Effect of genetically proxied use of PDE5 inhibitors on risk of CHD: A drug target Mendelian Randomization study

doi:10.21203/rs.3.rs-5236402/v1

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Effect of genetically proxied use of PDE5 inhibitors on risk of CHD: A drug target Mendelian Randomization study

https://doi.org/10.21203/rs.3.rs-5236402/v1

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Background and aim

There have been previous and recent studies generating conflicting findings on effect of phosphodiesterase 5 (PDE5) inhibitors with CHD, Diabetes, breast cancer and prostatic cancer. Since we intended to use naturally occurring variation in genes encoding PDE5 to investigate association between genetically proxied PDE5 inhibitors and them.

Method

We used drug target mendelian randomization as main analytical method. 60,801 cases and 123,504 controls from 48 GWAS studies, mainly European ancestry (77%) for CHD were included. Inverse-variance weighted (IVW) random-effects model was employed as the primary analysis method to estimate the causal effect. And several robust methods were also used to detect the causal association as sensitive analysis. What’s more, colocalization analysis was also applied to verify the association.

Result

We observed strong evidence for the causal effect of genetically proxied PDE5 inhibitors on decreased CHD risk (IVW method, OR 1.22, 95% confidence interval (95%CI) 1.14-1.29, p-value=7.16E-07). Colocalization analysis also proved the association (H4=99.99%). Besides, we found weak association between genetically proxied inhibition of PDE5 and lower risk of breast cancer as well as prostatic cancer. At last, we found no evidence for effect of PDE5 inhibitors on risk of Diabetes.

Conclusion

We performed a drug target mendelian randomization supporting that use of PDE5 inhibitors is associated with lower risk of CHD. Though in 1990s studies found frustrating effect of PDE5 inhibitors on curing CHD, future RCT studies can focus on protective effect of PDE5 inhibitors on CHD. Our result may enlighten clinical use of PDE5 inhibitors.

PDE5 inhibitor

coronary heart disease

Mendelian randomization

Colocalization analysis

Cyclic nucleotide phosphodiesterases (PDEs) is a family of enzymes maintaining the second messengers at cellular levels, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which mediates vasodilator and inhibiting proliferation of vascular smooth muscle cells^1-3. Phosphodiesterase 5 (PDE5), the focus of our study, is a cGMP-specific member of PDEs and mainly present in the smooth muscle cells of the corpus cavernosum, platelets and cardiovascular system⁴. PDE5 inhibitors (PDE5i), such as sildenafil (Viagra™), tadalafil (Cialis™) and vardenafil (Levitra™), are usually used for the treatment of erectile dysfunction and pulmonary hypertension⁵.

There have been plenty of preclinical and clinical studies exploring other promising clinical uses of PDE5i including in coronary heart disease (CHD), diabetes, breast cancer and prostatic cancers et al⁶. However, the traditionally observational study is easily biased by confounders and reverse causation. As to randomized controlled trial (RCT), the studies are challenging to perform and unstable due to the requirement of long-term observation and influence of sample size.

During meiosis, the genetic variants for certain phenotype are randomly allocated, which can imitate the random allocation of intervention to this phenotype in RCT, letting them unlikely to be associated with other nongenetic factors^7,8. Hence, Mendelian randomization (MR) is considered as a “Natural” RCT, by using genetic variants as instrumental variables (IVs) to identify the causal relationship between a risk factor of interest and outcome disease, minimizing the confounders from environmental factor and reverse causation⁹. MR are based on following three Instrumental Variables (IVs) assumptions: i) the genetic variants are associated with the risk factor (one and only directly testable assumption); ii) there are no confounders between genetic variants and outcome; iii) the only causal pathway from genetic variants to outcome is through risk factor. In three assumptions, the latter two is untestable but falsifiable¹⁰.

