Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD). To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function. We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11).

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure. Objectives: To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease. Methods: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n ¼ 1,085 and 369 subjects). Measurements and Main Results: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 3 10 223; FEV 1 /FVC, 1.5 3 10 235; FEV 1 , 2.2 3 10 240 ). Conclusions: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This largescale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.Keywords: chronic obstructive pulmonary disease; epigenetics; DNA methylation; smoking Chronic obstructive pulmonary disease (COPD) is a multifactorial complex human disease of the lungs with world-wide impact (1). Genome-wide genetic association studies have identified variants associated with COPD (2, 3) and lung function (4-6), yet each identified locus explains only a small amount of the risk for COPD. Variation in the a 1 -antitrypsin (AAT) gene (SER-PINA1) is a monogenic cause of COPD, but even in the presence of AAT deficiency the development of COPD is unpredictable. COPD fits well in the common disease genetic and epigenetic hypothesis, which promulgates that epigenetic variation may be an important mediator between genetic variation and environmental exposures (7). Specifically, DNA methylation may provide further explanation for features of COPD that are not explained fully by DNA sequence variation, such as the variable susceptibility to develop lung disease in smokers, as well as the continued elevated risk for lung function decline years after smoking cessation (8). Epigenetic studies might shed new insights into the pathogenesis of COPD susceptibility and severity.Cigarette smoking is the major environmental risk factor for lung function decline and COPD. Cigarette smoking has been demonstrated to impact global hypomethylation of repetitive genomic elements (...

Rationale: Vitamin D insufficiency (a serum 25(OH)D ,30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans. Objectives: To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors. Methods: A cross-sectional study was conducted of 560 children ages 6-14 years with (n ¼ 287) and without (n ¼ 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genomewide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates. Measurements and Main Results: Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.9; P ¼ 0.001) and atopy, and a lower FEV 1 /FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2-21.6; P ¼ 0.002) than in atopic (OR, 2; 95% CI, 1-4.1; P ¼ 0.04) cases. Conclusions: Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.Keywords: vitamin D; asthma exacerbations; Puerto Ricans; childhood Vitamin D insufficiency (a serum level of 25(OH)D ,30 ng/ml) is common among children in the United States mainland. For example, a nationwide study of 2,759 U.S. children ages 6-11 years found vitamin D insufficiency in approximately 62% of nonHispanic whites, approximately 86% of Hispanics, and approximately 96% of non-Hispanic blacks (1). Vitamin D insufficiency has been associated with increased asthma morbidity, particularly severe disease exacerbations, in observational studies of children of school age in Costa Rica (2) and North America (3).Although current evidence from observational (2-5) and experimental studies (6-9) suggests that vitamin D insufficiency leads to severe asthma exacerbations or increased asthma morbidity in childhood (10), no study of vitamin D and asthma morbidity has accounted for objectively assessed racial ancestry and time spent outdoors. This is critical to exclude whether vitamin D insufficiency is associated with severe asthma exacerbations or asthma morbidity through "reverse causation" (e.g., more severe asthma leading to reduced time outdoors and thus decreased exposure to sunlight ...

Background: Epigenetic mechanisms may alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. Here we aim to identify DNA methylation profiles that are associated with-and accurately classify-atopy and atopic asthma in school-aged children.

