Genetic Diversity in Bronchial Asthma Susceptibility: Exploring the Role of Vitamin D Receptor Gene Polymorphisms in Varied Geographic Contexts.

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma-both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed.

The Association of Vitamin D Receptor Gene Polymorphisms with Vitamin D, Total IgE, and Blood Eosinophils in Patients with Atopy.

BACKGROUND: In order to improve the control of atopic diseases, it is important to clarify the pathogenesis of atopy and identify its various triggers. Single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene (VDR) may impact atopy. The aim of this study was to investigate the possible associations between VDR SNPs and vitamin D, total IgE, and eosinophils in atopy. METHODS: In total, 203 adults, including 122 patients with atopic diseases (45 with atopic dermatitis, 77 with allergic asthma) and 81 healthy controls, were involved in the study. The blood eosinophil count was determined with an automated hematology analyzer. Vitamin D and total immunoglobulin E (IgE) levels were evaluated using the ELISA method. Polymorphisms in the VDR gene were analyzed with real-time PCR using TaqMan probes. RESULTS: We analyzed six VDR single nucleotide polymorphisms and found a significant association between VDR rs731236 GG genotype and normal vitamin D levels in atopic patients and healthy subjects (OR 11.33; 95% CI: 1.049-122.388 and OR 4.04; 95% CI: 1.117-14.588, respectively, p < 0.05). Additionally, the study results revealed a significant relationship between the VDR rs2228570 GG genotype and normal vitamin D levels in patients with atopy and healthy subjects (OR 3.80; 95% CI: 1.190-12.134 and OR 2.09; 95% CI: 1.044-4.194, respectively, p < 0.05). The rs2228570 allele A was associated with decreased vitamin D levels in patients with atopy and healthy subjects (OR 0.28; 95% CI: 0.098-0.804 and OR 0.229; 95% CI: 0.069-0.761, respectively, p < 0.05). The VDR rs3847987 genotypes AA and AC were significantly associated with normal vitamin D levels in healthy subjects (OR 35.99; 95% CI: 6.401-202.446 and OR 4.72; 95% CI: 1.489-15.007, respectively, p < 0.05). In addition, a decreased amount of vitamin D was associated with atopic diseases such as atopic dermatitis and allergic asthma (OR 0.49; 95% CI: 0.439-1.308 and OR 0.58; 95% CI: 0.372-0.908, respectively, p < 0.05). The rs11168293 allele T was associated with the normal range of total IgE in atopy (OR 2.366; 95% CI: 1.133-5.027; p < 0.05). Significant associations were found between VDR rs731263 allele G, rs11168293 allele G, and increased blood eosinophil levels in patients with atopy (OR 0.319; 95% CI: 0.163-0.934 and OR 0.323; 95% CI: 0.112-0.935, respectively, p < 0.05). CONCLUSIONS: A decreased vitamin D level showed a significant relationship with atopic diseases (atopic dermatitis and allergic asthma). The association between the VDR gene polymorphisms rs2228570, rs731236, and rs11168293 and vitamin D, total IgE, and blood eosinophils in patients with atopy suggested that VDR polymorphisms and the vitamin D level should be considered when examining the factors associated with atopy.

Vitamin D receptor and vitamin D binding protein gene polymorphisms in patients with asthma: a pilot study.