The genetic variants, usually single-nucleotide polymorphisms (SNP), are mostly drawn from Genome-wide association studies (GWAS) of interest exposure with only a single SNP selected for per locus of genome to ensure the variants are independent, which means the variants are in linkage disequilibrium (LD)¹¹. It’s worth noting that the process of extracting SNPs in traditional Two-Sample MR is not gene locus specific. In contrast, the drug target MR, as a burgeoning and ponderable method, utilizes variants locating within specific gene locus (acting in cis) to mimic the effect of drug use¹². Under such circumstance, we performed a drug target MR study, perturbing variants within PDE5i target gene, to identify repurposing opportunities and inspect side effect of PDE5i on CHD, diabetes, breast cancer and prostatic cancer.

Study overview

We used a drug target MR study to detect the effect of genetically mimicked PDE5i use on CHD, diabetes, breast cancer and prostatic cancer (Figure 1).

Data source

The exposure data was extracted from a published and well-designed MR study by Benjamin Woolf et al, which selected genetic variants locating within PDE5 coding gene locus and significantly associated with diastolic blood pressure (instead of using systolic blood pressure as biomarker for phenotype because the stronger effect of PDE5i on diastolic blood pressure), following positive control by validating association between variants and erectile dysfunction and pulmonary hypertension^13,14. For outcome data, we obtained information on genetic association data of CHD, diabetes and cancers from several most recently published GWAS meta-analysis (GWAS for CHD: N=184,305 from 48 studies for a GWAS meta-analysis, mainly European ancestry (77%), 60,801 cases and 123,504 controls; GWAS for diabetes: N=484,598, sex as covariate, European ancestry, 24,659 cases and 459,939 controls; GWAS for prostatic cancer: N=90,332, adjusted for age, age2, sex, age × sex, age2 × sex, East Asian ancestry, 5,672 cases and 84,660 controls; GWAS for breast cancer: N= 79,550, adjusted for age, age2, sex, age × sex, age2 × sex, East Asian ancestry, 6,325 cases and73,225 controls)^15-18.

Statistical analysis

Mendelian randomization Inverse-variance weighted (IVW) random-effects model was employed as the primary analysis method to estimate the causal effect of genetically proxied PDE5i on CHD, diabetes and cancers risk for multiple IVs. The model is considered as the most efficient analysis method and would provide unbiased causal inference if meets the assumption of balanced pleiotropy (i.e., the possibility of pleiotropic effects on the outcome are equal to be positive as negative)^19,20.

Sensitive analysis To verify assumption ii and iii, series of sensitive analyses were performed. We utilized several robust analysis methods which are under weaker assumption than standard IVW method including MR-Egger, maximum likelihood (ML), penalized weighted median (PWM) and weighted median (WM) as sensitive analysis to provide valid causal estimates²¹. The MR-egger method assumes all genetic variants have pleiotropic effect but justifies treating pleiotropy as a random effect which would not interfere the SNP-exposure effect, avoiding violation of assumption iii and satisfying the InSIDE assumption (Instrument Strength Independent of Direct Effect)²². The ML method is based on the “plurality valid” assumption, weaker than “majority valid” assumption and stating more than 50% of the used SNPs are valid IVs²³. As for WM method and PWM method, make more robust assumption to outliers (majority assumption) and downweigh genetic variants with heterogeneous ratio estimate, respectively^24,25. MR-PRESSO test, including MR-PRESSO global test and MR-PRESSO distortion test, were used to assess horizontal pleiotropy and remove outliers if detected²⁶. Cochran’s Q statistic, as a part of a polygenic Mendelian randomization investigation, was employed to measure the heterogeneity²⁰. And intercept term in MR Egger regression was used to detect whether the results was driven by directional horizontal pleiotropy. Additionally, Leave-one-out (LOO) analysis which would remove one variant from the analysis and re-estimate the causal effect was used to identify if a single SNP is dominating the estimate of the causal effect²⁷.

