasing evidence that a patient-oriented approach that takes into account the several co-existing components of chronic disease is required. This "change of concept" implies the need for medical specialists to extend their expertise to broader diagnostic and treatment approaches that are traditionally the purview of internal medicine. This new approach also requires a differentapproach to clinical research and teaching, followed by extensive rewriting of medical textbooks and remodelling of teaching curricula to reflect the complexity of the patient affected by chronic diseases

A novel marker of systemic inflammation in psoriasis and related comorbidities: Chitotriosidase

Background/aim: Chitotriosidase (ChT) is an enzyme secreted by activated macrophages and neutrophils in response to proinflammatory signals. There is growing evidence indicating that ChT activity reflects the systemic inflammatory status. This study aimed to investigate whether serum ChT activity increased in patients with psoriasis and related comorbidities. Materials and methods: This cross-sectional study included 53 (28 with associated comorbidities and 25 without comorbidities) patients with psoriasis and 52 healthy volunteers. All participants underwent laboratory investigations for serum ChT levels, complete blood count, erythrocyte sedimentation rate, C-reactive protein, and serum lipid levels. Results: The patients with psoriasis showed significantly higher levels of ChT activity as compared to the healthy controls (23.5 ± 11.4 vs. 17.5 ± 10.4 μmol/mL/hour; p = 0.015). Additionally, the ChT activity was significantly higher in patients with comorbidities than in those without (p = 0.042). Conclusion: Our data support the pathogenetic role of inflammatory processes induced by macrophage activation in patients with psoriasis and related comorbidities. We believe that high ChT activity in patients with psoriasis may serve as an early prediction of the possible related comorbidities. © TÜBİTAK