A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities

Abstract

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10^-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10^-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Keywords: MUC5B; idiopathic pulmonary fibrosis; interstitial lung abnormalities; polygenic risk score.

Figure 1.

Schematic of study design. AUC = area under the receiver operating characteristic curve; COPDGene = Genetic Epidemiology of COPD; FHS = Framingham Heart Study; GWAS = genome-wide association study; ILA = interstitial lung abnormalities; IPF = idiopathic pulmonary fibrosis; LTRC = Lung Tissue Research Consortium; M5B = mucin 5B (oligomeric/gel-forming) (MUC5B); MESA = Multiethnic Study of Atherosclerosis; PRS = polygenic risk score; PRS-M5B = a PRS including the MUC5B region; PRS-NO-M5B = a PRS excluding the MUC5B region (500-kb window [i.e., ±250 kb]).

Figure 2.

(A) Distribution (density) of the polygenic risk score excluding the MUC5B region (PRS) in the Denver testing cohort. (B) Quintile plot showing adjusted ORs and 95% CIs of the PRS association with IPF for each quintile compared with the first quintile as the reference group (adjusted for clinical data). The colors correspond to quintiles of the PRS in both parts of the figure. Multivariable models were adjusted for age, sex, smoking status, and principal components of genetic ancestry. CI = confidence interval; IPF = idiopathic pulmonary fibrosis; OR = odds ratio.

Figure 3.

Receiver operating characteristic (ROC) curves for idiopathic pulmonary fibrosis prediction in the Denver testing cohort based on a clinical model (age, sex, smoking status) and genetic factors (rs35705950-T, polygenic risk score excluding the MUC5B region [500-kb window (i.e., ±250 kb)] [PRS-NO-M5B]). PRS-NO-M5B is abbreviated to “PRS.” AUCs are shown in the lower right. DeLong P values were used to compare models: P (rs35705950-T + clinical vs. clinical alone) = 0.5; P (PRS + clinical vs. rs35705950-T + clinical factors) = 0.003; P (PRS + rs35705950-T + clinical vs. PRS + clinical factors) = 0.0016. AUC = area under the receiver operating characteristic curve.

Figure 4.

Forest plots showing inverse-variance meta-analysis results of multivariable associations of the polygenic risk score (PRS) excluding the MUC5B region (PRS) with (A) interstitial lung abnormalities (ILA) and (B) ILA progression in European and non-European ancestry (when available) cohorts. AA = African American; CI = confidence interval; COPD = chronic obstructive pulmonary disease; COPDGene = Genetic Epidemiology of COPD; FHS = Framingham Heart Study; HIS = Hispanic; MESA = Multiethnic Study of Atherosclerosis; NHW = non-Hispanic white; OR = odds ratio; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study.