Background Epidemiological studies consistently show associations between asthma and obesity. Shared genetics may account for this association. Objective To identify genetic variants associated with both asthma and obesity. Methods Based on a literature search, we identified genes from: 1) Genome-wide association studies (GWAS) of Body Mass Index (BMI) (n=17 genes), 2) GWAS of asthma (n=14) and 3) candidate gene studies of BMI and asthma (n=7). We used GWAS data from the Childhood Asthma Management Program (CAMP) to analyze associations between single nucleotide polymorphisms (SNPs) in these genes and asthma (n=359 subjects) and BMI (n=537). Results One top BMI GWAS SNP from the literature, rs10938397 near GNPDA2, was associated with both BMI (p=4 × 10−4) and asthma (p=0.03). Of the top asthma GWAS SNPs and the candidate gene SNPs, none was found to be associated with both BMI and asthma. Gene-based analyses that included all available SNPs in each gene found associations (p<0.05) with both phenotypes for several genes: NEGR1, ROBO1, DGKG, FAIM2, FTO and CHST8 among the BMI GWAS genes; ILRL1/IL18R1, DPP10, PDE4D, MYB, PDE10A, IL33 and especially PTPRD among the asthma GWAS genes; and PRKCA among the BMI and asthma candidate genes. Conclusions SNPs within several genes showed associations to BMI and asthma at a gene level, but none of these associations were significant after correction for multiple testing. Our analysis of known candidate genes reveals some evidence for shared genetics between asthma and obesity, but other shared genetic determinants are likely to be identified in novel loci.

Background Puerto Ricans and African Americans share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults. Objective To examine whether a greater proportion of African ancestry is associated with lower FEV1 and FVC in Puerto Rican children, independently of socioeconomic status (SES), healthcare access or key environmental/lifestyle (EL) factors. Methods Cross-sectional case-control study of 943 Puerto Rican children ages 6 to 14 years with (n=520) and without (n=423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford (CT, n=383) and San Juan (PR, n=560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV1 and FVC using linear regression. Multivariate models were adjusted for indicators of SES and healthcare, and selected EL exposures. Results After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower pre-bronchodilator(BD) FEV1 (−105 ml, 95% confidence interval [CI] = −159 ml to −51 ml, P <0.001) and FVC (−133 ml, 95% CI −197 ml to −69 ml, P <0.001), and post-BD FEV1 (−152 ml, 95% CI=−210 ml to −94 ml, P <0.001) and FVC (−145 ml, 95% CI= −211 to −79 ml, P <0.001) in children with asthma. Similar but weaker associations were found for pre- and post-BD FEV1 (change for each 20% increment in African ancestry= −78 ml, 95% CI= −131 to −25 ml, P=0.004), and for post-BD FVC among children without asthma. Conclusions Genetic and/or EL factors correlated with African ancestry may influence childhood lung function in Puerto Ricans.

Rationale: Epigenetic and/or genetic variation in the gene encoding the receptor for adenylate-cyclase activating polypeptide 1 (ADCYAP1R1) has been linked to post-traumatic stress disorder in adults and anxiety in children. Psychosocial stress has been linked to asthma morbidity in Puerto Rican children. Objectives: To examine whether epigenetic or genetic variation in ADCYAP1R1 is associated with childhood asthma in Puerto Ricans. Methods: We conducted a case-control study of 516 children ages 6-14 years living in San Juan, Puerto Rico. We assessed methylation at a CpG site in the promoter of ADCYAP1R1 (cg11218385) using a pyrosequencing assay in DNA from white blood cells. We tested whether cg11218385 methylation (range, 0.4-6.1%) is associated with asthma using logistic regression. We also examined whether exposure to violence (assessed by the Exposure to Violence [ETV] Scale in children 9 yr and older) is associated with cg11218385 methylation (using linear regression) or asthma (using logistic regression). Logistic regression was used to test for association between a single nucleotide polymorphism in ADCYAP1R1 (rs2267735) and asthma under an additive model. All multivariate models were adjusted for age, sex, household income, and principal components. Measurements and Main Results: Each 1% increment in cg11218385 methylation was associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.6; P ¼ 0.03). Among children 9 years and older, exposure to violence was associated with cg11218385 methylation. The C allele of single nucleotide polymorphism rs2267735 was significantly associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.02-1.67; P ¼ 0.03). Conclusions: Epigenetic and genetic variants in ADCYAP1R1 are associated with asthma in Puerto Rican children.

Background: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. Objective: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. Methods: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n 5 244).