Aim: We aimed to identify genetic variants associated with ACE inhibitor (ACEI)-induced cough. Materials & methods: A nested case-control study was performed among hypertensive Chinese patients receiving enalapril-only therapy. Whole-exome sequencing and genome-wide association analysis were performed. Results: We identified that PNPT1 rs13015243 (odds ratio [OR]: 0.47; 95% CI: 0.34-0.66; p = 7.45 × 10-6), PNPT1 rs13009649 (OR: 0.48; 95% CI: 0.35-0.67; p = 9.96 × 10-6) and PCGF3 rs1044147 (OR: 2.67; 95% CI: 1.71-4.17; p = 9.91 × 10-6) were significantly associated with ACEI-induced cough. Nearly genome-wide significant associations in previously reported candidate risk genes CLASP1, ACE, CES1, CPN1, XPNPEP1, PDE11A or SLC38A were detected in our dataset. Conclusion: Our results suggest that ACEI-induced cough is associated with noncoding SNPs of PNPT1 and PCGF3, all of which are independent of the bradykinin pathway. Study registration: NCT03259399.
Keywords: angiotensin-converting enzyme inhibitor; candidate gene; genome-wide association analysis; nested case–control study; nonproductive cough; whole-exome sequencing.