Publication Spotlight

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Publication Spotlight

Publication Spotlight


The papers listed here were publication spotlights to highlight important scientific advancements published by members of the ATS Section of Genetics and Genomics. As these papers include major advancements in the field, this page will be used to archive each featured publication to allow easy access to this body of literature.

Age-of-onset information helps identify 76 genetic variants associated with allergic disease

Author: Gerard H. Koppelman, MD, PhD, Executive Committee Member
Description: The majority of studies of allergic disease to date have focused on incidence of disease rather than age at onset. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic diseases, including asthma, first develop. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. We also determined that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. When considering both allergic status and age of onset a further 26 SNPs were identified. Of the 76 total variants, 18 were novel. We identified 81 likely target genes of these variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, including ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7, and UBE2L3. In sum, these findings support the hypothesis that early and late-onset allergic diseases have partly distinct genetic architectures. GWAS of other complex diseases might also benefit from considering age-of-onset information.

Author: Michael H. Cho, MD, Former Executive Committee Co-chair

Description: In this manuscript, we develop a polygenic risk score using genome-wide association study summary statistics of lung function from more than 400 000 participants from the UK Biobank and SpiroMeta, and demonstrate that it can be used to predict the diagnosis of COPD in nine population-based and case-control cohorts of multiple ethnicities. The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. This score uses more variants and larger sample sizes than previous studies and has been tested in a greater number of validation cohorts. As such, we show this new score is superior to previously described genetic risk scores and when combined with clinical risk factors (ie, age, sex, and smoking pack-years), shows improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The score was also associated with CT imaging phenotypes and patterns of reduced lung growth that could predispose individuals to COPD. These findings could have important implications for understanding the mechanisms underlying COPD and provide future opportunities for prevention and early intervention, as genomics becomes more widely adopted in health care.

GWAS Functional Variant rs2076295 Regulates Desmoplakin (DSP) Expression in Airway Epithelial Cells

Author: Xiaobo Zhou, PhD, Committee Member

Description: Intriguingly, the non-coding variant rs2076295 at 6q24, is associated with the susceptibility of Idiopathic Pulmonary Fibrosis (IPF) and with Chronic Obstructive Pulmonary Disease (COPD), but with opposite directions of effect for the risk allele. The aim of this study was to identify the causal gene and causal variant for the association in this locus to try and disentangle this further. Using CRISPR/Cas9 based genome editing approaches, the authors were able to demonstrate that rs2076295 is the functional variant that regulates DSP expression in airway epithelial cells. DSP encodes desmoplakin which forms cell-cell adhesion complexes enabling tissues to resist mechanical forces. Reduced levels of DSP, associated with the risk allele leads to increased expression of extracellular matrix genes and promotes migration of airway epithelial cells, which may explain the relationships with IPF and COPD. These findings demonstrate the applicability and utility of post-GWAS functional studies.

Author: Ann Chen Wu, MD, MPH, Nominating Committee Member  
Description: In this study, for the first time, we examined the real-world effectiveness of inhaled corticosteroids (ICS)  including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), considering patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. We assessed longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination; and defined Asthma exacerbations as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We found that in this real world setting ICS-LABA therapy reduced all types of exacerbations by a factor of 1.76 (95% CI (1.06, 2.93),  p = 0.03) per day and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53),  p = 0.037). We concluded that ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.

Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function

Author: Christine Wendt, MD

Description: Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. The hypothesis of this study is that lung stromal cells activate pathological gene expression programs that support oncogenesis. This was explored by conducting a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. The authors identified the activation of two distinct stromal gene expression programs that promote cancer initiation; and determined that which one was activated was dependent on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. This work has important implications both for screening strategies and for personalized approaches to cancer treatment.

Author: Dr. Victor Ortega, Co-Chair, Section on Genetics and Genomics
Description: Ortega and colleagues comprehensively evaluated the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in 1,693 non-Hispanic Whites, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking using deep DNA sequencing of the gene encoding α1-antitrypsin, SERPINA1. This integrative sequencing study is the first to perform deep gene sequencing in combination with α1-antitrypsin concentrations in multiple ethnic groups to detect the cumulative effects of PI Z, S, and additional, rare SERPINA1 variants combined and independently.