A drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing: mendelian randomisation study

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Abstract

Objective To investigate the association of genetically proxied (using a surrogate biomarker) inhibition of phosphodiesterase 5 (PDE5), an established drug target for erectile dysfunction, with fertility, sexual behaviour, and subjective wellbeing.

Design Two sample cis-mendelian randomisation study.

Setting Summary data on genetic associations obtained from the International Consortium for Blood Pressure and UK Biobank.

Participants Individuals of European ancestry from the International Consortium for Blood Pressure (n=757 601) for estimating PDE5 inhibition (using the surrogate biomarker of diastolic blood pressure reduction), and UK Biobank (n=211 840) for estimating the fertility, sexual behaviour, and subjective wellbeing outcomes in male participants.

Intervention Genetically proxied PDE5 inhibition.

Main outcome measures Number of children fathered, number of sexual partners, probability of never having had sexual intercourse, and subjective wellbeing.

Results Genetically proxied PDE5 inhibition was associated with male participants having 0.28 (95% confidence interval 0.16 to 0.39) more children (false discovery rate corrected P<0.001). This association was not identified in female participants. No evidence was found of an association between genetically proxied PDE5 inhibition and number of sexual partners, probability of never having had sexual intercourse, or self-reported wellbeing in male participants.

Conclusions The findings of this study provide genetic support for PDE5 inhibition potentially increasing the number of children fathered by male individuals. Absence of this association in female participants supports increased propensity for sustained and robust penile erections as a potential underlying mechanism. Further studies are required to confirm this, however, and these findings should not promote indiscriminate use of PDE5 inhibitors, which can also have harmful adverse effects.

Introduction

Phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil are commonly used for the treatment of erectile dysfunction and pulmonary hypertension.1 PDE5 is an enzyme that promotes the breakdown of cyclic guanosine monophosphate in vascular smooth muscle cells. By inhibiting PDE5, increased cyclic guanosine monophosphate activity induces vascular smooth muscle relaxation and vasodilation. In the setting of erectile dysfunction, this increases blood flow to the penis to facilitate sustained and robust erections.1 In the setting of pulmonary hypertension, PDE5 inhibition induces dilation of the pulmonary vasculature and improves ventilation-perfusion matching.2

Although randomised clinical trials provide vital data on drug efficacy, safety, and adverse effects, the limited duration of use does not always permit investigation of longer term outcomes. For PDE5 inhibitors, longer term outcomes could include effects on fertility, sexual behaviour, and subjective wellbeing. As PDE5 inhibitors are available to buy over the counter in countries such as the UK, it is important to understand their potential application for improving fertility3 and wellbeing.4 It is feasible that facilitation of penile erections and resultant fulfilling sexual intercourse may simultaneously increase the probabilities of both conception and improved subjective wellbeing.

Investigating such effects using traditional observational studies is undermined by confounding from environmental factors and reverse causation. Mendelian randomisation is an alternative epidemiological approach for strengthening causal inference in observational study designs.5 6 Mendel’s laws of inheritance state that genetic variants are inherited independently during meiosis and should therefore not systematically relate to environmental factors. In the mendelian randomisation paradigm, random allocation of genetic variants predicting a given phenotype at conception is analogous to random allocation to intervention on this phenotype in a randomised clinical trial.7 Furthermore, genetic variants are fixed at conception, which confers a greater robustness of mendelian randomisation studies to bias from reverse causation.

Given that most drug targets are proteins and that genes encode proteins, mendelian randomisation has been paradigmatically extended to study the effects of perturbing specific drug targets.8 In such drug-target mendelian randomisation studies, variants located at the gene encoding the protein drug target of interest, so-called cis variants, are used as instrumental variables for studying the effect of perturbing that drug target pharmacologically.9 Such cis-mendelian randomisation can provide quasi-randomised evidence for outcomes that might otherwise be impractical or unethical to investigate within a randomised clinical trial. For example, a recent cis-mendelian randomisation study investigated genetic evidence for the safety of two major antihypertensive drug classes in pregnancy.10

Given the known effects of PDE5 inhibitors on promoting sustained and robust penile erections, and the ability of this physiological state to facilitate fulfilling sexual intercourse, we hypothesised that PDE5 inhibition may have effects on male fertility, sexual behaviour, and subjective wellbeing. We therefore performed cis-mendelian randomisation to investigate associations of genetically proxied PDE5 inhibition with each of these three outcomes.

