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?Do SNPs keep you down? The genetic etiology of ED
By martinmacinnis, Section Biology Posted on Thu Apr 29th, 2010 at 04:20:12 PM PST

Background Erectile dysfunction (ED) is a medical condition affecting many men throughout the world. Many lifestyle factors contribute to the risk of ED (e.g. alcohol, drugs, obesity), but there seems to be a genetic component as well [1]. ED is also linked to cardiovascular morbidities (e.g. coronary heart disease, hypertension), and these co-morbidities of ED have genetic etiologies [2]. Without going into too many details, the process of having an erection involves neural and vascular pathways under the control of various chemical agents (e.g. dopamine, oxytocin, nitric oxide), and the final smooth muscle response is governed by a series of transmitter-generating enzymes, receptors, receptor-coupled proteins, and effector enzymes/proteins [1]. Thus there are many potential targets for genetic disturbance, and to date, variants of several SNPs have been associated with ED (e.g. angiotensin-converting enzyme (ACE), and nitric oxide synthase (eNOS)) [2]. Sildenafil (i.e. Viagra) is a phophodiesterase type 5 inhibitor, which blocks the degradation of cGMP in smooth muscles, allowing relaxation and erection (under the "right" conditions). While Viagra has been a successful drug, some individuals do not respond to it, and effectiveness varies with genotype [2].

Proposal
I propose to study the genetic etiology of ED using a genome wide association study (GWAS). Because of the large environmental effect, I think it would be best to look at early onset (e.g. 30s?) cases of primary ED. This is a more narrow phenotype and easier to assess through GWAS. Many subjects will be needed, but the high prevalence should allow for enough recruitment to ensure sufficient statistical power. The second component of this study would be a GWAS investigating the molecular basis of Viagra responders and non-responders. Each ED subject could be tested for Viagra response, and the group could be divided into responders and non-responders. As the rate of no response is lower, this may have to be a candidate gene approach (but hopefully there would be enough people for a GWAS, perhaps with a more liberal statistical threshold).
Outcomes
ED is linked to other morbidities, so understanding its genetic etiology is important. This study will shed light on the molecular basis of ED, as well as erectile function, and provide new targets for pharmaceutical and medical interventions. Importantly, Phizer's Viagra patent is set to expire in ~ 2 years, and identification of new drugs for ED and new drugs for Viagra non-responders would be a profitable venture.
References
1. Hedlund, P. (2003). Genes and erectile function. Curr. Opin. Urol, 13:397-403.
2. Eisenhardt, et al. (2008). Urologe, 47: 1579-1581.

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Do SNPs keep you down? The genetic etiology of ED | 4 comments (4 topical, 0 editorial)

[new] multistage approach (none / 0) (#1)
by KP on Thu Apr 29th, 2010 at 02:59:14 PM PST
(User Info)

This is an interesting proposal! Do you know the incidence of early onset ED? If its fairly low the candidate gene approach definitely seems like the way to go especially since we know where viagra acts. You could even use a pathway approach to identify potential genes involved.
You can even use a multistage approach where you have a discovery cohort of patients followed by a replication cohort within the study. This will give more time to find patients and also give you an idea if you can observe an association before genotyping a larger cohort. Then you can combine the results at the end.

[new] Re: multistage approach (none / 0) (#3)
by martinmacinnis on Thu Apr 29th, 2010 at 04:30:23 PM PST
(User Info)

I tried to find the incidence of early onset ED, but I couldn't get a number. I agree that the known pathways would facilitate a candidate gene-based approach, so that might be a good idea if numbers were low. I also like the multistage approach, as suggested by you and Hirschorn and Daly (2005, GWAS for common diseases and complex traits, Nature). I think dealing with multiple hypothesis testing restricts the effectiveness of GWAS for relatively rare conditions where it is difficult to find huge samples. But, the multistage approach is a much more cost effective method that also shows that the initial findings can be replicated. The advantage to the multistage GWAS compared to the candidate-gene approach is the unbiased sampling of most of the genome. This is important, as we probably don't know all of the genes involved in ED, but there may be a higher risk of false positives. Tough call - if I had the money, I'd go for the multistage GWAS I think... Great ideas, thanks for the comment!

[ Parent ]

[new] Viagra Pharmocokinetics (none / 0) (#2)
by kjs86 on Thu Apr 29th, 2010 at 04:19:51 PM PST
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Do you think the SNPs are affecting Viagra directly, ie: changing the conformation of the protein to make the interaction with the Viagra inhibitor less effective?

I think if that's the case you might only need to sequence the phosphodiesterase gene, or a few of the genes that produce proteins that interact with it.

On the other hand, sequencing more might find SNPs that change a protein that's connected indirectly to the phosphodiesterase, and that would be potentially more useful!

[new] Re: Viagra Pharmacokinetics (none / 0) (#4)
by martinmacinnis on Thu Apr 29th, 2010 at 04:53:57 PM PST
(User Info)

In the article I cited by Eisenhardt, the polymorphisms that affected Viagra response were in the ACE (converts angiotensin I to angiotensin II, a vasoconstrictor), eNOS (produces nitric oxide, a vasodilator), and GNB3 (involved in signal transduction) genes. There were no associated polymorphisms in the phosphodiesterase gene itself. This is probably because of a lack of investigation, as opposed to a lack of association. Looking at polymorphisms in the phosphodiesterase, which is inhibited by viagra, is a great idea, and I'm suprised it hasn't been done (I couldn't find anything in PubMed). As I said in my last post, this pathway lends itself well to a candidate gene approach (although, we can't assume we know all of the players in the pathway). With a limited budget, I would likely start with the genes for proteins directly involved in the regulation of blood flow, as you suggested. On a bit of a side note, the effect size of some of the investigated polymorphisms is quite large (for GNB3, only 50% of carriers of the 852C allele respond to Viagra, whereas >90% of TT genotypes responded). This opens up a huge market for pharmacogenomics and ED!

[ Parent ]

Do SNPs keep you down? The genetic etiology of ED | 4 comments (4 topical, 0 editorial)

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