Juan M. Combe

Effect of urbanisation on asthma, allergy and airways inflammation in a developing country setting

Background Asthma is a growing public health problem in developing countries. However, few studies have studied the role of urbanisation in this phenomenon. It was hypothesised that children living in a peri-urban setting in Peru have higher rates of asthma and allergy than rural counterparts. Methods 1441 adolescents aged 13–15 years were enrolled from two settings: a peri-urban shanty town in Lima (n=725) and 23 rural villages in Tumbes (n=716). Participants filled in questionnaires on asthma and allergy symptoms, environmental exposures and sociodemographics, and underwent spirometry, and exhaled nitric oxide (eNO) and allergy skin testing. Indoor particulate matter (PM) concentrations were measured in 170 households. Results Lima adolescents had higher rates of lifetime wheezing (22% vs 10%), current asthma symptoms (12% vs 3%) and physician-diagnosed asthma (13% vs 2%; all p <0.001). Current rhinitis (23% vs 12%), eczema (12% vs 0.4%), atopy (56% vs 38%), personal history of cigarette smoking (7.4% vs 1.3%) and mean indoor PM (31 vs 13 μg/m3) were also higher in Lima (all p <0.001). The peri-urban environment of Lima was associated with a 2.6-fold greater odds (95% CI 1.3 to 5.3) of asthma in multivariable regression. Forced expiratory volumes were higher and FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity) ratios were lower in Lima (all p <0.001). Higher eNO values in Lima (p <0.001) were attributable to higher rates of asthma and atopy. Conclusions Peri-urban adolescents had more asthma, atopy and airways inflammation and were exposed to more indoor pollution. The findings provide evidence of the risks posed to lung health by peri-urban environments in developing countries.

Effects of distance from a heavily transited avenue on asthma and atopy in a periurban shantytown in Lima, Peru.

BACKGROUND Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes. OBJECTIVE We sought to determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a periurban shantytown in Lima, Peru. METHODS We enrolled 725 adolescents aged 13 to 15 years who were administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing, and exhaled nitric oxide (eNO). We calculated distances from the main avenue for all households and measured indoor particulate matter in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO levels, and FEV(1)/forced vital capacity ratio as a function of distance. RESULTS Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (P < .05). The odds of atopy increased by a factor of 1.07 for every 100-meter difference in the distance from the avenue (P = .03). We found an inverse relationship in prebronchodilator FEV(1)/forced vital capacity and distance to the avenue in female subjects (P = .01) but not in male subjects. We did not find an association between eNO or household particulate matter levels and distance. CONCLUSION Living in close proximity to a high-traffic-density avenue in a periurban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile-source pollutants in periurban areas of developing countries might help reduce the burden of asthma symptoms and atopy.

Socioeconomic and Nutritional Factors Account for the Association of Gastric Cancer with Amerindian Ancestry in a Latin American Admixed Population

Gastric cancer is one of the most lethal types of cancer and its incidence varies worldwide, with the Andean region of South America showing high incidence rates. We evaluated the genetic structure of the population from Lima (Peru) and performed a case-control genetic association study to test the contribution of African, European, or Native American ancestry to risk for gastric cancer, controlling for the effect of non-genetic factors. A wide set of socioeconomic, dietary, and clinic information was collected for each participant in the study and ancestry was estimated based on 103 ancestry informative markers. Although the urban population from Lima is usually considered as mestizo (i.e., admixed from Africans, Europeans, and Native Americans), we observed a high fraction of Native American ancestry (78.4% for the cases and 74.6% for the controls) and a very low African ancestry (<5%). We determined that higher Native American individual ancestry is associated with gastric cancer, but socioeconomic factors associated both with gastric cancer and Native American ethnicity account for this association. Therefore, the high incidence of gastric cancer in Peru does not seem to be related to susceptibility alleles common in this population. Instead, our result suggests a predominant role for ethnic-associated socioeconomic factors and disparities in access to health services. Since Native Americans are a neglected group in genomic studies, we suggest that the population from Lima and other large cities from Western South America with high Native American ancestry background may be convenient targets for epidemiological studies focused on this ethnic group.

