Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Zhou, Haixia; Yang, Jing; Li, Dengxue; Xiao, Jun; Wang, Bo; Wang, Lan; Ma, Chunlan; Xu, Sicheng; Ou, Xuemei; Feng, Yu

doi:10.1038/jhg.2012.104

Cited by 34 publications

(36 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The significance of the top SNP, rs17486278, located within CHRNA5, in the analysis of COPD with PAE relative to smoking control subjects was reduced to 4.08 3 10 26 in the analysis of PAE versus no PAE within subjects with COPD. Although the association of the CHRNA3 locus with COPD has been reported to be significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking (39,41). IREB2 may have a different role for COPD pathogenesis from the other genes on 15q25.1, and our study provides additional evidence for this hypothesis.…”

Section: Discussioncontrasting

confidence: 52%

IREB2 and GALC Are Associated with Pulmonary Artery Enlargement in Chronic Obstructive Pulmonary Disease

Lee

Cho

Hersh

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Pulmonary hypertension is associated with advanced chronic obstructive pulmonary disease (COPD), although pulmonary vascular changes occur early in the course of the disease. Pulmonary artery (PA) enlargement (PAE) measured by computed tomography correlates with pulmonary hypertension and COPD exacerbation frequency. Genome-wide association studies of PAE in subjects with COPD have not been reported. To investigate whether genetic variants are associated with PAE within subjects with COPD, we investigated data from current and former smokers from the COPDGene Study and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study. The ratio of the diameter of the PA to the diameter of the aorta (A) was measured using computed tomography. PAE was defined as PA/A greater than 1. A genome-wide association study for COPD with PAE was performed using subjects with COPD without PAE (PA/A ≤ 1) as a control group. A secondary analysis used smokers with normal spirometry as a control group. Genotyping was performed on Illumina platforms. The results were summarized using fixed-effect meta-analysis. Both meta-analyses revealed a genome-wide significant locus on chromosome 15q25.1 in IREB2 (COPD with versus without PAE, rs7181486; odds ratio [OR] = 1.32; P = 2.10 × 10(-8); versus smoking control subjects, rs2009746; OR = 1.42; P = 1.32 × 10(-9)). PAE was also associated with a region on 14q31.3 near the GALC gene (rs7140285; OR = 1.55; P = 3.75 × 10(-8)). Genetic variants near IREB2 and GALC likely contribute to genetic susceptibility to PAE associated with COPD. This study provides evidence for genetic heterogeneity associated with a clinically important COPD vascular subtype.

show abstract

Section: Discussioncontrasting

confidence: 52%

IREB2 and GALC Are Associated with Pulmonary Artery Enlargement in Chronic Obstructive Pulmonary Disease

Lee

Cho

Hersh

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…57,58 SNPs at the 15q25 locus containing genes encoding the nAChRs CHRNA3 and CHRNA5 have been associated with lung cancer, COPD, and lung function. 59–62 nAChR in the lung has been reported to have a role in cell proliferation and apoptosis in response to carcinogens, 63,64 as well as in inflammation. 65 Other compounds that reverse the COPD gene signature affect dopamine; these include disulfiram, which is used as a treatment for alcohol dependence and is being explored for use in cocaine dependence.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying variations in lung function: a systems genetics analysis

Obeidat

Hao

Bossé

et al. 2015

The Lancet Respiratory Medicine

View full text Add to dashboard Cite

Summary Background Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. Methods The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. Findings SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. Interpretation The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. Funding The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.

show abstract

“…Four SNPs were studied, including 9 studies on rs1051730 [11]–[13], [15]–[18], [20], 5 on rs8034191 [7], [13], [18], [20], 4 on rs6495309 [9], [14], [17], and 3 on rs16969968 [11], [18]–[19]. A total of 6 studies assessed associations between SNPs in the CHRNA3/5 locus and COPD risk in Asian populations [9], [14]–[15], [17]–[18]. A total of 10 studies were case-control, while all others were population-based.…”

Section: Resultsmentioning

confidence: 99%

Four SNPs in the CHRNA3/5 Alpha-Neuronal Nicotinic Acetylcholine Receptor Subunit Locus Are Associated with COPD Risk Based on Meta-Analyses

Cui

2014

PLoS ONE

View full text Add to dashboard Cite

BackgroundSeveral single nucleotide polymorphisms (SNPs) in an α-neuronal nicotinic acetylcholine receptor subunit (CHRNA3/5) were identified to be associated with chronic obstructive pulmonary disease (COPD) in a study based on a Norwegian population. However, results from subsequent studies have been controversial, particularly in studies recruiting Asians. In the present study, we conducted a comprehensive search and meta-analyses to identify susceptibility SNPs for COPD in the CHRNA3/5 locus.MethodsA comprehensive literature search was conducted to find studies that have reported an association between SNPs in the CHRNA3/5 locus and COPD risk. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each SNP were calculated with the major allele or genotype as the reference group. The influence of individual studies on pooled measures was assessed, in addition to publication bias.ResultsA total of 12 articles with 14 eligible studies were included in this analysis. Association between 4 SNPs in the CHRNA3/5 locus and COPD was evaluated and included rs1051730, rs8034191, rs6495309, and rs16969968. Significant associations between the 4 SNPs and COPD were identified under allele (rs1051730: OR = 1.14, 95%CI = 1.10–1.18; rs8034191: OR = 1.29, 95%CI = 1.18–1.41; rs6495309: OR = 1.26, 95%CI = 1.09–1.45; rs16969968: OR = 1.27, 95%CI = 1.17–1.39) and genotype models. Subgroup analysis conducted for rs1051730 showed a significant association between this SNP and COPD risk in non-Asians (OR = 1.14, 95%CI = 1.10–1.18), but not Asians (OR = 1.23, 95%CI = 0.91–1.67). Rs1051730 and rs6495309 were also significantly associated with COPD after adjusting for multiple variables, including age and smoking status.ConclusionOur results indicate that 4 SNPs in the CHRNA3/5 locus are associated with COPD risk. Rs1051730 was particularly associated with COPD in non-Asians, but its role in Asians still needs to be verified. Additional studies will be necessary to assess the effect of rs6495309 on COPD. Although rs1051730 and rs6495309 were shown to be independent risk factors for COPD, validation studies should be performed.

show abstract

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Cited by 34 publications

References 32 publications

IREB2 and GALC Are Associated with Pulmonary Artery Enlargement in Chronic Obstructive Pulmonary Disease

IREB2 and GALC Are Associated with Pulmonary Artery Enlargement in Chronic Obstructive Pulmonary Disease

Molecular mechanisms underlying variations in lung function: a systems genetics analysis

Four SNPs in the CHRNA3/5 Alpha-Neuronal Nicotinic Acetylcholine Receptor Subunit Locus Are Associated with COPD Risk Based on Meta-Analyses

Contact Info

Product

Resources

About