Discussion

In this study, we investigated the association of genetically proxied PDE5 inhibition with measures of fertility, sexual behaviour, and wellbeing. We did not find evidence of an effect of PDE5 inhibition on number of sexual partners, probability of never having had sexual intercourse, or wellbeing in either male or female participants. We did, however, identify genetic evidence that lifelong PDE5 inhibition may increase the number of children had by male patients. Similar evidence was not identified in female patients, consistent with the notion that any effects of PDE5 inhibition on fertility in male patients may be attributable to penile mechanisms.29 30 31 32 Erectile function is reduced in male patients with infertility, and it is estimated that more than one third of the male partners in couples seeking fertility treatment experience erectile dysfunction.33 34 However, extra-penile mechanisms may also be at play. For example, a systematic review and meta-analysis found that oral PDE5 inhibitors improved sperm motility in male patients experiencing difficulties with infertility.35 Similarly, oral PDE5 inhibitors are associated with an increased proportion of morphologically normal sperm in male patients experiencing difficulties with infertility, and with improved sperm-oocyte binding.35

Although epidemiological evidence that PDE5 inhibition may have beneficial effects on fertility in female patients and reproductive outcomes exists,36 37 38 39 40 Cochrane systematic reviews have concluded that such evidence remains inadequate to derive any definitive policy recommendations.41 42 However, a general limitation of population based studies is difficulty in appropriately quantifying fertility. The number of children people have is a function not only of their ability to have children but also of their desire to have children, among a range of other sociocultural factors. Fertility estimates can be artificially inflated by reproductive assistance, or artificially lowered by contraceptive use, unknown pregnancies, pregnancy termination, and miscarriages.

The potential implication of our research is that use of PDE5 inhibitors could improve fertility in male patients, particularly when this is related to erectile dysfunction. Further clinical study is, however, necessary to validate these findings. Consistent with our null finding in people who do not have penises, the effect of PDE5 inhibitors on fertility in male patients may be through effects on erectile function. Of relevance, random samples of general populations in the UK generally report higher age specific estimates of erectile dysfunction than the UK Biobank, where prevalence is less than 3%.43 Participants of UK Biobank may also have been undertreated when compared to a modern cohort. Since PDE5 inhibitors were widely approved for treating erectile dysfunction in the 1990s, most UK Biobank participants would likely already have attempted to have children before access to the drug class was widely available for erectile dysfunction. Mechanisms other than through erectile function may also be at play, including endocrine effects.

Because fertility is declining in many countries,44 45 an intervention to improve sexual performance could help reverse this trend. We do not, however, recommend indiscriminate use of PDE5 inhibitors, which can have serious adverse effects, including loss of vision. Other potential implications of incorrect PDE5 inhibitor use might include hypotension and inappropriately timed erections. We emphasise that literal interpretations of mendelian randomisation estimates can be misleading, especially in instances where the causal estimate is likely to vary across the life course.46 47 Thus, further research is required to estimate how PDE5 inhibitor use may affect fertility.

Conclusions

We found genetic evidence to support the hypothesis that PDE5 inhibition may result in male patients fathering more children. This suggests that use of PDE5 inhibitors, and perhaps improved sexual performance in male patients more generally, might potentially help alleviate the declining fertility rates observed in many countries. However, further studies are required to confirm this, and we absolutely do not advocate indiscriminate use of PDE5 inhibitors—although relatively rare, PDE5 inhibitors can have harmful adverse effects.

What is already known on this topic

PDE5 inhibitors are a drug class commonly used for the treatment of erectile dysfunction, but their effects on fertility, sexual behaviour, and subjective wellbeing in male patients are not known
Drug target mendelian randomisation is a quasi-experimental method that uses genetic variants as instrumental variables for studying the effects of drug target perturbation

What this study adds

Evidence from drug target mendelian randomisation supports the potential for PDE5 inhibition to increase the number of children fathered by male patients, but with no evidence of such an effect in female patients
No strong evidence was found for PDE5 inhibitors affecting number of sexual partners, probability of never having had sexual intercourse, or subjective wellbeing in either male or female patients

Let’s Talk about Sex and Diabetes

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Though certain sexual disorders are well-understood in men with diabetes, we know a lot less about the prevalence, impact, and management of sexual dysfunction in women with diabetes. At the ADA Scientific Sessions, Dr. Sharon Parish gave a broad overview of what we do know about this topic.

Dr. Sharon Parish, professor of medicine, clinical psychology and professor of clinical medicine at Weill Cornell Medicine, delivered a fascinating presentation on the third day of the 82nd ADA Scientific Sessions that included a broad overview of sexual disorders and dysfunction in women with diabetes.

What sexual disorders do women with diabetes face?

There are a number of sexual disorders that can affect women and women with diabetes specifically. These include hypoactive sexual desire disorder (HSDD) (reduced sexual desire and motivation), female sexual arousal disorder (reduced sexual arousal), and female orgasm disorder (reduced frequency, intensity, or pleasure of orgasms, and/or delayed, spontaneous, or premature orgasms), among many others.

How common is sexual dysfunction?

