Using a two sample Mendelian randomization approach to explore the causal relationship between erectile dysfunction and lung function
Original Article

Using a two sample Mendelian randomization approach to explore the causal relationship between erectile dysfunction and lung function

Yurui Luo1#, Shiqi Su1#, Yong Yang2, Nanyan Xiang1, Tingting Fu3, Su Lui4, Yifei Lin5,6, Jin Huang5

1Department of Urology, Innovation Institute for Integration of Medicine and Engineering, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; 2Innovation Institute for Integration of Medicine and Engineering, West China Hospital, Sichuan University, Chengdu, China; 3Department of Urology, Innovation Institute for Integration of Medicine and Engineering, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, and Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China; 4Department of Radiology, West China Hospital of Sichuan University, Chengdu, China; 5Department of Urology, Innovation Institute for Integration of Medicine and Engineering, West China Hospital, Sichuan University, Chengdu, China; 6Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Contributions: (I) Conception and design: Y Luo, Y Lin, J Huang; (II) Administrative support: Y Lin, J Huang; (III) Provision of study materials or patients: Y Luo, S Su; (IV) Collection and assembly of data: Y Luo, S Su, Y Yang, N Xiang, T Fu; (V) Data analysis and interpretation: Y Luo, S Su, Y Yang, S Lui; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Jin Huang, PhD. Department of Urology, Innovation Institute for Integration of Medicine and Engineering, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610000, China. Email: michael_huangjin@163.com; Yifei Lin, MD. Department of Urology, Innovation Institute for Integration of Medicine and Engineering, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610000, China; Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, 677 Huntington Ave., Boston, MA, USA. Email: ylin@hsph.harvard.edu.

Background: Recently, some observational studies have suggested potential associations between erectile dysfunction (ED) and respiratory function. However, the underlying biological mechanisms and causal relationships between ED and lung function require further investigation. This study aimed to explore the causalities between ED and lung function traits.

Methods: Single-nucleotide polymorphisms (SNPs) for ED were extracted from the Finngen_r7 (1,154 cases and 94,024 controls), and the summary statistics of respiratory function were extracted from the UK Biobank (UKB) (n=321,047). We utilized several Mendelian randomization (MR) methods to mitigate the impact of weak instrument bias and pleiotropy. To address potential confounding effects, multivariable MR (MVMR) analyses were also conducted, adjusting for demographic factors and respiratory conditions. Moreover, recently developed latent causal variable (LCV) modeling was also performed to enhance the robustness of the findings.

Results: Totally 15 SNPs robustly associated with ED were included. We found that higher risk of ED was associated with decreased of forced expiratory volume in the first second (FEV1) [odds ratio (OR) 0.992, 95% confidence interval (CI): 0.986, 0.997, P=0.003], as was the case for forced vital capacity (FVC) (OR 0.994, 95% CI: 0.989, 1.000, P=0.04), peak expiratory flow (PEF) (OR 0.990, 95% CI: 0.990, 0.990, P=0.01) and FEV1/FVC ratio (OR 0.991, 95% CI: 0.985, 0.997, P=0.002). After adjusting for confounding factors, ED only demonstrated causal effects on FEV1/FVC ratio. Notably, the LCV analysis provided additional support for the positive causal impact of ED on FEV1 and FVC. Conversely, reverse MR analysis did not reveal compelling evidence for a causal effect of lung function on ED.

Conclusions: Our study suggests a potential causal relationship between higher ED susceptibility and reduced respiratory function, as indicated by decreased FEV1, FVC, PEF, and the FEV1/FVC ratio. The results enhanced understanding of the intricate interrelationships between ED and lung function.

Keywords: Mendelian randomization (MR); erectile dysfunction (ED); lung function; causal relationship; genetic epidemiology

Submitted Jun 29, 2024. Accepted for publication Nov 07, 2024. Published online Nov 28, 2024.

doi: 10.21037/tau-24-321

Highlight box

Key findings

• The study found higher erectile dysfunction (ED) susceptibility was linked to decreased forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), peak expiratory flow and FEV1/FVC ratio through Mendelian randomization (MR). However, no significant causal associations of lung functions on ED were detected.

