Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Abstract

Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.

Genetic Risk for Developing Chronic Obstructive Pulmonary Disease

“…This observation is supported by familial aggregation studies and reports of associations among polymorphisms in nitric oxide synthase (NOS) 3, glutathione s-transferase pi (GSTPI), tumour necrosis factor (TNF), interleukin-(IL)10, iron regulatory binding protein (IREB)2 and cholinergic nicotine receptor alpha3 (CHRNA3) and COPD phenotypes including lung function in AAT deficiency, suggesting that there are other genes which act as modifier genes in the condition 16,17 . Many of these genes have also been linked to COPD susceptibility in normal individuals (Table 1) 8,9,18,19 . About 1 in 30 individuals in the USA are heterozygous for mutations associated with AAT deficiency, the vast majority of which are of the PiMZ genotype.…”

“…Additionally, familial aggregation has been observed in COPD 6,7 , and several monogenetic conditions including alpha-1 antitrypsin (AAT) deficiency and cutis laxa are associated with the development of COPD, further supporting a role for genetic susceptibility in disease pathogenesis. Genetic linkage and candidate gene studies, genome-wide association studies (GWAS), exome and whole genome sequencing (WGS) have identified genes and loci associated with the condition 8,9 . Importantly, these studies have the potential to provide insights into COPD pathogenesis, improve risk prediction and lead to the development of new therapies for the disease and to the personalisation of COPD care 10 .…”

“…Importantly, these studies have the potential to provide insights into COPD pathogenesis, improve risk prediction and lead to the development of new therapies for the disease and to the personalisation of COPD care 10 . However, though numerous COPD susceptibility loci have been identified 8 , they only explain a fraction of disease hereditability 5,[11][12][13] .…”

Contemporary Concise Review 2019: Chronic obstructive pulmonary disease

“…Hall et al provided a comprehensive overview of the most salient findings from large-scale genome-wide association (GWA) studies in COPD over the past decade. 33 These GWA studies have been largely powered on two phenotypes: (i) lung function parameters (and most notably FEV 1 or FEV 1 /forced vital capacity (FVC) ratio) and (ii) a clinical diagnosis of COPD. Although there is significant overlap of genome-wide 'hits' between these two phenotypes, there are genetic loci that are distinct for each.…”

‘Omics’: The new language in medicine that we all must learn

“…reviewed genome‐wide association studies (GWAS) that delineate populations at risk of respiratory disease. Single nucleotide polymorphisms (SNP) are common mutations in people and may be associated with disease such as ADAMTS4 and asthma …”