The prevalence of these conditions is disheartening. Research shows that in sexually active women with type 2 diabetes, as many as:

50% experience desire problems
34% experience arousal problems
36% experience lubrication problems
36% experience orgasm problems

More recent data shows these rates may actually be slightly lower, and there are differences with type 1 vs. type 2 diabetes. Women with type 1 diabetes having a greater prevalence of sexual dysfunction, including decreased desire, lubrication, and arousal. In women who do have sexual dysfunction, there are also higher rates of diabetes distress, impaired emotional well-being, and anxiety.

The reasons these conditions show up more prominently in women with diabetes could include hormonal reasons, infections, hyperglycemia that affects vaginal lubrication, neurological damage, and increased rates of mental health conditions like depression.

What are the risk factors?

Risk factors for these sexual dysfunctions include older age, obesity, smoking, higher A1C, and longer duration of diabetes. Interestingly, depression and marital status are significant predictors of sexual dysfunction in women.

The importance of screening for sexual dysfucntion and reducing stigma

Parish stressed that screening is key, but that these conversations should be initiated by healthcare providers by asking open-ended questions. “Have them tell you a story, ask follow-up questions,” she said.

And as a person with diabetes, being honest with your healthcare provider about how diabetes affects your sex life can help them help you. If they don’t bring the topic up, and you are comfortable, initiate the conversation yourself. This can help normalize talking about sex and reduce the stigma associated with these conversations – all people deserve to have a healthy and fulfilling sex life.

Treatment options for some sexual disorders in women with diabetes

For women with HSDD, Parish broke down three treatment options. If you have this condition, ask your healthcare provider if any of these may be available to you.

For pre-menopausal women, Flibanserin could elevate hormones in your brain that lead to sexual desire and Bremelanotide (an injection taken on-demand) can increase desire and decrease distress. Though there is less research in the area, there is some evidence that testosterone injections given off-label could moderately improve desire in post-menopausal women.

In addition, if the root cause of HSDD is determined to be tied to a psychological or relationship/lifestyle issue, counseling, cognitive behavioral therapy, or psychotherapy could also be good options for treatment.

Finally, Parish explained some signs and symptoms of vulvovaginal atrophy (VVA) and genitourinary syndrome of menopause (GSM) and treatment options. These conditions, which occur post-menopause, can lead to loss of elasticity, soreness, dryness, irritation, and burning. They may be able to be treated with lubricants and moisturizers or low-dose vaginal estrogen.

Why is sexual health important?

Sexual health is an important part of your overall health. Talking to your healthcare team about how diabetes affects your sex life, and finding ways to address the root causes of any issues you notice, could improve not only this area of your life but also your emotional and mental well-being. It’s also important for healthcare providers to help initiate these conversations in their clinics.

Sexual Well-Being in Women With Diabetes

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If you’re a woman with diabetes, you may be at greater risk for certain sexual issues. Here’s more on how to manage it.

Your sexual life is an important part of your well-being, but if you’re a woman with diabetes, you may be at greater risk for sexual problems like low libido, less sexual stimulation, and yeast infections.

It’s not always easy to talk about sexual problems with your clinician, but it’s a good first step toward finding the right treatment. It’s important to prioritize women’s sexual health and for both healthcare professionals and patients to bring up these issues.

Impact on women with diabetes

“The risk of sexual dysfunction is very high in diabetes, but we have a number of solutions if the issue is carefully addressed by doctors,” said Dr. Emmanuele Jannini, researcher and professor of endocrinology and sexual medicine at the University of Rome Tor Vergata.

In a 2023 review, researchers looked at sexual dysfunction in premenopausal women with type 1 diabetes. Among them, 36% experienced some type of sexual problem. The study also found that women with type 1 diabetes are three times more likely to experience sexual issues compared to those without diabetes.

For women with type 2 diabetes, the numbers are even higher. A 2019 meta analysis found that roughly 67% of women with type 2 diabetes experienced sexual dysfunction.

Reasons for sexual dysfunction

There are several reasons why women with diabetes may be at greater risk for sexual problems, including:

Lubrication issues. When your blood sugar is consistently high, this can cause damage to your blood vessels, including those in your vagina. When this happens, your vagina may not be able to properly lubricate itself, leading to dryness.
Less stimulation. High blood sugar can also lead to nerve damage. When the nerves in your vagina and vulva are damaged, you may not be able to feel as much sexual stimulation.
Difficulty feeling aroused. Sexual arousal triggers increased blood flow to your vagina and vulva. If your blood vessels are damaged by diabetes, you may have restricted blood flow to these areas.
Urinary tract infections (UTIs). If you have diabetes, you’re at a greater risk for developing a UTI due to extra sugars present in the tissues of your urinary tract. This creates an environment that’s easier for bacteria to grow and cause an infection. Having a UTI can also seriously affect your sex life. Having sex may put extra pressure on your bladder, which can trigger intense pain or discomfort.
Yeast infections. People with diabetes are more likely to get yeast infections because yeast grows more easily in urine that’s high in sugar. Yeast infections are also a side effect of SGLT-2 inhibitors, which are used to manage blood sugar in people with diabetes. Yeast infections can cause pain and itching in your vulva, and make sex extremely uncomfortable.
Low libido. Diabetes can disrupt the normal balance of sex hormones like estrogen and testosterone. Changes in these hormones can reduce your sex drive and make it harder to become aroused.