Colocalization It is recommended that cis-mendelian randomization with positive results should be accompanied by a corresponding colocalization analysis²⁸. Since we performed enumeration Colocalization with Bayesian approaches to detect the potential association and whether the violation of instrumental assumption due to linkage disequilibrium for a given genetic region exists²⁹. The method presents posterior probability for five hypotheses: H₀: no causal variant for either trait; H₁: causal variant for trait 1 but not trait 2; H₂, causal variant for trait 2 but not trait 1; H₃: association with both traits but at separate causal variants; and H₄: a shared causal variant for both traits ³⁰. We consider posterior probability H₄ >0.8 as a result supporting colocalization. And if posterior probability H₃ >0.8, the colocalization indicates the existence of linkage disequilibrium meaning the violation of instrumental assumption (i.e. horizontal pleiotropy). However, when posterior probability of both H3 and H4 are <0.8, the result means that the colocalization provides insufficient evidence to discriminate between whether the mendelian randomization association ascribes to a shared causal variant or a confounding variant in linkage disequilibrium¹³.

Replicate using independent GWAS data We replicated our MR analysis using other independent GWAS data to validate the significantly causal estimation between genetically proxied PDE5i and outcomes (GWAS for CHD: N=86,995 from 14 studies for a GWAS meta-analysis, European ancestry, 22,233 cases and 64,762 controls; GWAS for prostatic cancer: N=211,227, European ancestry, 11,599 cases and 199,628 controls; GWAS for breast cancer: N= 257,730, European ancestry, 17,389 cases and 240,341 controls).

Standard of significant results Accounting for multiple outcome testing, we used a Bonferroni correction to establish a P value threshold of <0.0125 (false positive rate = 0.05/4statistical tests). We consider the results significant if the p-value <0.0125, and results with p-value provides insufficient evidence for causal estimation, meaning insignificant results.>0.05. As to p-value >0.05 which is between 0.125 and 0.05, that means weak evidence for causal effect.

Software All analyses were conducted in R software version 4.3.1 using the “TwoSampleMR”, “MR-PRESSO” and “coloc” packages.

Figure 2 Results of drug target MR. IVW random-effects model was employed as the primary analysis method to estimate the causal effect. Besides, MR Egger, ML, PWM and WM methods were also used to detect the causal association as sensitive analysis. Only significant results are displayed. IVW: Inverse-variance weighted method; ML: Maximum likelihood method; PWM: penalized weighted median method; WM: weighted median method; OR: Odds ratio; pval: P-value.

Genetically proxied PDE5i on CHD

We observed strong evidence for the causal effect of genetically proxied PDE5i on decreased CHD risk (IVW method, OR 1.22, 95% confidence interval (95%CI) 1.14-1.29, p-value=7.16E-07, Figure 2). The other robust methods also found significant association except MR Egger method (not significant, but also in the same direction of effect, p-value=0.38, OR=1.24). Colocalization analysis indicated that the fifth hypothesis (H4=0.999) was the most likely, suggesting that the result of MR ascribes to a shared causal variant instead of linkage disequilibrium (Table S4). There was no heterogeneity and pleiotropy detected by Cochran’s Q statistic and intercept term in MR Egger regression indicated the result was unlikely driven by pleiotropy (Table S5-6). MR-PRESSO global test found no pleiotropy. And MR-PRESSO distortion test detected no outliers (Table S7). Additionally, the leave-one-out analysis showed that the causal associations between genetically predicted PDDE5 inhibitor and CHD were not driven by a single SNP (FigureS1). We also found strong evidence for the causal association between genetically proxied PDE5i and decreased CHD risk in the replication using GWAS data of 22,233 CHD cases and 64762 controls of European ancestry¹⁸.

Genetically proxied PDE5i on PC and BC

We also identified significantly causal effect for genetically proxied PDE5i on decreased PC and BC risk (PC: IVW method, OR 1.32, 95%CI 1.15-1.49, p-value=1.62E-03; BC: IVW method, OR 1.28, 95%CI 1.13-1.44, p-value=1.78E-03, Figure 2). However, when utilizing other robust MR method to verify the results, only ML method identified significant results (PC: OR 1.32 95%CI 1.14-1.49 p-value=1.78E-03; BC: OR 1.29 95%CI 1.12-1.45 p-value=2.33E-03). As for the rest methods, merely weak, even insignificant (PC: p-value=7.76E-01; BC: p-value= 4.22E-01; both by MR Egger method) evidences were found for the causal association. Furthermore, sensitive analyses else detected no evidence for the existence of heterogeneity and pleiotropy. Results of replication in other independent GWAS provided little support for causal estimate. And Colocalization analysis supported the second hypothesis (PC: H1= 0.99; BC: H1=0.99), indicating that insufficient evidence for distinguish the causal effects of MR were driven from shared variants or linkage disequilibrium.

