DSP variants may be associated with longitudinal change in quantitative emphysema

Chronic obstructive pulmonary disease (COPD), defined by the presence of airflow obstruction on spirometry, is the third leading cause of death worldwide [1]. Despite the increasing burden of the disease, there is no medication that clearly ameliorates the progression of COPD. In addition to lung function, progression of this disease can also be assessed by worsening emphysema. Emphysema, characterized by the destruction of lung parenchyma, is a key component of COPD and associated with increased morbidity and mortality. The presence of emphysema is variable among subjects with similar degrees of airflow obstruction.

Advances in computed tomography (CT) imaging provide the opportunity to assess the extent and progression of emphysema quantitatively, and to study its related risk factors. The progression of emphysema (as determined by quantitative CT imaging) was examined in smokers [2], patients with alpha1-antitrypsin deficiency (AATD) [3, 4] and smokers with COPD [5]. Longitudinal change in quantitative emphysema is associated with spirometric measures of lung function, severity of COPD and ongoing smoking, and as such has been proposed as a marker of response to therapy for COPD [6].

Although smoking is a strong risk factor for emphysema, there is evidence of genetic influences on emphysema. The estimated heritability of quantitative emphysema measured by CT scan was approximately 30% [7]. The longitudinal decline in lung function is reported to be moderately heritable (forced expiratory volume in the first second (FEV1): 0.05, forced vital capacity (FVC): 0.18 and FEV1/FVC: 0.13) [8]. Previous genome-wide association studies (GWAS) have identified multiple genetic variants significantly associated with cross-sectional measures of quantitative emphysema based on CT imaging [9‐13]. However, genetic determinants of longitudinal change in quantitative emphysema remain largely unknown. Identification of genetic factors for emphysema progression may identify different or more specific pathways than an analysis of overall lung function decline, expand our understanding of the genetics of COPD and contribute to the development of new drug therapies to slow the loss of lung density.

Our study aims to examine genetic variants for association with change in quantitative emphysema measured by CT imaging from two longitudinal cohort studies: COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). The specific objectives of the study are as follows: 1) to conduct GWAS to identify genetic variants associated with change in quantitative emphysema measured by CT imaging, and 2) to examine the association with change in quantitative emphysema for genetic loci previously identified as significantly associated with cross-sectional quantitative emphysema, COPD or lung function.

Interestingly, in our candidate region analysis, a variant in the DSP gene (rs2076295 T > G) was associated with annual change in %LAA-950, passing the Bonferroni corrected significance. The effect size was similar across studies of European ancestry. This finding is particularly interesting since rs2076295 is associated with COPD (risk allele = T, P = 4.95e-08, OR (95% CI) =1.11(1.07–1.15)) [20] and a spirometric measure of lung function (FEV1/FVC ratio) (risk allele = T, P = 6.95e-23, β (SE) = − 0.02 (0.002)) [21], as well as idiopathic pulmonary fibrosis (risk allele = G, P = 1.14E-16, OR (95% CI) =1.43(1.32–1.55)) [23]. The T allele of rs2076295 is associated with greater progression of emphysema, higher risk of COPD, and lower lung function, but has a protective effect on pulmonary fibrosis.

rs2076295 is intronic to the DSP gene. The DSP gene encodes desmoplakin, a major protein in desmosomes which are critical to cell-cell adhesion [24]. Desmosomes mechanically connect cells and stabilize tissue architecture [25]. Desmosomes are essential in cell proliferation, differentiation, migration, morphogenesis, and apoptosis [25]. Mutations in DSP have been linked to several Mendelian syndromes involving palmoplantar keratoderma [26], left ventricular cardiomyopathy [26], familial arrhythmogenic right ventricular dysplasia [27], and lethal ancantholytic epidermolysis bullosa [28]. The DSP gene is highly expressed in the airway epithelia [29]. rs2076295 in the DSP gene is associated with differential gene expression of idiopathic pulmonary fibrosis in human lung [23, 29]. This region was not previously reported to be associated with quantitative emphysema in cross-sectional studies. Thus, whether this association represents true progression of emphysema or (for the opposite allele) development of fibrosis, or both needs confirmation by further studies.