BACKGROUND: The effects of vitamin D are exerted by interaction with the vitamin D receptor (VDR) and vitamin D binding protein (VDBP). Polymorphisms in VDR or VDBP genes may affect vitamin D levels, influencing the pathogenesis of asthma and atopy. The aim of this study was to investigate the possible association of VDR and VDBP gene single-nucleotide polymorphisms (SNP), 25-hydroxyvitamin D (25(OH)D), blood eosinophils and total IgE level in subjects with asthma in comparison with healthy individuals. METHODS: This case-control study enrolled 63 subjects with asthma (45 allergic and 18 non-allergic) and 32 healthy subjects were involved in the study. Sensitization of subjects to inhaled allergens was determined by a skin prick test, lung function was evaluated by spirometry. Blood eosinophil count was determined by standard methods. Serum 25(OH)D and total IgE levels were evaluated by ELISA. Polymorphisms in the VDR and VDBP genes on the 12q13.11 and 4q13.3 chromosomal region were analyzed using TaqMan SNP Genotyping Assay probes. RESULTS: In asthma patients with vitamin D deficiency (< 20 ng/ml) the allele G of rs11168293 of VDR was more common than in those having insufficiency (20-30 ng/ml) of vitamin D (63% and 31%, p < 0.05). Moreover, asthmatic subject with rs11168293 G allele has significant higher blood eosinophil count compared to asthmatic without the rs11168293 G allele (8.5 ± 12.3% vs. 5.1 ± 1.5%, p < 0.05). Significantly higher IgE level was found in subjects with allergic asthma with the allele A of rs7041 on VDBP gene than in those without this allele (540 ± 110 and 240 ± 80 IU/ml, p < 0.05). CONCLUSIONS: The association of polymorphisms in VDBP and VDR gene, the rs11168293 G allele and the rs7041 A allele, with 25(OH)D, blood eosinophil and total IgE level in asthma, let us suggest that vitamin D, VDR and VDBP gene polymorphisms are important in pathogenesis of asthma despite its form in relation to atopy.

Clusters based on immune markers in a Lithuanian asthma cohort study.

OBJECTIVE: Asthma is divided into various distinct phenotypes on the basis of clinical characteristics, physiological findings, and triggers, and phenotyping is usually performed in a hypothesis-driven univariate manner. However, phenotyping can also be performed using computer algorithms to evaluate hypotheses-free relationships among many clinical and biological characteristics. We aimed to identify asthma phenotypes based on multiple demographic, clinical, and immunological characteristics. METHODS: Cluster analysis in R v3.5.0 was performed using asthma patient data. A total of 170 adult patients with asthma (diagnosed according to the GINA recommendations) were recruited to the study. All patients completed questionnaires about their smoking history and underwent physical examination, spirometry, skin-prick test, blood sample collection to evaluate peripheral blood cell counts and serum IgE, periostin, and interleukin (IL)-33 levels, as well as body mass index measurements. Data normality was checked with histograms and QQ plots. Hierarchical clustering was performed using Ward's linkage with Ward's clustering criterion. The optimal number of clusters was validated using the Dunn criterion as well as by comparing different clustering algorithms using the clValid package. RESULTS: Three clusters characterizing asthma phenotypes were identified: (1) early-onset, highly atopic, and eosinophilic asthma associated with male sex and high levels of IL-33 and periostin; (2) late-onset, eosinophilic asthma associated with female sex and low levels of IL-33 and periostin; and (3) late-onset, obese, neutrophilic asthma associated with female sex, persistent airway obstruction, and very low IL-33 and periostin levels.

Systemic and local cytokine profile and risk factors for persistent allergic airway inflammation in patients sensitised to house dust mite allergens.

OBJECTIVE: To evaluate cytokine profile, vitamin D status, symptom score and quality of life in patients with persistent allergic airway diseases sensitised to house dust mites (HDM) in comparison with healthy individuals. MATERIAL AND METHODS: Patients sensitized to HDM with persistent AR and having symptoms for at least 2 years with or without AA were involved into the study. Measurements of vitamin D level in serum and IL-10, IL-13, IL-17, IL-22, IL-33 and IFN-gamma in serum and nasal lavage were performed by ELISA. RESULTS: Eighty-one subjects were involved into the study. Serum IL-10 concentration was higher in patients with AR than in patients with AR and AA (6.71 ± 1.73 vs. 1.98 ± 0.24, p < 0.05). IFN-gamma level in nasal lavage was higher in patients with AR and AA than in patients with AR (p < 0.01) and healthy individuals (p < 0.05) (7.50 ± 0.37 vs. 6.80 ± 0.99 vs. 6.50 ± 0.22). Serum IL-22 negatively correlated with IL-22 in nasal lavage, whereas serum IFN-gamma positively correlated with IFN-gamma in nasal lavage. Positive correlation between serum IL-17 and total IgE and negative correlation between IL-17 in nasal lavage and eosinophils in nasal smear were found in patients with AR and AA. Serum IFN-gamma decreased the risk of AR for healthy individuals. Serum IL-10 and vitamin D decreased risk for development of AA for patients with AR. IL-22 in serum and IL-10 and IL-33 in nasal lavage increased this risk. CONCLUSION: Novel cytokines such as IL-22, IL-17 and IL-33 and vitamin D may be involved in pathogenesis of persistent airway inflammation in patients sensitized to HDM.