Genetically proxied PDE5i on diabetes

There was no evidence supporting the causal effect of genetically proxied PDE5i on decreased diabetes risk. Additionally, sensitive analysis also found similar results.

We have performed a drug target mendelian randomization to investigate the causal effect of genetically predicted PDE5i on the risk of CHD, diabetes, prostatic cancer as well as breast cancer in the context of former epidemiological studies only detected obscure association. Strong evidence for the causal association between PDE5i and lower risk of CHD was identified. And we did find weak effect of PDE5i on lower risk of prostatic cancer and breast cancer. Nevertheless, use of PDE5i and the risk of diabetes suggested to be not significantly associated according to the results. We verified the causal hypothesis that PDE5i could significantly protect against CHD, while we did not give a concrete effect estimation to the causality considering the limitation of MR that genetic differences are life-long but typically smaller when compared to clinical interventions in magnitude of change in the exposure³¹.

Potential mechanism for protective effect of PDE5i on CHD

The main implication of our study that PDE5i could protect against CHD is consistent with numerous epidemiologic, invitro, animal and short-term clinical studies. Simon et al. performed an observational study of 5956 men with T2D which indicated that taking a PDE5i was significantly associated with low risk of AMI³². A retrospective observational study found that in men without CHD but who had the risk factor of CHD, PDE5i exposure was associated with reductions in major adverse cardiovascular events, and the effect was exposure degree relevant³³. A cohort study including 18542 men with stable coronary artery disease (CAD) treated with PDE5i compared to alprostadil (16,548 with PDE5i and 1,994 with alprostadil) found PDE5i treatment was associated lower risk of cardiovascular mortality³⁴.

Overall, we consider that the effect of PDE5i on lower risk of CHD may mainly depend on its cardiovascular- and cardiomyocyte-protection mechanism (Figure 3). Under the physiological condition, the bioactive NO, which produced by NO synthase (NOS) play a critical part in the cardiovascular protection through the soluble guanylate cyclase (sGC) –cGMP pathway, leading to smooth muscle relaxation and inhibition of platelet, also leukocyte adhesion^3,35. PDE5i could stimulate downstream pathway of NO signal by inhibiting the effect of PDE5 breaking down cGMP into the inactive GMP⁶. Lifestyle factors known to protect against cardiovascular disease (CVD) as well as several commonly used cardiovascular therapies are associated with enhancive NO bioactivity³⁶. On the other hand, In patients with high risk factors of cardiovascular diseases (diabetes, cigarette smoking, etc.) associated with endothelial dysfunction show insufficiently bioactive NO³⁷. The reduction of bioactive NO may due to increased ROS (enhanced oxidative stress) seen in cardiovascular diseases, resulting in degradation of NO and eNOS uncoupling³⁸. In mice models, administration of PDE5i before coronary occlusion could increase endothelial- and inducible-NO synthase³⁹. Additionally, numerous animal and human studies have shown a continuous protective effect of PDE5i on cardiovascular system by improving hemodynamic parameters including arterial stiffness, flow-mediated dilation, and peak systolic velocity, even after discontinuation³⁴. Given the condition that in the cardiovascular system, both Neuronal NOS (nNOS) and Endothelial NOS (eNOS) are constitutively expressed, involving in the production of bioactive NO, when the predominant eNOS becomes dysfunctional, the nNOS expressed in low level in vascular smooth muscle cells would play an auxiliary role in maintaining a certain degree of vasodilation^3,40. And Silvia et al.⁴¹ using NOS inhibitor-treated rats found that even under the inhibition of NOS, the PDE5i could have a cardiomyocyte-protection shown by attenuating the accumulation of necrotic and fibrotic tissue, as well reducing myocardial lesions of rats. Simultaneously, it is worth mentioning that study found that in smokers and nonsmokers, inhibition of PDE5 by sildenafil both significantly increased NO-mediated vasodilation and the activities of PDE5 may be similar, also proving that PDE5i’s cardiovascular-protection effect still exists even under the risk factor of CHD which may lead to the inhibition of NOS⁴².