To jointly examine the effect of 279 SNPs of lung function on the annual change in quantitative emphysema, we applied a previously constructed PRS weighted by FEV1/FVC effect sizes in European ancestry [21]. The PRS of lung function was strongly associated with baseline emphysema. These findings are consistent with the strong correlation between emphysema and lung function. In addition, we found suggestive evidence that individuals with higher PRS showed more rapid emphysema progression. Subjects in the highest decile of PRS showed a trend toward greater emphysema progression than those in the lowest decile, even though it was not statistically significant (P > 0.05). Our findings suggest that genetic variants associated with cross-sectional lung function might affect development and progression of emphysema, and to our knowledge, are the first description of an association of a genetic risk score with disease progression in COPD.

Our study showed differences in spirometry grade and emphysema measures between two studies, COPDGene and ECLIPSE (Table 1). It may be due to the different imaging protocols; in COPDGene, volumetric inspiratory CT acquisitions were obtained at 200mAs [30], and in ECLIPSE [31], all subjects underwent a low-dose volumetric inspiratory CT scan at 40mAs. In addition, ECLIPSE included a higher percentage of COPD subjects than COPDGene.

Despite our finding in our candidate region analysis, we did not find significant variants in the genome-wide analysis. The failure to identify novel genome-wide significant variants is likely due to several factors. First, CT measures to quantify the extent of the emphysema inherently have large variation [32]. While previous successful GWASs for cross-sectional quantitative emphysema used the same CT measures as our current study [9, 10], and previous epidemiologic studies have found significant longitudinal associations of ALD with severity of COPD [2], our sample size was smaller than these prior studies, and likely effect sizes for longitudinal change in emphysema are considerably smaller than for cross-sectional genetic association or epidemiologic analyses. In a genome-wide setting, more accurate CT emphysema measures may be needed to detect the genetic variants with relatively small effect size associated with longitudinal change in emphysema. Second, the follow-up period in our study may be too short to capture the natural history of emphysema in adults. Our follow-up period (approximately 5.5 years in COPDGene and 2.6 years in ECLIPSE) is sufficient to show emphysema progression, showing an increase in %LAA-950 and decrease in ALD, but very short in the context of the natural history of emphysema. To estimate the true emphysema trajectory in adults, such a follow-up period may not be sufficient. The emphysema progression in our population may have an episodic rather than gradual pattern of progression, which could interfere with our ability to detect genetic associations. Also, the observed annual change in emphysema may be influenced by the regression to the mean due to the short follow-up period and the measurement error of CT measures. Longer follow-up may provide more accurate data to estimate the emphysema progression. Third, our study populations were enriched for COPD patients. Though we observed emphysema progression in our population, to measure the true emphysema trajectory, normal subjects without lung abnormalities at baseline may be required to detect the genetic variants associated with emphysema progression. Fourth, emphysema progression may be less heritable than cross-sectional quantitative measures of emphysema. Traits of progression (as demonstrated by the heritability of cross-sectional lung function, versus progression [8]) are likely to be less heritable than ones of development.

Genetic determinants of emphysema progression remain poorly understood. This is the first GWAS investigating change in quantitative emphysema measured by CT imaging. No genetic variants were associated with annual change in emphysema at genome-wide significance. Further study with larger sample sizes and longer follow-up periods may be required to identify genetic determinants of emphysema progression. However, we observed a significant association of a DSP variant, previously reported in idiopathic pulmonary fibrosis, COPD and spirometric measures of lung function, with change in quantitative emphysema over time. This finding represents the first genetic association with emphysema progression measured by CT scan. PRS based on spirometric measures of lung function may also predict emphysema progression. Additional investigation of the DSP gene, and improved genetic risk scores are likely to provide further insights into the disease progression in emphysema and COPD.