Determinants of Lung Fissure Completeness

Abstract

Rationale: New advanced bronchoscopic treatment options for patients with severe chronic obstructive pulmonary disease (COPD) have led to increased interest for COPD phenotyping, including fissure completeness. Objectives: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD. Methods: We used data from 9,926 participants of the COPDGene study who underwent chest computed tomographic (CT) scans. Fissure completeness was calculated from CT scans after quantitative CT analysis at baseline and 5-year follow-up. Clinical and environmental factors, including sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD, were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic White subjects and African American subjects. Measurements and Main Results: African American subjects had significantly higher fissure completeness than non-Hispanic White subjects for all three fissures (P < 0.001). There was no change in fissure completeness between baseline and 5-year follow-up. For all fissures, no clinically relevant differences in fissure completeness were found for other clinical or environmental factors, including COPD severity. Rs2173623, rs264866, rs2407284, rs7310342, rs4904145, rs6504172, and rs7209556 showed genome-wide significant associations with fissure completeness in non-Hispanic White subjects. In African American subjects, rs264866, rs4904145 and rs6504172 were identified as significant associations. Rs2173623, rs6504172, and rs7209556 lead to WNT5A and HOXB antisense RNA expression, which play an important role during embryogenesis. Conclusions: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD (including exacerbation frequency), maternal smoking during pregnancy, or maternal COPD.

Keywords: COPD; epidemiology; genetics.

Figure 1.

Manhattan plots of the left major, right major, and right minor fissures in non-Hispanic White and African American subjects. The results are shown for all non-Hispanic White and African American subjects. The upper horizontal line represents the general threshold of genome-wide significance (P = 5 × 10⁻⁸); the lower horizontal line represents the threshold of P = 1 × 10⁻⁵.

Figure 2.

Fissure completeness of the left major, right major, and right minor fissures per genotype of the top SNPs in non-Hispanic White and African American subjects. Boxplots are shown of fissure completeness scores for all non-Hispanic White and African American subjects. SNPs with an association interaction with fissure completeness (P ⩽ 1 × 10⁻⁵) are indicated with an asterisk.

Figure 2.

Fissure completeness of the left major, right major, and right minor fissures per genotype of the top SNPs in non-Hispanic White and African American subjects. Boxplots are shown of fissure completeness scores for all non-Hispanic White and African American subjects. SNPs with an association interaction with fissure completeness (P ⩽ 1 × 10⁻⁵) are indicated with an asterisk.

Figure 3.

Expression quantitative trait loci violin plots for the top SNPs in lung, esophagus, and intestine tissue. The results are derived from GTExPortal. NES = normalized effect size.