Pharmacogenetic Variation and Its Clinical Relevance in a Latin American Rural Population

Latin-American populations have been largely underrepresented in genomic studies of drug response and disease susceptibility. In this paper, we present a genome-wide Chilean dataset from Talca based on the Illumina Global Screening Array. This let us to compare the frequency of gene variants involved in response to drugs among our population and others, taking data from the 1000 Genomes Project. We found four single-nucleotide polymorphisms with low prevalence in Chileans when compared with African, Amerindian, East and South Asian, and European populations: rs2819742 (RYR2), rs2631367 (SLC22A5), rs1063320 (HLA-G), and rs1042522 (TP53). Moreover, two markers showed significant differences between lower and higher proportion of Mapuche ancestry groups: rs1719247 (located in an intergenic region in chromosome 15; p-value = 6.17 × 10-5, Bonferroni corrected p-value = 0.02) and rs738409 (A nonsynonymous gene variant in the PNPLA3 gene; p-value = 9.02 × 10-5, Bonferroni corrected p-value = 0.04). All of these polymorphisms have been shown to be associated with diverse pathologies, such as asthma, cancer, or chronic hepatitis B, or to be involved in a different response to drugs, such as metformin, HMG-CoA reductase inhibitors, or simvastatin. The present work provides a pharmacogenetic landscape of an understudied Latin American rural population and supports the notion that pharmacogenetic studies in admixed populations should consider ancestry for a higher accuracy of the results. Our study stresses the relevance of the pharmacogenomic research to provide guidance for a better choice of the best treatment for each individual in a population with admixed ancestry. Keywords: Chile; Latin-American; ancestry; personalized medicine; pharmacogenetics; single nucleotide polymorphism

Associations between the duration of active commuting to school and academic achievement in rural Chilean adolescents

Background: Habitual active commuting to school may be positively associated with academic achievement. The aim of this study was to examine the relationship between duration of walking or otherwise actively commuting to school and academic achievement. Methods: This cross-sectional study included 389 adolescents from seven rural schools (12-13 years). Mode and duration of active commuting to school (use of active means such as walking or biking to and from school) and screen time were self-reported. Academic achievement was determined by the outcome in basic grades (language and mathematics). Results: Active commuting to school was not associated with higher scores in any grades after adjustment for potential confounders. No evidence was found of interactions between gender and academic achievement, but there was interaction with duration of walking (<30 min, 30-60 min, and >60 min). Adjusted binary logistic regression analysis suggested that adolescents who spent between 30 and 60 min actively commuting were more likely to obtain high academic achievement (language and mathematics). Conclusions: Thirty to 60 min of ACS may have a positive influence on academic achievement in adolescents, so, it is necessary to make recommendations for the children to walk from and/or to school. This could help society to recognize the relevance of physical activity to health as well as to academic performance. © The Author(s). 2017

Can physical activity attenuate the negative association between sitting time and cognitive function among older adults? A mediation analysis

The purpose of this study was to examine the combined association of sitting time and physical activity with cognitive function and to determine whether moderate-to-vigorous physical activity (MVPA) is a mediator of the association between sitting time and cognitive function in a nationally representative sample of older adults from Chile. Data from 989 older adults (≥65 years old, 61.3% female) from the 2009-2010 Chilean Health Survey were analyzed. Physical activity and sitting time were measured using the Global Physical Activity questionnaire. Cognitive function was assessed using the modified Mini-Mental State levels Examination. Physical activity levels were categorized as "inactive" (<600 metabolic equivalent value minutes per week) or "active" (≥600 metabolic equivalent value minutes per week). Sitting time was categorized as "sedentary", defined as ≥4 h of reported sitting time per day, or "non-sedentary", defined as <4 h. We created the following groups (i) non-sedentary/active; (ii) non-sedentary/inactive; (iii) sedentary/active; and (iv) sedentary/inactive. Hayes's PROCESS macro was used for the simple mediation analysis. Compared with the reference group (individuals classified as non-sedentary/active), older adults who were classified as sedentary/active had elevated odds of cognitive impairment (OR = 1.90, [95% CI, 1.84 to 3.85]). However, the odds ratio for cognitive impairment was substantially increased in those classified as sedentary/inactive (OR = 4.85 [95% CI, 2.54 to 6.24]) compared with the reference group. MVPA was found to mediate the relationship between sitting time and cognitive function (Indirect Effect = -0.070 [95% CI, -0.012 to -0.004]). The present findings suggest that, whether overall physical activity is high or low, spending large amounts of time sitting is associated with elevated odds of cognitive impairment and that MVPA slightly weakens the relationship between sitting time and cognitive function