Vitamin D receptor gene polymorphisms in atopy.

BACKGROUND: The occurrence of allergic conditions, for example allergic asthma, rhinitis, and atopic dermatitis, is rising worldwide. These allergic conditions are associated with poor life quality. Vitamin D is proposed to be linked with increased risk and severe forms of allergic diseases. AIMS: This review article aimed to evaluate the vitamin D level role and polymorphisms of vitamin D receptor gene (VDR) in atopy. METHODS & MATERIALS: We analyzed publications that were focusing on levels of vitamin D and/or polymorphism analysis of vitamin D receptor gene in allergic asthma, rhinitis, and atopic dermatitis patients. RESULTS: We noticed that levels of vitamin D are extensively studied in atopy by many research groups, however, polymorphisms of vitamin D receptor gene and their link with levels of vitamin D lack comprehensive data. There is evidence that vitamin D may be associated with anti-inflammatory effects in allergic diseases. Some of VDR polymorphisms also may play a role in pathogenesis of these diseases. However, the data from different studies are controversial. DISCUSSION: The results of different studies are usually inconsistent, most probably due to populational bias or differences in methodology. Even though, more evidence shows a positive impact of vitamin D on the risk and outcomes of allergic diseases, especially atopic dermatitis, and asthma. CONCLUSIONS: There is controversial data about the level of vitamin D and its role in atopy; however, more evidence shows a positive impact on the risk and outcomes of allergic diseases.

Translation, adaption and validation of the total nasal symptom score (TNSS) for Lithuanian population.

BACKGROUND: Allergic rhinitis is one of the most prevalent allergic diseases worldwide which diagnosis is based on typical clinical signs and positive results of allergic tests. Selection and evaluation of treatment is based mainly on subjective symptoms. Objective measurement of patients' complaints is necessary for proper documentation and follow-up. There are no short simple validated questionnaire assessing nasal symptoms in patients with allergic rhinitis in Lithuania. Total nasal symptoms score (TNSS) is a brief questionnaire which evaluate the severity of main symptoms of allergic rhinitis widely used in different countries. Our aim was to translate the TNSS in the Lithuanian language and to validate it. METHODS: Prospective cross-cultural adaption and validation study was performed. Linguistic validation of TNSS was performed and validity and reliability were assessed. Patients with chronic allergic and non-allergic rhinitis and healthy individuals were included in this study. Patients had to complete translated version of TNSS. Patients with allergic rhinitis additionally were asked to fill Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS: Seventy-six individuals were involved into the study: 16 with non-allergic rhinitis (NAR) (21.1%), 49 with allergic rhinitis (AR) (64.5%) and 11 healthy individuals (14.5%). Cronbach's α was 0.87. TNSS score was significantly higher in patients with NAR and AR compared with healthy individuals (3.56 ± 2.28 vs. 4.28 ± 2.46 vs. 0.27 ± 0.91). Positive significant correlation was found between TNSS score and RQLQ score (rs = 0.77, p < 0.01). CONCLUSIONS: The Lithuanian version of the TNSS proved to be a valid instrument for assessing nasal symptoms in patients with allergic rhinitis.

Role of IL-22 in persistent allergic airway diseases caused by house dust mite: a pilot study.

