Rationale: Chest computed tomographic imaging can detect interstitial lung abnormalities (ILA), which can progress to idiopathic pulmonary fibrosis (IPF). The MUC5B promoter variant rs35705950 is common and confers substantial risk for both IPF and ILA. We hypothesized that a polygenic risk score (PRS) excluding the MUC5B region would add complementary predictive value to rs35705950 for IPF and ILA.

Methods: Using previously-published European-ancestry genome-wide association summary statistics for IPF, we developed an IPF PRS excluding a 500 kb region around rs35705950 (PRS-NO-M5B). We tested the association of the PRS-NO-M5B and rs35705950 with IPF and ILA in external datasets: Lung Tissue Research Consortium (LTRC) and Genetic Epidemiology of COPD (COPDGene) study. Multivariable models were adjusted for age, sex, and smoking. Area-under-the-curve (AUC) analyses were used to assess predictive performances. Results: In LTRC (270 controls, 255 IPF cases), the PRS-NO-M5B (OR 4.5 [95% CI: 3.3 – 6.1], p=8.0e-22) and rs35705950 (OR 3.6 [95% CI: 2.4 – 5.2], p=6.4e-11) were both associated with IPF; there was no evidence of interaction (p=0.7). There was a stepwise increase in predictive performances of models including rs35705950 (AUC 0.74), PRS-NO-M5B (AUC 0.83), and PRS+M5B (AUC 0.86). Phenotypic variability in IPF explained by PRS+M5B (R2=0.41) was greater than PRS-NO-M5B (R2=0.33) and rs35705950 alone (R2=0.12). In COPDGene (6417 controls, 250 ILA), rs35705950 (OR 1.88 [95% CI: 1.49-2.39], p=1.5e-7) and PRS-NO-M5B (OR 1.19 [95% CI: 1.06-1.34], p=3.2e-3) were associated with ILA.

Conclusions: The MUC5B rs35705950 variant and a PRS excluding the MUC5B region offered complementary predictive value for IPF and ILA.