The importance of women’s sexual health in clinical care

According to some experts, most of the research on sexual problems focuses on men with diabetes – not women.

There is early research on medications that may help for sexual dysfunction in women, including testosterone therapy and Cialis (tadalafil). However, more studies are needed to prove these treatments work effectively for females.

Due to the general lack of research regarding women’s sexual health, healthcare providers don’t have a way to accurately measure sexual dysfunction in women. Developing this kind of assessment would help determine which women need treatment and shine a light on how common the problem truly is.

As a starting point, clinicians should directly ask patients if they’re having any sexual issues, as many may be uncomfortable bringing up the subject on their own. Along with testing, researchers and healthcare experts need to focus on developing treatment methods that specifically target women’s sexual health issues.

Education for doctors is also important. Many clinicians who specialize in endocrinology may not have education in sexual medicine, Jannini said, and this needs to change.

Treatment options

Despite the challenges around sexual dysfunction in women with diabetes, there are treatment options available. For those experiencing sexual pain or discomfort, hormone therapy, physiotherapy, and certain medications may help. There are tons of varieties of lubricants found at your local pharmacy or sex shop to help with vaginal dryness.

For issues with stimulation and sexual arousal, sex therapy or counselling can teach you more about ways to increase intimacy and learn more about your body’s sexual responses. While more research is needed, medications including sildenafil (Viagra) and buproprion (an antidepressant) have shown positive results in improving and even reversing sexual dysfunction in women.

The bottom line

Many women with diabetes experience sexual issues; getting the right testing and treatment can make a big difference. Doctors and medical policymakers need to prioritize this issue by developing better testing measures and treatments that specifically target women’s needs.

Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data

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The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women.

Methods

We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks’ duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073.

Findings

Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference −0·27, 95% CI −0·36 to −0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded.

Interpretation

Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation.

How is erectile dysfunction treated?

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The oral administration of phosphodiesterase 5 inhibitors such as Sildenafil, Tadalafil, Avanafil, and Vardenafil is considered the first-line treatment for the management of erectile dysfunction. The administration of phosphodiesterase 5 inhibitors results in:

An increase in the concentration of nitric oxide in the cavernosum smooth muscle cells,
Relaxation of cavernous smooth muscle, and
Accumulation of blood in corpora cavernosum.

However, these drugs were not found to be much effective in men with diabetes in comparison to men without diabetes. A combination therapy that comprises phosphodiesterase 5 inhibitors and alpha-blockers have been shown to improve both sexual function and urinary tract symptoms at the same time. The phosphodiesterase 5 inhibitors act on the nitric oxide receptors of the urinary bladder. This not only relaxes the bladder but also leads to an increase in the urinary flow.

Vacuum erection and external support devices are the second-line treatment for erectile dysfunction. These devices pull the blood through the creation of negative pressure around the penis, which leads to penile erection. Following the erection, a compression device is required to be put at the base of the penis. Cold penis during intercourse and decreased sexual sensation due to nerve compression are some of the limitations associated with the use of these devices.

Intra-cavernosum injections, prostaglandin E1 injections, etc., are considered the therapy of choice when treatment with oral administration of inhibitors has failed. They can be administered directly into the corpus cavernosum. They cause penile vasodilatation, which results in immediate penile erection. A high response rate has been obtained when they are injected directly. Although, certain limitations are also associated with this process which include penile pain, haematoma, fibrosis, the necessity of administration before every intercourse, etc.^[1] The intra-urethral suppository of prostaglandin E1 is not effective in comparison to prostaglandin E1 injections. Moreover, the process is very cumbersome.

Regular Use of Erectile Dysfunction Drugs Associated With Eye Problems.

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GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology

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Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10⁻¹⁴), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.

Main Text

Erectile dysfunction (ED) is the inability to develop or maintain a penile erection adequate for sexual intercourse.

ED has an age-dependent prevalence, with 20%–40% of men aged 60–69 years affected.

The genetic architecture of ED remains poorly understood, owing in part to a paucity of well-powered genetic association studies. Discovery of such genetic associations can be valuable for elucidating the etiology of ED and can provide genetic support for potential new therapies.