BACKGROUND: Persistent allergic airway diseases cause a great burden worldwide. Their pathogenesis is not clear enough. There is evidence that one of the recently described cytokine interleukin (IL) 22 may be involved in the pathogenesis of these diseases. Scientists argue if this cytokine acts as proinflammatory or anti-inflammatory agent. The aim of this study was to investigate IL-22 level in patients with persistent allergic airway diseases caused by house dust mite (HDM) in comparison with healthy individuals and to evaluate its relationship with IL-13 and IL-10 level, symptoms score and quality of life. METHODS: Patients with persistent allergic rhinitis caused by HDM and having symptoms for at least 2 years with or without allergic asthma were involved into the study. Measurements of IL-22, IL-13 and IL-10 and in serum and nasal lavage was performed by ELISA. Questionnaires assessing symptoms severity and quality of life were used. RESULTS: A tendency was observed that IL-22 in serum and nasal lavage was higher in patients with allergic airway diseases compared to control group (14.86 pg/ml vs. 7.04 pg/ml and 2.67 pg/ml vs. 1.28 pg/ml, respectively). Positive statistically significant correlation was estimated between serum IL-22 and serum IL-10 (rs = 0.57, p < 0.01) and IL-13 (rs = 0.44, p < 0.05) level. Moreover, positive significant correlation was found between IL-22 in nasal lavage and IL-10 in nasal lavage (rs = 0.37, p < 0.05). There was a negative statistically significant correlation between serum IL-22 and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (rs = - 0.42, p < 0.05). CONCLUSION: Our study showed a possible anti-inflammatory effect of IL-22 in patients with persistent allergic airway diseases caused by HDM.

Immune system in the pathogenesis of chronic cough.

Chronic cough is a common symptom of various chronic diseases. However, the vast majority of individuals with conditions that are commonly associated with cough, such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. It is known that in the pathogenesis of cough, the nervous system plays a vital role. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature. The aim of this article is to review the most recent data about the role of the immune system in the pathogenesis of chronic cough.

Interleukin-22 in Allergic Airway Diseases: A Systematic Review.

The immune system plays an important role in the pathogenesis of many disorders, including allergic airway diseases. There are studies suggesting that interleukin (IL)-22 can be important in the development of these diseases. However, it is not known if this cytokine acts as proinflammatory or anti-inflammatory agent. This systematic review aimed to analyze level and role of IL-22 in patients with allergic airway diseases in comparison with healthy individuals. Systematic review included only observational studies with patients having allergic rhinitis and/or allergic asthma. The primary outcome measure was IL-22 level in patients with allergic asthma and/or allergic rhinitis. A total of 95 articles were found. Overall, 6 articles were included in systematic review. Five of these studies showed that IL-22 was increased in patients with allergic airway diseases compared with control group. Majority of studies revealed relation between IL-22 level and severity of allergic asthma and allergic rhinitis. Some studies showed positive relation between IL-22 level and total immunoglobulin E (IgE), specific IgE, and eosinophil count in nasal mucosa. IL-22 level is increased in children and adults with allergic airway diseases and is likely to be associated with proinflammatory features.

Analysis of citizens' subjective perception of safe antibiotic use in European Union countries.