What is known and what is new?

• Observational studies have suggested potential associations between ED and respiratory function.

• This study contributed new evidence by employing bidirectional MR analysis to illustrate adverse genetic causal relationships between susceptibility to ED and lung function.

What is the implication, and what should change now?

• Our findings prompt clinicians to prioritize timely interventions for patients with ED to prevent complications. Additionally, they will also pave the way for more targeted and personalized treatment approaches for susceptible individuals.

Introduction

Erectile dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient for satisfactory sexual intercourse (1). Affecting approximately 20% of all men globally, ED accounts for nearly 3 million outpatient visits annually (2). This condition imposes a significant economic burden, encompassing not only the expenditure of millions of dollars annually on diagnosis and treatment but also the loss of work hours and diminished productivity attributable to the patient’s distress (3). However, the embarrassment associated with disclosing sexual health issues results in ED’s frequent underdiagnosis (4), thereby impeding essential research and having profound effects on diagnosis, treatment, patient management, health outcomes, and overall quality of life.

ED is considered as a common comorbidity of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and chronic rhinosinusitis (CRS) (5-7). Recently, several studies have reported a correlation between ED and decreased lung function. Ettala et al. explored that forced expiratory volume in one second (FEV1 <65%) was associated with 2.66 [95% confidence interval (CI): 1.18–5.99] increased risk of moderate to severe ED (8). Moreover, a case report found that FEV improved in patients with ED after using Sildenafil, which is used to treat ED (9). However, the exact biological mechanisms of this bidirectional relationship and the establishment of a causal connection are still poorly understood, hindered by confounding variables and the lack of randomized controlled trials (RCTs).

Mendelian randomization (MR) represents an epidemiological method designed to estimate the causal associations by utilizing genetic variants as instrumental variables (10). These variables are presumed to be free from the biases of confounding and reverse causation commonly encountered in other forms of observational epidemiology (11). In this context, we employed a two-sample MR approach to investigate the causal inferences between ED and lung function, including FEV1, forced vital capacity (FVC), peak expiratory flow (PEF) and FEV1/FVC ratio, to help clinicians and decision-makers better manage chronic patients. We present this article in accordance with the STROBE-MR reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-321/rc).

Methods

This two-sample MR analysis was conducted to assess the causal effects between ED and lung function (12), with data sourced from two independent databases, the UK Biobank (UKB) and the FinnGen research project. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Data sources

ED data source

Data for ED was obtained from the fifth public release of the FinnGen research project, consisting of 1,154 cases and 94,024 controls (Table S1). The diagnostic criteria for ED were defined by ATC codes (G04BE) and associated with electronic health records, as the inability to achieve or maintain an erection during sexual activity (13). The ED data from the FinnGen research project did not overlap with the data from UKB.

Respiratory data source

We obtained genetic instruments for respiratory function from the UKB, measured by continuous biomarkers including FEV1 (N=321,047), FVC (N=321,047), PEF (N=321,047), FEV1/FVC ratio (N=321,047) from UKB (Table S1) (14).

Instrumental variable selection

Firstly, we applied SNPs as genetic instrumental variables. SNPs reaching genome-wide significance (P<5×10−8) were selected using the PLINK clumping method, with exclusion criteria based on linkage disequilibrium (r2≥0.1, clumping window ≤1,000 kb) (15). Since no ED-related instrumental SNPs reached genome-wide significance (P<5×10−8), we had to relax the restrictions to P<5×10−6 to obtain valid instrumental variables.

Statistical analysis

To obtain an unbiased estimate, MR analysis should meet three core assumptions: (I) the instrumental variable is significantly associated with the exposure factor (in this case, ED); (II) the variant is independent of any confounding factors associated with the exposure-outcome association; (III) the variation does not affect the outcome unless it might do so through other unknown biological pathways associated with the exposure factor (15).

To explore the potential causal links between lung function traits and ED, various MR approaches were employed. Initially, inverse-variance weighted (IVW) was performed. This method assumes the validity of all instrumental variables. However, it is susceptible to bias if any instrument demonstrates horizontal pleiotropy (16). In response to the limitations inherent in the conventional IVW method, the Contamination Mixture (ConMix) method and the Robust Adjusted Profile Score (RAPS) were implemented. Comparing to other robust methods, Contamination mixture method has the lowest mean squared error across a range of realistic scenarios (17). Additionally, MR-RAPS could produce reliable causal estimates. This was achieved by running a linear model while accounting for the profile likelihood of the summary data, even when weak instrumental variables existed (18).

To satisfy the critical third assumption of MR, where instrumental variables are presumed to influence the outcome solely through the exposure variable, we initially applied the MR-Egger regression technique to address unmeasured pleiotropy. The MR-Egger approach, while sensitive to outliers, can provide consistent causal effect estimates. To further combat the issue of horizontal pleiotropy, we utilized the Pleiotropy Residual Sum and Outlier (PRESSO) method, designed to identify and eliminate potential outliers. Additionally, we employed both the mode-based estimate (MBE) and the weighted median approach as complementary strategies to affirm the exposure-outcome relationship. The inherent diversity in the assumptions underlying these MR techniques enhances the credibility of our findings.

Moreover, MVMR is an extension of MR designed to estimate the effects of two or more correlated exposure variables (19). Since several demographic factors and respiratory diseases have been reported to influence the relationship between ED and lung function, we further conducted MVMR to adjust for variants, including education, residence, CRS, asthma and COPD.

Subsequently, in order to enhance the robustness of the findings, we employed recently developed latent causal variable (LCV) model that have emerged in recent years, under which the genetic correlation between two traits is mediated by a latent variable having a causal effect on each trait (20). It has been shown in simulations that LCV has major advantages over MR methods.

All analyses were executed using the R software, version 4.0.3. We utilized the “MendelianRandomization” package for conducting the ConMix, IVW, weighted median, MBE, and MR-Egger methods. The MR-PRESSO method was applied through the “MR-PRESSO” package, and for the RAPS analysis, the “mr.raps” package was employed.

Results

Causal impact of ED on lung function

Based on summary-level data of ED, 15 SNPs were identified as significantly associated with genome-wide ED. In the forward analysis, utilizing SNPs significantly associated with ED and independent from one another, several causal relationships were investigated through MR analyses.

Specifically, the incidence of ED and a decline in FEV1 were estimated using IVW method [odds ratio (OR) 0.992, 95% CI: 0.986, 0.997, P=0.003], with this finding corroborated by three sensitivity analyses (Weighted Median, ConMix, and RAPS) (all P<0.05) and no detected horizontal pleiotropy (MR-PRESSO Global Test P=0.67, MR-Egger intercept P=0.83) (Table 1, Table S2, Figure 1). A significant causal link was also found between ED and decline in FVC through IVW method (OR 0.994, 95% CI: 0.989, 1.000, P=0.04), though this was supported only by the RAPS analysis (P=0.047) with no evidence of horizontal pleiotropy (MR-PRESSO global test P=0.81, MR-Egger intercept P=0.89) (Table 1, Table S2, Figure 1). Additionally, a significant association was noted between ED and a decline in PEF according to a ConMix analysis (OR 0.990, 95% CI: 0.990, 0.990, P=0.01) (Table 1, Figure 1) without horizontal pleiotropy (MR-PRESSO global test P=0.35, MR-Egger intercept P=0.31) (Table 1, Table S2). However, no other sensitivity analyses supported this finding. Similarly, a significant negative association was observed for the FEV1/FVC ratio (IVW OR: 0.991, 95% CI: 0.985–0.997, P=0.002) (Table 1, Figure 1). This assertion remained consistent across three sensitivity analyses (RAPS, weighted median, and ConMix), with no indications of horizontal pleiotropy (MR-PRESSO global test P=0.54, MR-Egger intercept P=0.61) (Table 1, Table S2).

Table 1

Results of the MR analyses testing the causal association of ED on lung function

Outcome SNPs Method OR 95% CI P value
FEV1 n=15 Weighted median 0.989 0.981, 0.997 0.009
IVW 0.992 0.986, 0.997 0.003
MR-Egger 0.991 0.978, 1.003 0.13
(Intercept) 0.000 −0.003, 0.004 0.83
MBE 0.987 0.971, 1.003 0.11
Contamination mixture 0.986 0.986, 0.996 0.01
RAPS 0.991 0.986, 0.997 0.004
FVC n=15 Weighted median 0.997 0.989, 1.005 0.43
IVW 0.994 0.989, 1.000 0.04
MR-Egger 0.993 0.981, 1.006 0.29
(Intercept) 0.000 −0.004, 0.004 0.89
MBE 1.000 0.987, 1.013 >0.99
Contamination mixture 0.992 0.982, 1.002 0.14
RAPS 0.994 0.988, 1.000 0.047
PEF n=15 Weighted median 0.992 0.984, 1.000 0.04
IVW 0.995 0.990, 1.001 0.09
MR-Egger 1.001 0.989, 1.013 0.89
(Intercept) −0.002 −0.006, 0.002 0.31
MBE 0.990 0.976, 1.004 0.15
Contamination mixture 0.990 0.990, 0.990 0.01
RAPS 0.995 0.989, 1.001 0.08
FEV1/FVC n=15 Weighted median 0.989 0.981, 0.997 0.007
IVW 0.991 0.985, 0.997 0.002
MR-Egger 0.994 0.981, 1.006 0.33
(Intercept) −0.001 −0.005, 0.003 0.61
MBE 0.985 0.969, 1.002 0.08
Contamination mixture 0.983 0.983, 0.993 0.007
RAPS 0.991 0.985, 0.997 0.002

MR, Mendelian randomization; ED, erectile dysfunction; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PEF, peak expiratory flow; SNPs, single nucleotide polymorphisms; IVW, inverse-variance weighted method; MBE, mode-based estimate; RAPS, Robust Adjusted Profile Score; OR, odds ratio; CI, confidence interval.

Figure 1 Forest plot of the main MR study investigating the causal effect of lung function on ED. IVW, inverse-variance weighted method; MR, Mendelian randomization; MBE, mode-based estimate; RAPS, Robust Adjusted Profile Score; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PEF, peak expiratory flow; ED, erectile dysfunction; OR, odds ratio; CI, confidence interval.

However, after adjusting for demographic factors and respiratory diseases, ED showed causal effects only on FEV1/FVC ratio in the fixed-effect model (OR 0.992, 95% CI: 0.988, 0.996, P<0.001) (Table S3).

Causal impact of lung function on ED

In the reverse MR analysis assessing the impact of lung function on ED, we selected 414, 343, 396 and 684 SNPs as instruments for FEV1, FVC, PEF and FEV1/FVC ratio, respectively. All univariable MR analyses revealed a non-significant causal association between lung function and ED (all P>0.05) (Table S4).

LCV

The LCV model was utilized to determine whether shared underlying genetic etiology could fully explain the observed negative causal effect of ED risk on lung function. The results identified evidence for partly genetic correlations between ED and decline in both FEV1 and FVC (Table 2).

Table 2

Results of LCV modelling for the genetic relationships between decreased lung function and ED

Trait 1 Trait 2 PLCV GCP (std err) Rho (std err)
ED FEV1 <0.001 0.56 (0.21) −0.11 (0.09)
FVC <0.001 0.77 (0.16) −0.17 (0.10)
PEF 0.74 0.30 (0.41) −0.05 (0.10)
FEV1/FVC 0.32 0.47 (0.29) 0.12 (0.08)

Rho denotes the genetic correlation between two traits, as estimated through LD score regression. GCP quantifies the genetic component of trait 1 that causally influences trait 2. A value approaching 1 indicates a stronger causal effect of trait 1 on trait 2. LCV, latent causal variable; ED, erectile dysfunction; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PEF, peak expiratory flow; GCP, genetic causal proportion; std err, standard error; LD, linkage disequilibrium.

Discussion

In this study, we applied a bidirectional two-sample MR method to explore the causal relationship of lung function and ED based on summary statistics from large-scale datasets. Utilizing significant, independent SNPs associated with ED, our findings revealed a significant genetic causal association between predisposition to ED and a reduction in key respiratory function metrics (FEV1, FVC, PEF, and FEV1/FVC ratio). Furthermore, LCV analysis provided additional support for the negative causal impact of ED on FEV1 and FVC. However, no significant associations were detected in the reverse analysis. This highlights a potential genetic linkage between ED and pulmonary function decline.

In our study, we found that elevated risk of ED had a negative causal effect on FEV1. Similar findings were seen by Ettala et al. in a cross-sectional population-based study conducted in 2005 in Finland. The study indicated that moderately impaired FEV1 was associated with increasing risk of moderate to severe ED in rate-dependent manner in apparently healthy men (8). The reduction in FEV1, attributable to increased airway resistance during expiration, is linked with obstructive sleep apnea (OSA) (21). Patients with OSA exhibit decreased sex hormone levels and a higher incidence of ED, stemming from the detrimental impact of sleep disturbances characteristic of OSA on the hypothalamus-pituitary-gonadal axis (22). Consequently, we propose that OSA might mediate the causal relationship between ED and FEV1 ED by altering expiratory flow and subsequently regulating sex hormone levels.

The discovery of our research that the risk of ED served as a protective factor for FVC aligned with prior research, which identified an association between elevated risk of ED and decreased FVC (23). Previous research has demonstrated that hemodynamic constraints in adult congenital heart disease (ACHD) serve as a risk factor for ED. Additionally, ACHD, characterized by impaired pulmonary blood flow, may hinder lung growth and reduce FVC. Therefore, our contention was that hemodynamic constraints played an intermediary role in the causal association between ED and FVC.

Our study corroborated the causal association between ED and PEF, aligning with the results of a case-control study that found a significant correlation between ED and PEF (24). Surmeli et al. identified that the presence of sarcopenia in older men is associated with an increased risk of moderate to severe ED (25). Besides, existing researches have investigated that PEF will decrease in patients with sarcopenia (26). Hence, we posited that sarcopenia may mediate the impact of ED on PEF.

Interestingly, our findings suggested that an elevated risk of ED has a protective effect against FEV1/FVC ratio, a novel discovery not reported in prior studies. After adjusting for demographic factors and respiratory diseases through MVMR analysis, the causal association remained significant. Sexual performance leads to increased tidal volume and breathing frequency, which raises pulmonary load and may surpass the respiratory capabilities of patients with severe airway obstruction (27). A reduced FEV1/FVC ratio indicated an obstructive ventilatory pattern (28), which is associated with nasal airway obstruction (29). Thus, we proposed that the ED influences FEV1/FVC ratio via altering this obstructive pattern. This hypothesis could elucidate the mechanisms underlying our observed results.

Considering that COPD, asthma, and CRS are comorbidities of ED (5-7), we conducted an MVMR analysis adjusting for these respiratory diseases. After adjustment, the causal relationship between ED and lung function traits (FEV1, FVC, PEF) was no longer significant, suggesting that the previously observed association may be largely attributable to the presence of respiratory complications. We have noticed that systemic inflammation may be a key mechanism underlying the comorbidity of these respiratory diseases with ED (5-7). Therefore, closely monitoring systemic inflammatory markers in ED patients may enable clinicians to identify and intervene in early lung function decline.

Our findings suggested that lung dysfunction was severe complication of ED, and to some extent supported that ED and impaired lung function shared common risk factors like smoking, age, and systemic illnesses (30). The role of phosphodiesterases (PDEs), particularly PDE5, is pivotal in elucidating the pathophysiological relationship between COPD and ED (27). PDE5 inhibitors have established utility in managing ED and show promise in treating pulmonary conditions like hypertension, bronchiectasis, and other pulmonary vascular disease (31). Investigating medications that target both impaired lung function and ED could unveil novel strategies for preventing and managing ED in individuals with compromised pulmonary health.

This study has several strengths. Firstly, this present study was the first to rigorously investigate causal association between respiratory function and ED. Besides, we employed several MR methods for sensitivity analyses and LCV model to control for pleiotropy and obtained highly consistent results.

However, there were some limitations that need to be acknowledged. Firstly, the sample size of clinical incidence rates is comparatively lower due to the widespread usage of medications for ED, potentially leading to patient concealment and diminishing the study’s significance. Besides, the exclusive selection of samples from the European population implies potential limitations in generalizing findings to other ethnic groups. Thirdly, although relaxing the threshold when selecting instrumental variables may lead to an increased false positive rate, it allows for the detection of weaker associations that cannot be identified at the 5e−8 level.

Conclusions

In conclusion, this study identified a potential genetic causal relationship between ED susceptibility and reduced respiratory function. This prompts the possibility of considering ED as a potential precursor to the onset of chronic respiratory diseases. Future endeavors aim to delve deeper into understanding the genetic underpinnings that link these two entities.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (grant No. 32171285, to J.H. and grant No. 32471519, to Yifei Lin), Key Program of Science and Technology Department of Sichuan Province (grant No. 2023YFS0025, to J.H. and grant No. 2023YFS0102, to Yifei Lin) and 1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University (grant No. 2023HXFH044, to J.H.).