We conducted a genome-wide association study (GWAS) in the population-based UK Biobank (UKBB) and the Estonian Genome Center of the University of Tartu (EGCUT) cohorts and hospital-recruited Partners HealthCare Biobank (PHB) cohort. Subjects in UKBB were of self-reported white ethnicity, with subjects in EGCUT and PHB of European ancestry, as per principal components analyses (Supplemental Material and Methods).

ED was defined as self-reported or physician-reported ED using ICD10 codes N48.4 and F52.2, or use of oral ED medication (sildenafil/Viagra, tadalafil/Cialis, or vardenafil/Levitra), or a history of surgical intervention for ED (using OPCS-4 codes L97.1 and N32.6) (Supplemental Material and Methods). The prevalence of ED in the cohorts was 1.53% (3,050/199,352) in UKBB, 7.04% (1,182/16,787) in EGCUT, and 25.35% (1,943/7,666) in PHB (Table S1). Demographic characteristics of the subjects in each cohort are shown in Table S2. The reasons for the different prevalence rates in the three cohorts may include a higher median cohort age for men in PHB (65 years, compared to 59 years in UKBB and 42 years in EGCUT; Table S2), “healthy volunteer” selection bias in UKBB,

a lack of primary care data availability in UKBB, and intercultural differences, including “social desirability” bias.

⁴

Importantly, we note that the assessment of exposure-outcome relationships remains valid, despite the prevalence likely not being representative of the general population prevalence.

GWASs in UKBB revealed a single genome-wide significant (p < 5 × 10⁻⁸) locus at 6q16.3 (lead variant rs57989773, EAF_UKBB [C-allele] = 0.24; OR 1.23; p = 3.0 × 10⁻¹¹). Meta-analysis with estimates from PHB (OR 1.20; p = 9.84 × 10⁻⁵) and EGCUT (OR 1.08; p = 0.16) yielded a pooled meta-analysis OR 1.20; p = 5.71 × 10⁻¹⁴ (heterogeneity p value = 0.17; Figures 1A–1C). Meta-analysis of all variants yielded no further genome-wide loci. Meta-analysis of our results with previously suggested ED-associated variants also did not result in any further significant loci (Supplemental Material and Methods; Table S3), nor did X chromosome analysis in UKBB.

Figure thumbnail gr1 — Figure 16q16.3 (Lead Variant rs57989773) Is an Erectile Dysfunction-Associated Locus and Exhibits Pleiotropic Phenotypic Effects

The association of rs57989773 was consistent across clinically and therapy defined ED, as well as across different ED drug classes (Figures 1C and S1). No further genome-wide significant loci were identified for ED when limited to clinically or therapy defined case subjects (2,032 and 4,142 case subjects, respectively).

A PheWAS of 105 predefined traits (Table S4) using the lead ED SNP rs57989773 found associations with 12 phenotypes at a p value < 5 × 10⁻⁴ (surpassing the Bonferroni-corrected threshold of 0.05/105), including adiposity (nine traits), adult height, and sleep-related traits. Sex-stratified analyses revealed sexual dimorphism for waist-hip ratio (WHR; unadjusted and adjusted for body mass index) and systolic and diastolic blood pressure (Figure 1D; Table S5).

The lead variant at the 6q16.3 locus, rs57989773, lies in the intergenic region between MCHR2 and SIM1, with MCHR2 being the closest gene (distances to transcription start sites of 187 kb for MCHR2 and 284 kb for SIM1). Conditional and joint analysis (Supplemental Material and Methods) revealed no secondary, independent signals in the locus. Previous work has implicated the MCHR2-SIM1 locus in sex-specific associations on age at voice-breaking and menarche.

⁵

The puberty timing-associated SNP in the MCHR2-SIM1 region (rs9321659; ∼500 kb from rs57989773) was not in LD with our lead variant (r² = 0.003, D’ = 0.095) and was not associated with ED (p = 0.32) in our meta-analysis, suggesting that the ED locus represents an independent signal.

To identify the tissue and cell types in which the causal variant(s) for ED may function, we examined chromatin states across 127 cell types

⁶

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for the lead variant rs57989773 and its proxies (r² > 0.8, determined using HaploReg v.4.1) (Supplemental Material and Methods). Enhancer marks in several tissues, including embryonic stem cells, mesenchymal stem cells, and endothelial cells, indicated that the ED-associated interval lies within a regulatory locus (Figure 2A; Table S6).

