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The causality between CFTR and pulmonary hypertension: insights from Mendelian randomization studies

Pulmonary hypertension (PH) is significantly associated with an increased risk of death in cystic fibrosis (CF) patients with advanced lung diseases [1]. Most CF patients with nonsense mutations of CF transmembrane conductance regulator (CFTR) were observed to have pulmonary arterial enlargement, and some of them had higher pulmonary vascular resistance and other adverse outcomes [2]. In this study, we aimed to analyze whether increased PH risk was causally associated with CFTR.

The Mendelian randomization (MR) method, a novel approach for the estimation of causality, is generally utilized to eliminate the effect of confounders by using single-nucleotide polymorphisms (SNPs) as instrumental variables [3]. Specifically, we conducted a two-sample MR study to assess whether CFTR was the etiology of PH. Analyses were performed using the package TwoSampleMR (version 0.4.26) in R (version 3.6.3) [3]. The protein expression levels were detected using western blotting. See the Online Supplemental Material for details.

To demonstrate the potential relationship between CFTR dysfunction and PH, we conducted a two-sample MR study using one SNP associated with CFTR from the GTEx resource of a published independent cis-acting expression quantitative trait locus [4]. The beta value of rs35715578, which reflects the effect size on decreased CFTR expression, was −0.5794. We also derived the summary data of PH, which was identified with the secondary diagnosis ICD-10 code I27.0 Primary PH (UKB-b439, 285 cases and 462,725 controls). The Wald ratio method showed that the odds ratio in genetically determined CFTR was 0.9998 (95% confidence interval (CI) 0.9996–0.9999, P = 0.037). This study suggested that decreased CFTR expression was causally associated with a decreased risk of primary PH.

To further illustrate the causality between CFTR dysfunction and PH, we reported a young Chinese male with severe idiopathic pulmonary arterial hypertension (IPAH) carrying a missense mutation in CFTR. Sorting Intolerant From Tolerant (SIFT) software predicted c.650A > G (p. Glu217Gly) in CFTR, which affects a highly conserved amino acid, to be deleterious, with a score of −3.056 (Fig. 1). Western blot analysis indicated the upregulation of CFTR protein in the lung tissue of two rat models with established severe PH: sugen/hypoxia- or monocrotaline-induced PH (Fig. 2).

Fig. 1

Characterization of a novel CFTR missense mutation in the Chinese patient with IPAH. A Confirmation of a missense mutation in the CFTR by direct sequencing: a novel adenine-to-guanine substitution occurs at nucleotide 650 in exon 5 (c.650A > G). B SIFT software results showing c.650A > G to be a disease-causing mutation. C The variant in the CFTR affects a highly conserved amino acid.

Fig. 2

The expression of CFTR protein in lung tissue of experimental pulmonary hypertension rat models. A Representative immunoblots (a) and summarized data (b) showing the protein level of CFTR in lung tissue from normoxia- and sugen/hypoxia-exposed rats. Data were represented as means ± SE; n = 5 in each group. Independent t test was performed, **p < 0.01 vs. Nor. B Representative immunoblots (a) and summarized data (b) showing protein levels of CFTR in the lung tissue from control (Cont)- and monocrotaline (MCT)-treated rats. Data were represented as means ± SE; n = 6 in each group. Independent t test was performed, **p < 0.01 vs. Cont. The asterisk-marked band (*) indicates nonspecific binding by anti-CFTR antibody.

In summary, CFTR dysfunction may participate in the development of PH. The MR results suggested that decreased CFTR expression had a protective effect against primary PH. We identified the SNPs influencing some phenotypes as unconfounded indicators that were akin to randomly allocated in individuals such that a randomized controlled trial can be mimicked in MR analysis. Unfortunately, we cannot assess the impact on horizontal pleiotropy due to data limitations. Of note, we identified a novel CFTR missense mutation in a Chinese patient with IPAH, which provided evidence for the relationship between CFTR mutations and PAH. We observed that the expression of the CFTR protein was upregulated in lung tissues of PH rat models. Further studies are needed to explore the mechanisms of CFTR dysfunction in the development of PH.

Interestingly, Tabeling et al. demonstrated that defective CFTR in the lungs partially protected against PH and pulmonary arterial remodeling in chronic hypoxic mice [5]. To our knowledge, dysfunction of the CFTR protein, a cyclic adenosine monophosphate-dependent chloride channel that mediates contraction and relaxation in smooth muscle cells, may play an important role in the pathogenesis of PH. However, the absence of CFTR is generally recognized as the cause of classic CF phenotypes, which are generally accompanied by secondary PH in advanced lung diseases. Taken together, these studies draw attention to the viewpoint of whether CFTR dysfunction contributes to primary PH, but defective CFTR partially offsets the effect on PH secondary to CF, which should be reconsidered and needs verification in further research.


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We sincerely thank Caichen Li for his consultation and suggestion in the statistical analysis of the MR study. We also thank Yadan Hu, Lingzhu Chen, and Liang Yuan for their experimental assistance with this project. This work was supported in part by grants from the National Natural Science Foundation of China (81630004, 81800061, and 81970057), Department of Science and Technology of China Grants (2016YFC0903700, 2016YFC1304102, and 2018YFC1311900), Changjiang Scholars and Innovative Research Team in University grant IRT0961, Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155), Guangdong Department of Science and Technology Grants (2017A020215114 and 2019A050510046). This work has been presented as a conference at the 12th National Congress on Pulmonary Embolism and Pulmonary Vascular Diseases and the 10th International Symposium on Pulmonary Circulation Disorders. However, the data in the current manuscript have not been previously published in an article form, nor are they concurrently under submission to any other journal. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All applicable institutional and national guidelines for the care and use of animals were followed.

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JW and YC initiated the project and provided critical suggestions for the project. QY, ZZ, and JL designed the experiments, performed the analysis, and wrote and revised the manuscript. WL and KY provided critical suggestions in the design of the project. WH and CH collected the clinical data. JZ, CZ, XL, YN, and RW performed the experiments and prepared the figures. All authors approved the submission of the manuscript.

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Correspondence to Jian Wang or Yuqin Chen.

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The authors declare no competing interests. The manuscript has been approved by all authors for publication. This study was approved by the ethics committee of the First Affiliated Hospital of Guangzhou Medical University.

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Yang, Q., Zhang, Z., Liao, J. et al. The causality between CFTR and pulmonary hypertension: insights from Mendelian randomization studies. Hypertens Res (2021).

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