OBJECTIVES: Antibiotic consumption is high and varies between different European Union countries. One of the reasons could be different subjective perception of safe antibiotic use. The aim of our study was to analyse citizens' subjective perception of safe antibiotic use in the European Union countries in the context of different antibiotic policies. Some countries are prepared comprehensive national strategies and action plans and implement many activities in different areas while other countries implement actions only in particular fields and even do not have prepared strategy or action plan. METHODS: This article is based on conception of security by Barry Buzan. Variables collected from the Special Eurobarometer public opinion on Antimicrobial Resistance in European Union countries in 2016 were used for creation the factor of subjective perception of safe antibiotic use. Six contextual factors were selected from the scientific literature and their impact on subjective perception of safe antibiotic use was investigated. RESULTS: High differences in subjective perception of safe antibiotic use were observed in countries despite general European Union recommendations on antibiotic policy. The highest subjective perception of safe antibiotic use was in Netherlands, Finland, Sweden, Luxembourg, and Denmark. Significant negative correlation was observed between factor of subjective perception of safe antibiotic use and antibiotic consumption (r=-0.41, p<0.05). Created factor of information and communication technology (ICT) development, gross domestic product (GDP) and health expenditure had impact on subjective perception of safe antibiotic use (t=4.69, p<0.01). Consumption of antibiotics also had influence on subjective perception of safe antibiotic use (t=-2.43, p<0.05). CONCLUSIONS: Individuals' subjective perception of safe antibiotic use which is related to antibiotic consumption highly varies between different EU countries despite general EU recommendations on antibiotic policies and depends on ICT development, GDP, health expenditure and consumption of antibiotics.

Role of Th22 and IL-22 in pathogenesis of allergic airway diseases: Pro-inflammatory or anti-inflammatory effect?

A new population of T cells known as Th22 was described for the first time in 2009. These cells are usually identified by the production of IL-22. However, this cytokine is also secreted by other cells such as Th1, Th2, Th17, natural killers, and innate lymphoid cells. Th22 is known as a pro-inflammatory agent in allergic skin diseases. Recently, more evidence has emerged showing associations between these cells and other diseases. The role of Th22 in asthma and allergic rhinitis is controversial: some authors suggest that Th22 has a pro-inflammatory effect, while others state that Th22 has anti-inflammatory properties. The aim of this article was to review the role of Th22 and IL-22 in allergic airway diseases based on the most recent literature. This review suggests that Th22 plays a significant role in the pathogenesis of allergic airway diseases and has predominantly anti-inflammatory properties. More studies are needed to clarify the role of Th22 in more detail.

Use of interferon-gamma release assay and tuberculin skin test in diagnosing tuberculosis in Lithuanian adults: A comparative analysis.

BACKGROUND AND OBJECTIVE: Lithuania belongs to the group of countries with a high-incidence of tuberculosis (TB). Some scientific studies show that the interferon-gamma release assay is more accurate and correlates more highly with TB exposure as compared to the tuberculin skin test (TST). This study aimed at comparing the efficacy between the T SPOT TB and TST for diagnosing TB among Lithuanian adults. MATERIALS AND METHODS: Individuals with diagnosed TB, healthcare workers with known risk for TB and individuals without any known risk for TB underwent clinical examinations, interviews about their history of TB exposure and chest radiography. Then the TST and the T SPOT TB were performed on patients. RESULTS: A positive T SPOT TB was more common in the group with diagnosed TB compared to healthcare workers and the low risk for TB groups (97.5%, 36.4%, and 0%, respectively, P<0.01). Positive TST results did not differ between the groups with diagnosed TB and the healthcare workers (92.5% vs. 95.5%, P>0.05). Agreement between TST and T SPOT TB was poor (kappa 0.14, P>0.05). T SPOT TB had higher specificity and sensitivity compared to TST (area under the ROC 0.9±0.04, P<0.01, vs. 0.5±0.06, P>0.05). CONCLUSIONS: The T SPOT TB showed greater accuracy in diagnosing TB than TST did. Positive T SPOT TB result but not the TST was more common in patients with diagnosed TB.

Relationship of meteorological factors and acute stroke events in Kaunas (Lithuania) in 2000-2010.

Some researchers have hypothesised that meteorological factors may have an impact on acute cerebrovascular diseases. The aim of this study was to determine an impact of some meteorological factors on occurrence of acute cerebrovascular events in the middle-aged Kaunas population. Kaunas stroke register data were used. Data on meteorological factors for the time period from 2000 to 2010 were obtained from the Lithuanian Hydrometeorological Service Kaunas Meteorological Station. We analysed 4038 cases with stroke. Ischemic strokes composed 80.4% and haemorrhagic strokes-19.6%. According to Poisson regression analysis, significant negative correlation between ischemic, haemorrhagic and all types of stroke and ambient air temperature was found (ß coefficient - 0.007, -0.016, -0.009, p < 0.001, respectively). Results of ARIMA showed that ambient temperature of the day of stroke onset was associated with the occurrence of ischemic, haemorrhagic and all types of stroke: when temperature was lower, the risk of stroke was higher (-0.006, -0.003, -0.009, p < 0.001, respectively). Low temperature on the event day and 1 and 2 days before the event was associated with higher incidence of haemorrhagic stroke in women. Low ambient temperature on the event day increased incidence of haemorrhagic stroke in subjects 55-64 years. High wind speed on the event day was associated with higher incidence of ischemic stroke in older subjects. Meteorological factors may have some impact on the risk of acute cerebrovascular events. Health care providers should focus on preventive measures, which can reduce these risks.

Evaluation of proteasomal gene polymorphisms in Lithuanian patients with asthma.

OBJECTIVE: To investigate polymorphisms of proteasomal genes PSMA6 (rs1048990 and rs2277460), PSMC6 (rs2295826 and rs2295827) and PSMA3 (rs2348071) in Lithuanian patients with asthma. METHODS: One-hundred forty-six asthma patients and 150 control subjects were studied. DNA was extracted from peripheral blood samples. Five single nucleotide polymorphisms (SNP's) of the three proteasomal genes were analyzed using allele-specific amplification or the cleaved amplified polymorphic sequence method. RESULTS: While certain alleles and genotypes of PSMA6 rs2277460 and rs1048990 and PSMA3 rs2348071 SNP's occurred more frequently in asthma patients than in controls, no statistically significant differences in alleles or genotypes of PSMA6, PSMC6 or PSMA3 were observed between asthma patients and control subjects. However, when male and female study subjects were considered separately, we found that the CG genotype of PSMA6 rs1048990 is significantly more frequent in male asthma patients compared to male control subjects. CONCLUSIONS: We found no significant differences in frequencies of selected five proteasomal gene PSMA6, PSMC6 and PSMA3 SNP's between asthma patients and control subjects overall. Among male subjects, however, the CG PSMA6 rs1048990 genotype was significantly more frequent in asthma patients compared with control subjects.

Evaluation of vitamin D levels in allergic and non-allergic asthma.

BACKGROUND AND OBJECTIVE: Some researches show that low vitamin D may play a role in asthma pathogenesis. The aim of this study was to evaluate the serum vitamin D level in asthmatics with different phenotypes and to determine its associations with lung function, IgE, eosinophil count and body mass index (BMI). MATERIALS AND METHODS: The study population comprised 85 patients with asthma and 73 healthy persons. Patients with asthma were divided into groups according to phenotypes. Allergy was assessed using a skin prick test and measuring eosinophil count in peripheral blood and total IgE in serum. Lung function was evaluated by spirometry. Concentration of vitamin D (25(OH)D3) was measured using a commercial ELISA kit. Smoking history was assessed and BMI was calculated for all individuals. RESULTS: The vitamin D level was lower in asthmatics than in the control group (14.36±0.57 vs. 22.13±0.84 ng/mL, P<0.01). There were no significant differences in the vitamin D level between the groups with allergic and non-allergic asthma (14.36±0.77 vs. 14.35±0.74 ng/mL). The low vitamin D level increased the risk of asthma 1.2 times (OR, 1.194; 95% CI, 1.109-1.286, P<0.01). The vitamin D level did not correlate with lung function and markers of allergy in asthmatic patients. The vitamin D level correlated with FEV1/FVC (rs=0.72, P<0.05) in smoking patients with asthma. Correlation between the vitamin D level and BMI was found in all studied subjects (rs=-0.18, P<0.05). CONCLUSIONS: The vitamin D level was lower in asthmatic patients than in healthy individuals despite their hypersensitivity and increase risk of asthma. There was no relation between the vitamin D level and lung function, eosinophil count and total IgE level, whereas the lower vitamin D level was associated with higher BMI.