Refining Susceptibility Loci of Chronic Obstructive Pulmonary Disease with Lung eqtls

Lamontagne, Maxime; Couture, Christian; Postma, Dirkje S.; Timens, Wim; Sin, Don D.; Paré, Peter D.; Hogg, James C.; Nickle, David; Laviolette, Michel; Bossé, Yohan
July 2013
PLoS ONE;Jul2013, Vol. 8 Issue 7, p1
Academic Journal
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.


Related Articles

  • Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. Hansel, Nadia; Ruczinski, Ingo; Rafaels, Nicholas; Sin, Don; Daley, Denise; Malinina, Alla; Huang, Lili; Sandford, Andrew; Murray, Tanda; Kim, Yoonhee; Vergara, Candelaria; Heckbert, Susan; Psaty, Bruce; Li, Guo; Elliott, W.; Aminuddin, Farzian; Dupuis, Josée; O'Connor, George; Doheny, Kimberly; Scott, Alan // Human Genetics;Jan2013, Vol. 132 Issue 1, p79 

    Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung...

  • Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease. Qiu, Weiliang; Cho, Michael H.; Riley, John H.; Anderson, Wayne H.; Singh, Dave; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A.; Lomas, David A.; Crapo, James D.; Beaty, Terri H.; Celli, Bartolome R.; Rennard, Stephen; Tal-Singer, Ruth; Fox, Steven M.; Silverman, Edwin K.; Hersh, Craig P. // PLoS ONE;2011, Vol. 6 Issue 9, p1 

    Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from...

  • Systemic elastin degradation in chronic obstructive pulmonary disease. Maclay, John D.; McAllister, David A.; Rabinovich, Roberto; Haq, Imran; Maxwell, Scott; Hartland, Stephen; Connell, Martin; Murchison, John T.; van Beek, Edwin J. R.; Gray, Robert D.; Mills, Nicholas L.; MacNee, William // Thorax;Jul2012, Vol. 67 Issue 7, p606 

    Background Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation. Objectives To investigate whether patients with COPD have evidence of systemic elastin...

  • Association Of Cd40 Genotyping And Its Protein Expression With Airway Inflammatory Diseases. Muawia, Shaden; Zidan, Mohamed; Daabis, Rasha; Wagdy, Mona // Australian Journal of Basic & Applied Sciences;2011, Vol. 5 Issue 9, p1425 

    CD40 plays a substantial role in inflammation and has been linked to pathogenic processes of chronic inflammatory diseases such as asthma as well as chronic obstructive pulmonary disease (COPD). The aim of the study was to investigate the association of CD40 gene (-1C/T) single nucleotide...

  • Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility. Takahashi, Toru; Kobayashi, Seiichi; Fujino, Naoya; Suzuki, Takaya; Ota, Chiharu; He, Mei; Yamada, Mitsuhiro; Suzuki, Satoshi; Yanai, Masaru; Kurosawa, Shin; Yamaya, Mutsuo; Kubo, Hiroshi // Thorax;Dec2012, Vol. 67 Issue 12, p1067 

    Rationale The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. Objective To compare EMP numbers in stable COPD...

  • Increased Expression of Beta-Defensin 1 (DEFB1) in Chronic Obstructive Pulmonary Disease. Andresen, Ellen; Günther, Gunar; Bullwinkel, Jörn; Lange, Christoph; Heine, Holger // PLoS ONE;2011, Vol. 6 Issue 7, p1 

    On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for...

  • Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression. Nagelkerke, S Q; Tacke, C E; Breunis, W B; Geissler, J; Sins, J W R; Appelhof, B; van den Berg, T K; de Boer, M; Kuijpers, T W // Genes & Immunity;Sep2015, Vol. 16 Issue 6, p422 

    The human FCGR2/3 locus, containing five highly homologous genes encoding the major IgG receptors, shows extensive copy number variation (CNV) associated with susceptibility to autoimmune diseases. Having genotyped >4000 individuals, we show that all CNV at this locus can be explained by...

  • The Effect of Statins on Blood Gene Expression in COPD. Obeidat, Ma’en; Fishbane, Nick; Nie, Yunlong; Chen, Virginia; Hollander, Zsuzsanna; Tebbutt, Scott J.; Bossé, Yohan; Ng, Raymond T.; Miller, Bruce E.; McManus, Bruce; Rennard, Stephen; Paré, Peter D.; Sin, Don D. // PLoS ONE;10/13/2015, Vol. 10 Issue 10, p1 

    Background: COPD is currently the fourth leading cause of death worldwide. Statins are lipid lowering agents with documented cardiovascular benefits. Observational studies have shown that statins may have a beneficial role in COPD. The impact of statins on blood gene expression from COPD...

  • INCREASED SKELETAL MUSCLE-SPECIFIC MICRORNA-1 IN THE BLOOD OF COPD PATIENTS. Donaldson, A. V. J.; Lewis, A.; Natanek, A.; Man, W. D.; Kemp, P.; Polkey, M. I. // Thorax;Dec2011 Supplement, pA25 

    Introduction Quadriceps muscle dysfunction is an important prognostic comorbidity in COPD. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression. Skeletal muscle expresses a number of tissue-specific microRNA including miR-1, which modulates muscle phenotype. MicroRNAs can be...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics