Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics

Abstract

Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.

Objectives, design and main findings until 2020 from the Rotterdam Study

“…In a collaborative GWAS we identified 82 genetic loci significantly associated with COPD, of which 14 were shared with asthma or pulmonary fibrosis, confirming our previous observations of overlap between COPD loci and loci for lung function and pulmonary fibrosis [335]. Through epigenetic and transcriptomic studies, we demonstrated that genetic variants at chromosome 15q25.1 (encompassing the nicotinic acetylcholine receptor 3 [CHRNA3] gene and the iron-responsive element binding protein 2 [IREB2] gene) are differentially methylated in blood and differentially expressed in lung tissue of COPD cases and controls [336]. Similarly, we have elucidated the relation of the top COPD GWAS variant at chromosome 19q13.2 with DNA methylation and gene expression in blood and lung tissue [337].…”

“…An integrative cross-omics analysis of DNA methylation sites have identified multiple CpGs for T2D, glucose and insulin homeostasis, and further showed the differential methylation explains at least 16.9% of the association between obesity and insulin [96]. Multi-omics analysis using the Rotterdam Study epigenetics and transcriptomics data also showed that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking [336]. Likewise, a systematic analysis integrating GWAS, gene expression and DNA methylation data indicated multiple long non-coding RNAs associated with cardiometabolic disorders [358].…”

Transcriptome‐wide association study reveals candidate causal genes for lung cancer

“…24 COPD and lung cancer-associated variants in 15q25 are known expression and methylation QTL (eQTL and meQTL) for multiple genes and tissues. 3,25 It has not been possible so far to definitely identify all of the causal gene(s) at this locus, but most evidence points toward CHRNA5 (cholinergic receptor nicotinic alpha 5 subunit) or IREB2 (iron-responsive element binding protein 2). In our study, we focused specifically on gene expression in lung tissues with the hope to identify genes directly involved in lung cancer development.…”

Genetic regulation of gene expression of MIF family members in lung tissue

“…We then investigated whether MIF, DDT and DDTL expression levels were influenced by the presence of SNPs. To this end, we performed a cis-eQTL analysis 19 for these three genes using the entire lung tissue dataset (n = 1087), which contains mostly patients with COPD with or without lung cancer, lung cancer patients with normal lung function (Non-COPD controls), and a few patients with a variety of interstitial lung diseases. A schematic representation of the step-by-step approach for the eQTL, subsequent analyses and the main results are shown in Fig.…”

“…Here cis-eQTL is defined as the SNPs significantly associated with gene expression and located within 1 Mb from either side of the binding side of the probe. The eQTL analysis was performed using the lung tissue dataset, as described previously 19 . Briefly, the association between SNPs and the 2-log transformed gene expression of MIF, DDT and DDTL was tested in each cohort (Laval, British Columbia and Groningen).…”