Genome-Wide Association Analysis of Single-Breath Dl CO

Am J Respir Cell Mol Biol. 2019 May;60(5):523-531. doi: 10.1165/rcmb.2018-0384OC.

Abstract

DlCO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DlCO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DlCO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for DlCO in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and DlCO. We estimated the SNP-based heritability of DlCO in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with DlCO: variants near TGFB2, CHRNA3, and PDE11A loci (P < 5 × 10-8). In addition, 12 loci were suggestively associated with DlCO in European ancestry white (P < 1 × 10-5 in the combined analysis and P < 0.05 in both COPDGene and GenKOLS), including variants near NEGR1, CADM2, PCDH7, RETREG1, DACT2, NRG1, ANKRD18A, KRT86, NTN4, ARHGAP28, INSR, and PCBP3. Some DlCO-associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DlCO (P < 0.001). We identified several genetic loci that were significantly associated with DlCO and characterized effects of known COPD-associated loci on DlCO. These results could lead to better understanding of the heterogeneous nature of COPD.

Trial registration: ClinicalTrials.gov NCT00608764 NCT00292552.

Keywords: D; chronic obstructive pulmonary disease; genome-wide association study.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / genetics*
  • 3',5'-Cyclic-GMP Phosphodiesterases / metabolism
  • Adult
  • African Continental Ancestry Group
  • Cytochrome P-450 CYP2A6 / genetics
  • Cytochrome P-450 CYP2A6 / metabolism
  • Desmoplakins / genetics
  • Desmoplakins / metabolism
  • European Continental Ancestry Group
  • Female
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Gene Expression
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Lung / metabolism
  • Lung / physiopathology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Pulmonary Disease, Chronic Obstructive / ethnology
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Pulmonary Emphysema / ethnology
  • Pulmonary Emphysema / genetics*
  • Pulmonary Emphysema / metabolism
  • Pulmonary Emphysema / physiopathology
  • Receptors, Nicotinic / genetics*
  • Receptors, Nicotinic / metabolism
  • Respiratory Function Tests
  • Spirometry
  • Transforming Growth Factor beta2 / genetics*
  • Transforming Growth Factor beta2 / metabolism

Substances

  • DSP protein, human
  • Desmoplakins
  • FAM13A protein, human
  • GTPase-Activating Proteins
  • Receptors, Nicotinic
  • TGFB2 protein, human
  • Transforming Growth Factor beta2
  • nicotinic receptor subunit alpha3
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • PDE11A protein, human

Associated data

  • ClinicalTrials.gov/NCT00608764
  • ClinicalTrials.gov/NCT00292552