Moreover, treatment with PDE5i is associated with Inflammatory factor levels, including interleukin 6 which is involved in atherosclerosis progression and C-reactive protein, the most established inflammatory biomarker of CVD risk^34,43. What’s more, clinical research found a significant increase of circulating endothelial progenitor cells (EPC) in young males after PDDE5 inhibitors administration, which may attribute to cGMP increase caused by PDE5-inibition triggering the upregulation of matrix metalloproteinase 9 in the BM stem cell niches, contributing to the extracellular matrix proteolysis and release of EPC in consequence⁴⁴. Study found that over the days to weeks after ischemic stimulus, the EPCs could facilitate the generation of collateral circulation through an angiogenesis-mediated mechanism⁴⁵. The inverse relationship between EPC counts and cardiovascular diseases has been established which also supports its vasculoprotective effect⁴⁶.

Potential mechanism for protective effect of PDE5i on Breast cancer and Prostatic cancer

We have indicated a mildly significant association between PDE5i and lower risk of breast cancer as well as prostatic cancer. Many studies have reported the elevated PDE5 expression in multiple human carcinomas⁶. Since conflicting role of NO and cGMP in the signaling pathways involved in tumor cell proliferation and apoptosis, it is difficult to decipher the effect of PDE5 on oncogenesis and tumor progression^47-49. Accordingly, whether PDE5i could be a potential anti-tumor drug is still controversial.

Breast cancer The mortality of BC in high-income countries is decreasing, however the BC incidence has been steadily increasing, though certainly caused by the advance in diagnostic methods⁵⁰. Compared with normal breast tissues and benign tumors, PDE5 was found over-expressed in malignant breast tumors, resulting in decreased cGMP level as well as progression of tumor grade, stage and lymph node involvement^48,51. What’s more, upregulated PDE5 was considered as relevant symbol of cancer-associated fibroblasts (CAFs) and heterotypic signaling promotion within the breast tumor microenvironment, leading to tumor progression⁵². Overexpression of PDE5 and its adverse effect in breast tumor highlights PDE5i’s beneficial role, especially malignant tumors.

Prostatic cancer Prostatic cancer is the most common solid malignancy found in men⁵³. A retrospective study in 2013⁵⁴ found that in men with ED, using of PDE5i was associated with a reduced incidence rate of PC. However, there are more recent studies indicating that taking PDE5i is not significantly associated with the aggressiveness of PC^55,56. Several established theories may explain the potential mechanism for the decreased incidence rate of PC resulted from use of PDE5i, pointing out the possible involvement of PDE5 in cell growth regulation, apoptosis of prostate cancer cell and Hippo signaling pathway⁵³. Studies in vivo found the high expression of PDE5 in prostatic stromal compartment and different concentration of PDE5i had pronounced effect on reducing proliferation of prostate epithelial and stromal cells, respectively⁵⁷. Besides, PDE-5 inhibitor could facilitate the circulatory perfusion and reduced hypoxia, since reducing hypoxia-induced PC adaptive responses and emergence of aggressive phenotype PC⁵⁴.

Drug target mendelian randomization

Except randomized placebo-controlled trial, the drug target mendelian randomization would be a generally concise and easy to implement method to detect the causal association and resolve confounding and bias. With the design of conceptually random allocation of alleles at a drug target gene, drug target MR can eliminate interference and moreover, mimic lifelong effect instead of short intervention like normal RCT do. Take our study as an example, mostly in the majority of cases PDE5i are not prescribed to be used daily⁵⁸, however with the design of drug target MR using genetically proxied PDE5i could mimic the daily use of PDE5i and met the criteria of continuous exposure.