The Peru Urban versus Rural Asthma (PURA) Study: methods and baseline quality control data from a cross-sectional investigation into the prevalence, severity, genetics, immunology and environmental factors affecting asthma in adolescence in Peru

Objectives According to a large-scale international survey, Peru has one of the highest prevalences of asthma worldwide; however, data from this survey were limited to participants from urban Lima. The authors sought to characterise the epidemiology of asthma in Peru in two regions with disparate degrees of urbanisation. In this manuscript, the authors summarise the study design and implementation. Design A cross-sectional study. Participants Using census data of 13–15-year-old adolescents from two communities in Peru, the authors invited a random sample of participants in Lima (n=725) and all adolescents in Tumbes (n=716) to participate in our study. Primary and secondary outcome measures The authors asked participants to complete a questionnaire on asthma symptoms, environmental exposures and socio-demographics and to undergo spirometry before and after bronchodilator, skin allergy testing and exhaled nitric oxide testing. The authors obtained blood samples for haematocrit, total IgE levels, vitamin D levels and DNA in all participants and measured indoor particulate matter concentrations for 48 h in a random subset of 70–100 households at each site. Results Of 1851 eligible participants, 1441 (78%) were enrolled and 1159 (80% of enrolled) completed all physical tests. 1283 (89%) performed spirometry according to standard guidelines, of which 86% of prebronchodilator tests and 92% of postbronchodilator tests were acceptable and reproducible. 92% of allergy skin tests had an adequate negative control. The authors collected blood from 1146 participants (79%) and saliva samples from 148 participants (9%). Overall amounts of DNA obtained from blood or saliva were 25.8 μg, with a 260/280 ratio of 1.86. Conclusions This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting. The authors present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.

Interleukin-1 beta single-nucleotide polymorphism's C allele is associated with elevated risk of gastric cancer in helicobacter pylori-infected Peruvians

Particular alleles of the interleukin-1B (IL-1B) gene have been correlated with increased risk of atrophic gastritis and gastric cancer in the populations of East Asia and Europe. No such data exist from Peru, a developing country with a population genotypically different from others studied and with a high prevalence of Helicobacter pylori infection and gastric cancer. We conducted a case-control study comparing 334 hospitalized patients with atrophic gastritis or gastric cancer with 158 nonatrophic gastritis patients (controls). Conditional logistic regression analysis revealed that an increased risk of atrophic gastritis (odds ratio, 5.60) and gastric cancer (odds ratio, 2.36) was associated with the IL-1B-511 C allele. Our study is the first to establish this allele as a risk for these conditions. Given the high prevalence of H. pylori and recurrence rate after treatment, IL-1B-511 single-nucleotide polymorphism analysis may identify those individuals who would benefit most from robust H. pylori eradication efforts in Peru.

Association of Roadway Proximity with Indoor Air Pollution in a Peri-Urban Community in Lima, Peru.

The influence of traffic-related air pollution on indoor residential exposure is not well characterized in homes with high natural ventilation in low-income countries. Additionally, domestic allergen exposure is unknown in such populations. We conducted a pilot study of 25 homes in peri-urban Lima, Peru to estimate the effects of roadway proximity and season on residential concentrations. Indoor and outdoor concentrations of particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) were measured during two seasons, and allergens were measured in bedroom dust. Allergen levels were highest for dust mite and mouse allergens, with concentrations above clinically relevant thresholds in over a quarter and half of all homes, respectively. Mean indoor and outdoor pollutant concentrations were similar (PM2.5: 20.0 vs. 16.9 μg/m3, BC: 7.6 vs. 8.1 μg/m3, NO2: 7.3 vs. 7.5 ppb), and tended to be higher in the summer compared to the winter. Road proximity was significantly correlated with overall concentrations of outdoor PM2.5 (rs = −0.42, p = 0.01) and NO2 (rs = −0.36, p = 0.03), and outdoor BC concentrations in the winter (rs = −0.51, p = 0.03). Our results suggest that outdoor-sourced pollutants significantly influence indoor air quality in peri-urban Peruvian communities, and homes closer to roadways are particularly vulnerable.

Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies

Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC. We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean = 5.74, 95% CI, 4.97−6.50), gastritis patients with metaplasia (mean = 4.81, 95% CI, 3.77−5.84), and gastric cancer cases (mean = 3.38, 95% CI, 2.82−3.94), respectively (p < 0.0001). Promoter methylation of IRF4 (p < 0.0001), ELMO1 (p < 0.0001), CLIP4 (p < 0.0001), and MSC (p < 0.0001), is also associated with increasing severity from gastritis with no metaplasia to gastritis with metaplasia and gastric cancer. Our findings suggest that IRF4, ELMO1, CLIP4 and MSC promoter methylation coupled with a GDMI>4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.

Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry

BackgroundGastric adenocarcinoma is associated with chronic infection by Helicobacter pylori and with the host inflammatory response triggered by it, with substantial inter-person variation in the immune response profile due to host genetic factors.AimTo investigate the diversity of the proinflammatory genes IL8, its receptors and PTGS2 in Amerindians; to test whether candidate SNPs in these genes are associated with gastric cancer in an admixed population with high Amerindian ancestry from Lima, Peru; and to assess whether an IL8RB promoter-derived haplotype affects gene expression.MethodsWe performed a Sanger-resequencing population survey, a candidate-gene association study (220 cases, 288 controls) and meta-analyses. We also performed an in vitro validation by a reporter gene assay of IL8RB promoter.ResultsThe diversity of the promoter of studied genes in Native Americans is similar to Europeans. Although an association between candidate SNPs and gastric cancer was not found in Peruvians, trend in our data is consistent with meta-analyses results that suggest PTGS2-rs689466-A is associated with H. pylori-associated gastric cancer in East Asia. IL8RB promoter-derived haplotype (rs3890158-A/rs4674258-T), common in Peruvians, was up-regulated by TNF-α unlike the ancestral haplotype (rs3890158-G/rs4674258-C). Bioinformatics analysis suggests that this effect stemmed from creation of a binding site for the FOXO3 transcription factor by rs3890158G>A.ConclusionsOur updated meta-analysis reinforces the role of PTGS2-rs689466-A in gastric cancer in Asians, although more studies that control for ancestry are necessary to clarify its role in Latin Americans. Finally, we suggest that IL8RB-rs3890158G>A is a cis-regulatory SNP.

Effect of urbanisation on the relationship between total serum IgE and asthma

It is unclear if the relationship of total serum IgE with asthma varies with degree of urbanisation. We hypothesised that the relationship of total serum IgE to asthma is more pronounced in an urban versus a rural environment. We enrolled 1441 children aged 13–15 years in a peri-urban shanty town in Lima, Peru (n=725) and 23 villages in rural Tumbes, Peru (n=716). We asked participants about asthma and allergy symptoms, environmental exposures and sociodemographics; and performed spirometry, and exhaled nitric oxide and allergy skin testing. We obtained blood for total serum IgE in 1143 (79%) participants. Geometric means for total serum IgE were higher in Lima versus Tumbes (262 versus 192 kU·L−1; p<0.001). The odds of asthma increased by factors of 1.6 (95% CI 1.3–2.0) versus 1.4 (95% CI 0.9–2.1) per log unit increase in total serum IgE in Lima versus Tumbes, respectively. Atopy was an effect modifier of the relationship of total serum IgE on asthma. Among atopics and non-atopics, the odds of asthma increased by a factor of 2.0 (95% CI 1.5–2.7) and 1.0 (95% CI 0.7–1.4) per log unit increase in total serum IgE, respectively. Total serum IgE was associated with atopic asthma but not with non-atopic asthma. Urbanisation did not appear to be an effect modifier of this relationship.

Abstract LB-247: Early detection of gastric cancer using global and gene-specific promoter DNA methylation in endoscopic biopsies

Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Peru, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, genome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC. We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean= 5.74, 95% CI, 4.97-6.50), gastritis patients with metaplasia (mean= 4.81, 95% CI, 3.77-5.84), and gastric cancer cases (mean=3.38, 95% CI, 2.82-3.94), respectively (p 4, is a useful molecular tool for gastric cancer risk stratification in endoscopic biopsies. Citation Format: Francesca Pirini, Sassan Noazin, Martha Jahuira Arias, Sebastian Rodriguez-Torres, Leah Friess, Christina Michailidi, Jaime Cok, Juan Combe, Goria Vargas, William Prado, Ethan Soudry, Jimena Perez, Tikki Yudin, Andrea Mancinelli, Helen Unger, Carmen Ili, Priscilla Brebi, Douglas Berg, Masamichi Hayashi, David Sidransky, Robert Gilman, Rafael E. Guerrero-Preston. Early detection of gastric cancer using global and gene-specific promoter DNA methylation in endoscopic biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2017-LB-247