Lung CD57+ cell density is increased in very severe COPD

Among all inflammatory cells involved in COPD, those with a cytolytic or elastolytic activity are thought to play a key role in the pathogenesis of the disease. However, there is no data about the infiltration of cells expressing the CD57 marker in small airways and parenchyma of COPD patients. In this study, surgical specimens from 43 subjects undergoing lung resection due to lung cancer (9 non-smokers, 18 smokers without COPD and 16 smokers with moderate COPD) and 16 patients undergoing double lung transplantation for very severe COPD were examined. CD57+ cells, neutrophils, macrophages and mast cells infiltrating bronchioles (epithelium, smooth muscle and connective tissue) and parenchymal interstitium were localized and quantified by immunohistochemical analysis. Compared to the other groups, the small airways of very severe COPD patients showed a significantly higher density of CD57+ cells, mainly infiltrated in the connective tissue (p=0.001), and a significantly higher density of neutrophils located characteristically in the epithelium (p=0.037). Also, the density of neutrophils was significantly higher in parenchyma of very severe COPD patients compared with the rest of the groups (p=0.001). Finally, there were significant correlations between the bronchiolar density of CD57+ cells and the FEV1 values (R=-0.43, p=0.022), as well as between the parenchymal density of neutrophils and macroscopic emphysema degree (R=0.43, p=0.048) in COPD groups. These results show that CD57+ cells may be involved in COPD pathogenesis, especially in the most severe stages of the disease

Comparative analysis of COPD associated with tobacco smoking, biomass smoke exposure or both

Correction: https://doi.org/10.1186/s12931-018-0765-4Background: Exposure to noxious gases and particles contained in both tobacco smoking (TS) and biomass smoke (BS) are well recognized environmental risk factors for chronic obstructive pulmonary disease (COPD). COPD is characterized by an abnormal inflammatory response, both in the pulmonary and systemic compartments. The differential effects of TS, BS or their combined exposure have not been well characterized yet. This study sought to compare the lung function characteristics and systemic inflammatory response in COPD patients exposed to TS, BS or their combination. Methods: Sociodemographic, clinical and lung functional parameters were compared across 49 COPD patients with a history of smoking and no BS exposure (TS COPD), 31 never-smoker COPD patients with BS exposure (BS COPD), 46 COPD patients with a combined exposure (TS + BS COPD) and 52 healthy controls (HC) who have never been exposed neither to TS or BS. Blood cell counts, C-reactive protein (CRP), fibrinogen and immunoglobulin E (IgE) levels were quantified in all four groups. Results: TS + BS COPD patients exhibited significantly lower oxygen saturation than the rest of groups (p < 0.01). Spirometry and diffusing capacity were significantly higher in BS than in TS or TS + BS patients. CRP levels were significantly higher in TS COPD patients than in BS COPD group (p < 0.05), whereas fibrinogen was raised in COPD patients with a history of smoking (TS and TS + BS) when compared to control subjects (p < 0.01). Finally, COPD patients with BS exposure (BS and BS + TS groups) showed higher IgE levels than TS and HC (p < 0.05). Conclusions: There are significant physiological and inflammatory differences between COPD patients with TS, BS and TS + BS exposures. The latter had worse blood oxygenation, whereas the raised levels of IgE in BS exposed patients suggests a differential Th2 systemic inflammatory pattern triggered by this pollutant