Footnote

Reporting Checklist: The authors have completed the STROBE-MR reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-321/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-321/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. J.H. reports that National Natural Science Foundation of China (grant No. 32171285), Key Program of Science and Technology Department of Sichuan Province (grant No. 2023YFS0025), and 1·3·5 project for disciplines of excellence-Clinical Research Fund, West China Hospital, Sichuan University (grant No. 2023HXFH044) provided the funding for the research. Yifei Lin reports that National Natural Science Foundation of China (grant No. 32471519) and Key Program of Science and Technology Department of Sichuan Province (grant No. 2023YFS0102) provided funding for this research. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Kessler A, Sollie S, Challacombe B, et al. The global prevalence of erectile dysfunction: a review. BJU Int 2019;124:587-99. [Crossref] [PubMed]
  2. Rezaee ME, Ward CE, Brandes ER, et al. A Review of Economic Evaluations of Erectile Dysfunction Therapies. Sex Med Rev 2020;8:497-503. [Crossref] [PubMed]
  3. Elterman DS, Bhattacharyya SK, Mafilios M, et al. The Quality of Life and Economic Burden of Erectile Dysfunction. Res Rep Urol 2021;13:79-86. [Crossref] [PubMed]
  4. Hartmann U, Burkart M. Erectile dysfunctions in patient-physician communication: optimized strategies for addressing sexual issues and the benefit of using a patient questionnaire. J Sex Med 2007;4:38-46. [Crossref] [PubMed]
  5. Dias M, Oliveira MJ, Oliveira P, et al. Does any association exist between Chronic Obstructive Pulmonary Disease and Erectile Dysfunction? The DECODED study. Rev Port Pneumol 2006;2017:259-65. [Crossref] [PubMed]
  6. Chou KT, Huang CC, Chen YM, et al. Asthma and risk of erectile dysfunction--a nationwide population-based study. J Sex Med 2011;8:1754-60. [Crossref] [PubMed]
  7. Tai SY, Wang LF, Tai CF, et al. Chronic Rhinosinusitis Associated with Erectile Dysfunction: A Population-Based Study. Sci Rep 2016;6:32195. [Crossref] [PubMed]
  8. Ettala OO, Saaresranta T, Syvänen KT, et al. Decreased forced expiratory volume in first second is associated with erectile dysfunction in apparently healthy men. A preliminary study. Int J Impot Res 2020;32:420-5. [Crossref] [PubMed]
  9. Charan NB. Does sildenafil also improve breathing? Chest 2001;120:305-6. [Crossref] [PubMed]
  10. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014;23:R89-98. [Crossref] [PubMed]
  11. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 2018;362:k601. [Crossref] [PubMed]
  12. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA 2021;326:1614-21. [Crossref] [PubMed]
  13. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023;613:508-18. [Crossref] [PubMed]
  14. Shrine N, Guyatt AL, Erzurumluoglu AM, et al. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries. Nat Genet 2019;51:481-93. [Crossref] [PubMed]
  15. Lin Y, Yang Y, Fu T, et al. Impairment of kidney function and kidney cancer: A bidirectional Mendelian randomization study. Cancer Med 2023;12:3610-22. [Crossref] [PubMed]
  16. Mounier N, Kutalik Z. Bias correction for inverse variance weighting Mendelian randomization. Genet Epidemiol 2023;47:314-31. [Crossref] [PubMed]
  17. Burgess S, Foley CN, Allara E, et al. A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat Commun 2020;11:376. [Crossref] [PubMed]
  18. Zhang W, Zhang X, Li H, et al. Prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) in China: results from the China Health and Retirement Longitudinal Study. BMJ Open 2019;9:e022792. [Crossref] [PubMed]
  19. Sanderson E, Davey Smith G, Windmeijer F, et al. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol 2019;48:713-27. [Crossref] [PubMed]
  20. O'Connor LJ, Price AL. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat Genet 2018;50:1728-34. [Crossref] [PubMed]
  21. Wang D, Zhou Y, Chen R, et al. The relationship between obstructive sleep apnea and asthma severity and vice versa: a systematic review and meta-analysis. Eur J Med Res 2023;28:139. [Crossref] [PubMed]
  22. Li Z, Tang T, Wu W, et al. Efficacy of nasal continuous positive airway pressure on patients with OSA with erectile dysfunction and low sex hormone levels. Respir Med 2016;119:130-4. [Crossref] [PubMed]
  23. Turan O, Ure I, Turan PA. Erectile dysfunction in COPD patients. Chron Respir Dis 2016;13:5-12. [Crossref] [PubMed]
  24. Hasan HM, Afify EI, Tawfik TM, et al. Erectile dysfunction in male patients with severe chronic obstructive pulmonary disease. Al-Azhar Assiut Medical Journal 2017;15:67-70.
  25. Surmeli DM, Karpuzcu HC, Atmis V, et al. Association between sarcopenia and erectile dysfunction in older males. Arch Gerontol Geriatr 2022;99:104619. [Crossref] [PubMed]
  26. Fujita K, Ohkubo H, Nakano A, et al. Decreased peak expiratory flow rate associated with mortality in idiopathic pulmonary fibrosis: A preliminary report. Chron Respir Dis 2022;19:14799731221114153. [Crossref] [PubMed]
  27. Marinelli L, Lanfranco F, Motta G, et al. Erectile Dysfunction in Men with Chronic Obstructive Pulmonary Disease. J Clin Med 2021;10:2730. [Crossref] [PubMed]
  28. Saint-Pierre M, Ladha J, Berton DC, et al. Is the Slow Vital Capacity Clinically Useful to Uncover Airflow Limitation in Subjects With Preserved FEV(1)/FVC Ratio? Chest 2019;156:497-506. [Crossref] [PubMed]
  29. Romano A, Committeri U, Abbate V, et al. Is There a Correlation between Endoscopic Sinus Surgery and Improvement in Erectile Dysfunction? J Clin Med 2023;12:6626. [Crossref] [PubMed]
  30. Luo L, Zhao S, Wang J, et al. Association between chronic obstructive pulmonary disease and risk of erectile dysfunction: a systematic review and meta-analysis. Int J Impot Res 2020;32:159-66. [Crossref] [PubMed]
  31. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015;373:834-44. [Crossref] [PubMed]
Cite this article as: Luo Y, Su S, Yang Y, Xiang N, Fu T, Lui S, Lin Y, Huang J. Using a two sample Mendelian randomization approach to explore the causal relationship between erectile dysfunction and lung function. Transl Androl Urol 2024;13(11):2439-2447. doi: 10.21037/tau-24-321

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