Colocalization analysis

The purpose of Colocalization and MR is clearly similar, both to elucidate the nature of the relationship between traits. However, the Colocalization is generally more conservative, only aim to detect the association between two traits at a single genetic region. MR is much sterner in comparison with Colocalization. The IVs for MR are restricted to be only associated with exposure and irrelevant with downstream product of exposure or outcome. And MR normally needs be implemented in both directions, which is called bidirectional MR. The design of MR leads to a “one-way causality” from exposure to outcome whereas Colocalization indicates “association” between exposure and outcome. Since we consider Colocalization as a verification of MR. If a positive result of MR followed by proof of the existence of colocalization (H4>0.8), it would reinforce the reliability of MR. In contrast, when accompanied with result that H3 > 0.8, the result of MR may be not credible resulted from the weak IVs bias. Generally, the positive result of Colocalization provides additional support to MR result, and negative result indicates the lack of reliability of MR result.

Meaning of the finding

PDE5i was developed for its hypothesized beneficial effects on hypertension and symptomatic ischemic heart disease in 1990s. However, it did not show satisfying therapeutic effect in subsequent trials, and what makes it intriguing is its surprising effect on ED. Our results may encourage future RCT to detect the effect of PDE5i on risk of CHD, prostatic cancer and breast cancer, as well as support future change of PDE5i in clinical practice. Especially for CHD, our results enlighten that maybe future RCT should focus on the association between PDE5i use and risk of CHD in patients with or without conventional cardiac risk factors and other condition reflecting systemic endothelial damage.

Strength and Weakness

Leveraging drug target mendelian randomization, we have detected significantly causal effect of genetically proxied PDE5i use on lower risk of CHD, with colocalization analysis verifying and supporting the association. Our analytical approach is more robust to the influence of confounding and reverse causation compared with traditional observational research methods and more feasible than random control trial.

An obvious and important weakness of our study is that we merely detected significantly but non-sex specifically causal association between genetically proxied PDE5i and lower risk of CHD, and the results could be rediscussed in female only. Second weakness is the generalizability. Besides, Drug target MR can only detect effect of genetically proxied PDE5i use, which typically has smaller effects and life-long time needed to take effect compared with pharmacological agents. In other word, it would take a MR-deductively useful Drug longer time than Drugs found effective by relatively short-term RCT to show its effect on certain disease. Since we could not disclose the shortly intervening effect or exactly dose-response effect of PDE5i. Furthermore, we extracted IVs from a published though well-established MR study, making our results restricted to the reliability of the published data.

In conclusion, this study provides genetical evidence for association between use of PDE5i and lower risk of CHD, which may encourage future RCT and enlighten the directions. Though our result suggests potential change of clinical use of PDE5i, we still need sober view about the that considering the possible harmful effect of PDE5i. Studies should be conducted to confirm the causality and clarify the underlying mechanistic pathways between PDE5i and lower risk of CHD.

PDE5: Phosphodiesterase 5;

PDE5i: Phosphodiesterase 5 inhibitors;

CHD: Coronary heart disease

MR: Mendelian Randomization.

Ethic approval

All data are from publicly available GWAS, approved by the corresponding ethics committees or institutional review boards.

Consent for publication

All authors are consent for publication.

Conflicts of Interest

All authors declare no conflict of interest.

Funding

Not applicable

Availability of data and materials

All data are publicly available and can be downloaded freely.

Author contribution

L.C. and H.Z. proposed the original design of the study. H. Z., Z. D. and W. H. take responsibility for the integrity of the data and the accuracy of the data analysis. The manuscript was written by H. Z.. Y. C. and Q. D. performed visualization of results. G. C. and S. L. revised the article. L. C., Z. F. and G. L. supervised the study and are of responsibility for the article.

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No competing interests reported.

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Effect of genetically proxied use of PDE5 inhibitors on risk of CHD: A drug target Mendelian Randomization study

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