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editorial
. 2025 Sep 25;66(3):2501267. doi: 10.1183/13993003.01267-2025

Dissecting the genetics of chronic cough

Alyn Hugh Morice 1,
PMCID: PMC12461902  PMID: 40998561

Extract

In the 1980s a novel antihypertensive was introduced which inhibited the conversion of angiotensin I to the vasoactive angiotensin II. This mainly occurs in the endothelium of the pulmonary vasculature through the action of angiotensin-converting enzyme (ACE). The first ACE inhibitor, captopril, was introduced into our clinic. I reviewed a lady who complained that she had developed a dry cough. Simple investigations revealed no cause. She said, “it couldn't be that new drug you have given me doctor?”. I said, “don't be silly how could a tablet cause a cough”. We stopped the captopril and the cough abated. Reintroduced, the cough returned. There were sporadic case reports of ACE inhibitor associated cough in the literature, but the question remained. How could a tablet cause a cough?

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In the 1980s a novel antihypertensive was introduced which inhibited the conversion of angiotensin I to the vasoactive angiotensin II. This mainly occurs in the endothelium of the pulmonary vasculature through the action of angiotensin-converting enzyme (ACE). The first ACE inhibitor, captopril, was introduced into our clinic. I reviewed a lady who complained that she had developed a dry cough. Simple investigations revealed no cause. She said, “it couldn't be that new drug you have given me doctor?”. I said, “don't be silly how could a tablet cause a cough”. We stopped the captopril and the cough abated. Reintroduced, the cough returned. There were sporadic case reports of ACE inhibitor associated cough in the literature, but the question remained. How could a tablet cause a cough?

In a randomised controlled trial evaluating cough using an inhalational capsaicin challenge [1], the concentration–response curve was shifted to the left when captopril was compared to placebo. Captopril had increased the sensitivity of the cough reflex. How this occurs is still a matter of debate since ACE is a promiscuous enzyme. It removes the di/tri-peptide terminal of a number of short peptides including bradykinin, encephalin, and Substance P. Inhibition of ACE results in accumulation of these peptides. The suggestion that Substance P may be the primary candidate is supported by the recent demonstration of the amelioration of chronic cough by the neurokinin-1 receptor antagonist orvepitant [2].

A familial component of chronic cough is often observed in the clinic with first degree relatives accompanying the patient to find out why they also cough. The heritability of chronic cough has been studied by Emilsson et al. [3], who found in the RHINESSA generational study that 11% of the offspring of parents reporting a dry cough also coughed compared with 7% of those with non-coughing parents (adjusted odds ratio: 2), this is substantially more than the heritability of productive cough.

In this issue of the European Respiratory Journal, Coley et al. [4] present a genome-wide association study comparing patients with self-reported chronic cough and those who have had their ACE inhibitor swapped for an angiotensin II blocker, with the assumption that this was likely to be due to the development of a cough. Clinically ACE inhibitor cough and chronic cough share many of the attributes of the syndrome of cough hypersensitivity [5]. The seven novel genetic associations revealed by this analysis were mapped to 10 novel genes. Unsurprisingly, several of these genes are involved in neuronal function suggesting that there is an inherent tendency to hypersensitivity and this is supported by the subsequent polygenic score-based analysis (phenome-wide association studies), where associations with chronic pain, diabetes and asthma were revealed. This latter diagnosis, however, may be influenced by the reluctance of physicians to solely ascribe the cough to neuronal hypersensitivity even in the absence of TH2 inflammation. Perhaps the most consequential of these findings is that the genetics may direct drug discovery to more generalised mechanisms of neuronal hypersensitivity with broad applicability.

Although not a novel finding in this study the authors confirm the association with PREP, a gene which codes for prolyl endopeptidase, a serine protease which like ACE is responsible for the metabolism of a number of small neuropeptides including substance P and bradykinin. There is much redundancy within these metabolic pathways. Could the perineuronal milieux be shifted by ACE inhibition overloading the other endopeptidases?

Whether this is a potential mechanism or not, this exploration of the commonality of ACE inhibitor induced and chronic cough confirms a genetic basis to add to the unique demographic, pathophysiological and clinical evidence supporting the premise that chronic cough is a disease in its own right. For years it has been hiding in plain sight.

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Footnotes

Conflict of interest: A.H. Morice reports consultancy fees from Bellus, GSK, NeRRi and Trevi, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, Merck and Hilton, grant support from Axalbion, Bellus, GSK, Merck, Nocion, Philips, NeRRi and Trevi, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim.

References

  • 1.Morice AH, Lowry R, Brown MJ, et al. Angiotensin converting enzyme and the cough reflex. Lancet 1987; 2: 1116–1118. doi: 10.1016/S0140-6736(87)91547-9 [DOI] [PubMed] [Google Scholar]
  • 2.Smith J, Allman D, Badri H, et al. The neurokinin-1 receptor antagonist orvepitant is a novel antitussive therapy for chronic refractory cough: results from a phase 2 pilot study (VOLCANO-1). Chest 2020; 157: 111–118. doi: 10.1016/j.chest.2019.08.001 [DOI] [PubMed] [Google Scholar]
  • 3.Emilsson ÖI, Johansson H, Johannessen A, et al. Heritability of cough across two generations: the RHINESSA study. ERJ Open Res 2024; 10: 00071-2024. doi: 10.1183/23120541.00071-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Coley K, John C, Ghouse J, et al. Genomics of chronic dry cough unravels neurological pathways. Eur Respir J 2025; 66: 2402341. doi: 10.1183/13993003.02341-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Morice AH, Faruqi S, Wright CE, et al. Cough hypersensitivity syndrome: a distinct clinical entity. Lung 2011; 189: 73–79. doi: 10.1007/s00408-010-9272-1 [DOI] [PubMed] [Google Scholar]

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DOI: 10.1183/13993003.01267-2025.Shareable1

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