Significant increase of CD57+ cells in pulmonary lymphoid follicles of COPD patients

Although the presence of pulmonary lymphoid follicles (LFs) has been associated with the progression of chronic obstructive pulmonary disease (COPD), there is no information regarding the pattern of vascularisation, expression of addressins or inflammatory cell densities within these structures in COPD. Histological and immunohistochemical techniques were used to assess the prevalence, structure, localisation, vascularisation and cell proliferation/apoptosis of LFs, as well as the follicular density of B- and T-lymphocytes, macrophages, dendritic cells and CD57+ cells, in lung tissue of nine nonsmokers, 18 smokers without COPD, 16 smokers with moderate COPD and 16 patients with very severe COPD. The density of CD57+ cells within LFs of COPD patients was significantly increased compared to that of nonsmokers and smokers without COPD (p<0.05). Moreover, the percentage of LF profiles with cell apoptosis was also significantly higher in COPD patients (p = 0.03). By contrast, no significant differences among groups were observed in the follicular densities of other inflammatory cells, nor in the distribution of blood and lymphatic vessels within LFs. Since CD57+ cells are important effectors of cytotoxicity and immune regulation, an increase in their follicular density supports the hypothesis of local immune dysfunction in COPD

The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

Despite the significant differences in pathological background of neurodegenerative diseases,epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer 'sdisease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shownthat the risk of developing epilepsy is three to six times higher in patients with MS compared tothe general population. In this context, understanding the pathological processes underlying thisconnection will allow for the targeting of the common and shared pathological pathways involvedin both conditions, which may provide a new avenue in the management of neurological disorders.This review provides an outlook of what is known so far about the bidirectional association betweenepilepsy and M

Efectores celulares de la respuesta inflamatoria en la enfermedad pulmonar obstructiva crónica

Approximately 3 million people in the world die every year as a consequence of COPD, a pathological process with a high impact also in Chile. COPD is associated with an abnormal inflammatory response of the lung to noxious particles and gases. This inflammatory pattern causes histopathological changes that lead to a narrowing of small airways lumen and destruction of lung parenchyma, also known as emphysema. Classically, these changes were associated to macrophages and neutrophils, although T CD8+ lymphocytes were latter added to the equation, in order to explain the origin of emphysematous lesions. However, in recent years, multiple evidences have arisen indicating that inflammatory response in COPD is much more complex. These findings point to a key role for mast cells, dendritic cells, T CD4+ cells and B cells. The aim of this article is to review such evidence and present what is known so far about the protagonist cells of the inflammatory response in COPD

Correction: Deficient pulmonary IFN-β expression in COPD patients

COPD patients are prone to acute infectious exacerbations that impair their quality of life and hamper prognosis. The purpose of the present study was to investigate the in situ IFN-β response in the lungs of stable COPD and non-COPD patients. Lung samples from 70 subjects (9 control never smokers, 19 control smokers without COPD, 21 patients with moderate COPD and 21 patients with very severe COPD) were studied for the expression of IFN-β, its main transcription factor, IRF-7, and two products of its autocrine function, namely RIG-I and MDA-5, by immunohistochemical techniques and quantitative real-time PCR. IFN-β, IRF-7, RIG-I and MDA-5 were widely detected in most lung cell types. In epithelial tissues and alveolar macrophages, IFN-β and IRF-7 labeling scores were decreased up to 65% and 74%, respectively, for COPD patients, paralleling an analogous reduction (43% and 65%, respectively) in the amount of their lung mRNA. Moreover, this decreased production of IFN-β in COPD patients correlated with a similar decrease in the expression of RIG-I and MDA-5, two essential members of the innate immune system. Our study indicates that most lung cells from stable COPD patients show a constitutive decreased expression of IFN-β, IRF-7, RIG-I and MDA-5, suggesting that this deficiency is the main cause of their acute viral exacerbations