Rationale:Occupational exposures at the WTC site after September 11, 2001 have been associated with several presumably inflammatory lower airway diseases.Pulmonary arterial enlargement, as suggested by an increased ratio of the diameter of the pulmonary artery to the diameter of the aorta (PAAr) has been reported as a computed tomographic (CT) scan marker of adverse respiratory health outcomes, including WTC-related disease. In this study, we sought to utilize a novel quantitative CT (QCT) measurement of PAAr to test the hypothesis that an increased ratio is associated with FEV 1 below each subject's statistically determined lower limit of normal (FEV 1 < LLN). Methods: In a group of 1,180 WTC workers and volunteers, we examined whether FEV 1 < LLN was associated with an increased QCT-measured PAAr, adjusting for previously identified important covariates. Results: Unadjusted analyses showed a statistically significant association of FEV 1 < LLN with PAAr (35.3% vs 24.7%, P = 0.0001), as well as with height, body mass index, early arrival at the WTC disaster site, shorter WTC exposure duration, post-traumatic stress disorder checklist (PCL) score, wall area percent and evidence of bronchodilator response. The multivariate logistic regression model confirmed the association of FEV 1 < LLN with PAAr (OR 1.63, 95% CI 1.21, 2.20, P = 0.0015) and all the unadjusted associations, except for PCL score. Conclusions: In WTC workers, FEV 1 < LLN is associated with elevated PAAr which, although likely multifactorial, may be related to distal vasculopathy, as has been hypothesized for chronic obstructive pulmonary disease.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.for use under a CC0 license.

The clinical and socioeconomic burden of asthma exacerbations (AEs) represents a major public health problem. In the last four years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies (GWAS) of AEs, which in the latter case has led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omic” layers have contributed to prioritizing genomic regions of interest and/or understanding the functional consequences of genetic variation. Despite this, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (e.g., gene-environment interactions, next-generation sequencing, or polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have been scarcely investigated, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of host-airway microbiome interaction in the modulation of AEs risk. Leveraging -omics and deep-phenotyping data from sub-types or homogenous subgroups of patients will be crucial to overcome the inherent heterogeneity of AEs, and boost the identification of potential therapeutic targets and the implementation of precision medicine in clinical practice for AEs.