Figure thumbnail gr2 — Figure 2Functional Analysis of 6q16.3 Implicates *SIM1* in ED Pathogenesis

To predict putative targets and causal transcripts, we assessed domains of long-range three-dimensional chromatin interactions surrounding the ED-associated interval (Figure 2B). Chromosome conformation capture (Hi-C) in human embryonic stem cells

⁸

showed that MCHR2 and SIM1 were in the same topologically associated domain (TAD) as the ED-associated variants, with high contact probabilities (referring to the relative number of times that reads in two 40-kb bins were sequenced together) between the ED-associated interval and SIM1 (Figures 2B and S2). This observation was further confirmed in endothelial precursor cells,

⁹

where Capture Hi-C revealed strong connections between the MCHR2-SIM1 intergenic region and the SIM1 promoter (Figure 2C), pointing toward SIM1 as a likely causal gene at this locus.

We next used the VISTA enhancer browser

¹⁰

to examine in vivo expression data for non-coding elements within the MCHR2-SIM1 locus. A regulatory human element (hs576), located 30-kb downstream of the ED-associated interval, seems to drive in vivo enhancer activity specifically in the midbrain (mesencephalon) and cranial nerve in mouse embryos (Figure 2D). This long-range enhancer close to ED-associated variants recapitulated aspects of SIM1 expression (Figure 2D), further suggesting that the ED-associated interval belongs to the regulatory landscape of SIM1. Taken together these data suggest that the MCHR2-SIM1 intergenic region harbors a neuronal enhancer and that SIM1 is functionally connected to the ED-associated region.

Single-minded homolog 1 (SIM1) encodes a transcription factor that is highly expressed in hypothalamic neurons.

¹¹

Rare variants in SIM1 have been linked to a phenotype of severe obesity and autonomic dysfunction,

¹²

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including lower blood pressure. A summary of the variant-phenotype associations at the 6q16 locus in human and rodent models is shown in Table S7. Post hoc analysis of association of rs57989773 with autonomic traits showed nominal association with syncope, orthostatic hypotension, and urinary incontinence (Figure S3). The effects on blood pressure and adiposity seen in individuals with rare coding variants in SIM1 are recapitulated in individuals harboring the common ED-risk variants at the 6q16.3 locus (Figure 1D), suggesting that SIM1 is the causal gene at the ED-risk locus. SIM1-expressing neurons also play an important role in the central regulation of male sexual behavior as mice that lack the melanocortin receptor 4 (encoded by MC4R) specifically in SIM1-expressing neurons show impaired sexual performance on mounting, intromission, and ejaculation.

¹⁴

Thus, hypothalamic dysregulation of SIM1 could present a potential mechanism for the effect of the MCHR2-SIM1 locus on ED.

An alternative functional mechanism may be explained by proximity of the lead variant (rs57989773) to an arginase 2 processed pseudogene (LOC100129854), a long non-coding RNA (Figure 2A). RPISeq

¹⁵

predicts that the pseudogene transcript would interact with the ARG2 protein, with probabilities of 0.70–0.77. Arginine 2 is involved in nitric oxide production and has a previously established role in erectile dysfunction.

¹⁶

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GTEx expression data

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demonstrated highest mean expression in adipose tissue, with detectable levels in testis, fibroblasts, and brain. Expression was relatively low in all tissues, however, and there was no evidence that any SNPs associated with the top ED signal were eQTLs for the ARG2 pseudogene or ARG2 itself.

As a complementary approach, we also used the Data-driven Expression Prioritized Integration for Complex Traits and GWAS Analysis of Regulatory or Functional Information Enrichment with LD correction (DEPICT and GARFIELD, respectively; Supplemental Material and Methods)

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tools to identify gene-set, tissue-type, and functional enrichments. In DEPICT, the top two prioritized gene-sets were “regulation of cellular component size” and “regulation of protein polymerization,” whereas the top two associated tissue/cell types were “cartilage” and “mesenchymal stem cells.” None of the DEPICT enrichments reached an FDR threshold of 5% (Tables S8–S10). GARFIELD analyses, which assesses enrichment of GWAS signals in regulatory or functional regions in different cell types, also did not yield any statistically significant enrichments, therefore limiting the utility of these approaches in this case.

ED is recognized to be observationally associated with various cardiometabolic traits and lifestyle factors,

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including type 2 diabetes mellitus (T2D), hypertension, and smoking. To further evaluate these associations, we first conducted LD score regression

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to evaluate the genetic correlation of ED with a range of traits. LD score regression identified ED to share the greatest genetic correlation with T2D, limb fat mass, and whole-body fat mass (FDR-adjusted p values < 0.05; Table S11).

