Pnpt1 and Pcgf3 Variants Associated with Angiotensin-Converting Enzyme Inhibitor-Induced Cough: a Nested Case–Control Genome-Wide Study

Abstract

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

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/pgs-2019-0167

Author contributions

Guangyan Mu, Qian Xiang and Yimin Cui planned and organized the study. Guangyan Mu, Chengzhang Liu, Kun Hu and Zhe Wang contributed to sample collection and clinical data extraction. Guangyan Mu, Zhuo Zhang, Hanxu Zhang and Zhiyan Liu performed the bioinformatics and statistical analyses. Jie Jiang, Qiufen Xie, Shuang Zhou and Zining Wang supervised the clinical data extraction. Chengzhang Liu, Xiaocong Pang, Shanqun Jiang, Xianhui Qin and Qian Xiang supervised the bioinformatics and statistical analyses. Guangyan Mu, Zhuo Zhang, Chengzhang Liu and Hanxu Zhang contributed in writing of the manuscript. Shanqun Jiang, Xianhui Qin, Qian Xiang and Yimin Cui amended the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors gratefully thank investigators and participants of the China Stroke Primary Prevention Trial, the parent study, who made this research possible. The authors thank Genergy Biotechnology (Shanghai) Co., Ltd for the whole-exome sequencing service. The authors thank Y Huo (Department of Cardiology, Peking University First Hospital, Beijing, China), X-P Xu (National Center for Clinical Research in Kidney Disease, Guangdong Institute of Nephrology, Southern Medical University, Guangzhou, China), X-D Fang (CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China), Y Song (Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China), L-L Xie (A State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Key Laboratory of Organ Failure Research, Ministry of Education, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China), L-S Liu (Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China), J Mao (Gennlife [Beijing] Technology Co., Ltd, Beijing, China), W-W Tong (Gennlife [Beijing] Technology Co., Ltd, Beijing, China) and X-J Yang (3G [Changsha] Biotech Co., Ltd, Changsha, China) for their technical assistance.

Financial & competing interests disclosure

This study was supported by grants from the National Key R&D Program of China (no. 2016YFC0904900), the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (no. 2017ZX09304028-006, no. 2017ZX09101001 and no. 2018ZX09201014), theNational Natural Science Foundation of China (no.81673509 and no.81573504) and theNatural Science Foundation of Beijing Municipality (no.7171012). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This study was supported by grants from the National Key R&D Program of China (no. 2016YFC0904900), the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (no. 2017ZX09304028-006, no. 2017ZX09101001 and no. 2018ZX09201014), theNational Natural Science Foundation of China (no.81673509 and no.81573504) and theNatural Science Foundation of Beijing Municipality (no.7171012). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.