Next we performed Mendelian randomization

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(MR) analyses to evaluate the potential causal role of nine pre-defined cardiometabolic traits on ED risk (selected based on previous observational evidence linking such traits to ED risk

²¹

), i.e., T2D, insulin resistance, systolic blood pressure, LDL cholesterol, smoking heaviness, alcohol consumption, body mass index, coronary heart disease, and educational attainment (Tables S12–S15). MR identified genetic risk to T2D to be causally implicated in ED: each 1-log higher genetic risk of T2D was found to increase risk of ED with an OR of 1.11 (95% CI 1.05–1.17, p = 3.5 × 10⁻⁴, which met our a priori Bonferroni-corrected significance threshold of 0.0056 [0.05/9]), with insulin resistance likely representing a mediating pathway

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(OR 1.36 per 1 standard deviation genetically elevated insulin resistance, 95% CI 1.01–1.84, p = 0.042). Sensitivity analyses were conducted to evaluate the robustness of the T2D-ED estimate (Figure S5, Table S13), including weighted median analyses (OR 1.12, 95% CI 1.02–1.23, p = 0.0230), leave-one-out analysis for all variants (which indicated that no single SNP in the instrument unduly influenced the overall value derived from the summary IVW estimate

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), and a funnel plot (showing a symmetrical distribution of single-SNP IV estimates around the summary IVW causal estimate). The MR-Egger regression (intercept p = 0.35) provided no evidence to support the presence of directional pleiotropy as a potential source of confounding.

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We also identified a potential causal effect of systolic blood pressure (SBP), with higher SBP being linked to higher risk of ED (MR-Egger OR 2.34 per 1 standard deviation higher SBP, 95% CI 1.26–4.36, p = 0.007, with MR-Egger intercept [p = 0.007] suggesting presence of directional pleiotropy). LDL cholesterol (LDL-C) showed minimal evidence of a causal effect (OR 1.07 per 1 standard deviation higher LDL-C, 95% CI 0.98–1.17, p = 0.113), and there was limited evidence to support a role for smoking heaviness or alcohol consumption (Table S15). Genetic risk of coronary heart disease (CHD) showed weak effects on risk of ED, suggesting that pathways leading to CHD may be implicated in ED (OR 1.08, 95% CI 1.00–1.17, p = 0.061). Further, we identified no causal effects of BMI (using a polygenic score or a single SNP in FTO) or education on risk of ED.

Genetic variants may inform drug target validation by serving as a proxy for drug target modulation.

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ED is most commonly treated using phosphodiesterase 5 (PDE5) inhibitors such as sildenafil. To identify potential phenotypic effects of PDE5 inhibition (e.g., to predict side effects or opportunities for repurposing), we looked for variants in or around PDE5A, encoding PDE5, which showed association with the ED phenotype. Of all 4,670 variants within a 1 Mb window of PDE5A (chromosome 4:119,915,550–121,050,146 as per GRCh37/hg19), the variant with the strongest association was rs115571325, 26 kb upstream of PDE5A (OR_Meta 1.25, nominal p value = 8.46 × 10⁻⁴; Bonferroni-corrected threshold [0.05/4,670] = 1.07 × 10⁻⁵; Figure S6). Given the weak association with ED, we did not evaluate this variant in further detail.

We have gained insight into ED, a common condition with substantial morbidity, by conducting a large-scale GWAS and performing several follow-up analyses. By aggregating data from 3 cohorts, including 6,175 ED-affected case subjects of European ancestry, we identified a locus associated with ED, with several lines of evidence suggesting SIM1, highly expressed in the hypothalamus, to be the causal gene at this locus. Our findings provide human genetic evidence in support of the key role of the hypothalamus in regulating male sexual function.

Mendelian randomization implicated risk of T2D as a causal risk factor for ED with suggestive evidence for insulin resistance and systolic blood pressure, corroborating well-recognized observational associations with these cardiometabolic traits.

Further research is needed to explore the extent to which drugs used in the treatment of T2D might be repurposed for the treatment of ED. Lack of evidence for a causal effect of BMI on ED risk in MR analysis (using multiple SNPs across the genome) suggests that the association of the lead SNP (rs57989773) with BMI arises from pleiotropy and that the association of this variant with ED risk is independent of its association with adiposity.

In conclusion, in a large-scale GWAS of more than 6,000 ED-affected case subjects, we provide insights into the biological underpinnings of ED and have elucidated causal effects of various risk factors, including pathways involved in the etiology of T2D. Further large-scale GWASs of ED are needed in order to provide additional clarity on its genetic architecture and etiology and to shed light on potential new therapies.

Source:www.cell.com

Type 2 Diabetes Could Be a Cause of Erectile Dysfunction

Posted by zedie

Type 2 diabetes may be a causal factor in the development of erectile dysfunction (ED), with insulin resistance a likely mediating pathway, results of a large-scale genomic analysis suggest. The data also uncovered a genetic locus linked to ED.

Jonas Bovijn, MD, DPhil, Big Data Institute at the University of Oxford, United Kingdom, and colleagues gathered data on more than 220,000 men across three cohorts, of whom more than 6000 had ED.

The researchers initially showed that a region on chromosome 6 is linked to the development of ED. The location suggested that the condition is associated with dysregulation of the hypothalamus.

Next, they performed a Mendelian randomization analysis, which examined the relationship between gene mutations known to be associated, in this case, with cardiometabolic factors and the outcome of ED.

The research, published online December 20 in the American Journal of Human Genetics, showed that a genetic predisposition to type 2 diabetes increased the risk for ED. The risk was driven primarily by susceptibility to insulin resistance.

Bovijn said in a release: “We know that there is observational evidence linking erectile dysfunction and type 2 diabetes, but until now there has not been definitive evidence to show that predisposition to type 2 diabetes causes erectile dysfunction.”

“Further research is needed to explore the extent to which drugs used in the treatment of type 2 diabetes might be repurposed for the treatment of ED,” the team notes.

Co–senior author Anna Murray, PhD, University of Exeter Medical School, United Kingdom, said in the release that “until now little has been known” about the cause of ED.

Previous studies have suggested there is a genetic basis for ED. The new study goes further by demonstrating that a genetic predisposition to type 2 diabetes is linked to ED, according to Murray.

“That may mean that if people can reduce their risk of diabetes through healthier lifestyles, they may also avoid developing erectile dysfunction,” she said.

Michael Holmes, MD, PhD, of the Nuffield Department of Population Health at the University of Oxford, who was one of the senior authors, agreed.

“Our finding is important, as diabetes is preventable, and indeed one can now achieve ‘remission’ from diabetes with weight loss, as illustrated in recent clinical trials.

“This goes beyond finding a genetic link to erectile dysfunction to a message that is of widespread relevance to the general public, especially considering the burgeoning prevalence of diabetes,” Holmes said.

Large Studies Key

Although the prevalence of ED is known to increase with age, rising to 20% to 40% among men aged 60 to 69 years, the genetic architecture of the condition remains poorly understood. This is at least in part due to a lack of well-powered studies.

The researchers therefore conducted a genome-wide association study (GWAS) using data on 199,362 individuals from the UK Biobank cohort and 16,787 people from the Estonian Genome Center of the University of Tartu (EGCUT) cohort, both of which are population based.

In addition, they included information on 7666 participants in the hospital-recruited Partners HealthCare Biobank (PHB) cohort.

The prevalence of ED, which was determined on the basis of self- or physician-reported ED, the use of oral ED medication, or a history of ED surgical intervention, was 1.53% in the UK Biobank, 7.04% in EGCUT, and 25.35% in PHB.

The researchers believe that the difference in prevalence rates between the cohorts may relate to the older average age for men in PHB, at 65 years, vs 59 years in the UK Biobank and 42 in EGCUT. In addition, the prevalence in the UK Biobank cohort may have been affected by a “healthy volunteer” selection bias and a lack of primary care data.

GWAS on the UK Biobank data indicated that there was a single genome-wide significant locus at 6q16.3 between the MCHR2 and SIM1 genes, with rs57989773 the lead variant.

Pooled meta-analysis of the combined cohorts indicated that rs57989773 was associated with ED at an odds ratio of 1.20 per C-allele (P = 5.71 × 10^-14).

Synthesizing previous research on SIM1, which is highly expressed in the hypothalamus, in both human and rodent models, the team found that rs57989773 is associated with syncope, orthostatic hypotension, and urinary incontinence.

Moreover, the common risk variant for ED at 6q16.3 is linked to blood pressure and adiposity, as well as male sexual behavior in mice.

The researchers, therefore, suggest that a potential mechanism for the effect of the MCHR2-SIM1 locus on ED could be the hypothalamic dysregulation of SIM1.

The team also performed Mendelian randomization analyses to examine the potential causal role of cardiometabolic traits in ED risk.

Factors included type 2 diabetes, insulin resistance, systolic blood pressure (SBP), low-density lipoprotein (LDL) cholesterol levels, smoking heaviness, alcohol consumption, body mass index, coronary heart disease, and educational attainment.

The analysis revealed that type 2 diabetes was causally implicated in ED, with the risk for ED increased 1.11-fold with each 1-log higher genetic risk for type 2 diabetes (P = 3.5 × 10^-4).

Insulin resistance was found to be a likely mediating pathway for the relationship, with an odds ratio for ED of 1.36 per 1 SD genetic increase in insulin resistance (P = .042).

SBP also had a causal effect on ED risk, at an odds ratio of 2.34 per 1 SD increase in SBP (P = .007).

LDL cholesterol was found to have a minor impact on the risk for ED, at an odds ratio of 1.07 per 1 SD increase in levels (P = .113). There was no association between ED and either smoking heaviness or alcohol use.

Source:Medscape.com