Genetics of Erectile Dysfunction

Natalya A. Lopushnyan and Kanchan Chitaley*From the Department of Urology, University of Washington, Seattle, Washington

Purpose: Erectile dysfunction affects 50% of men older than 40 years. Recentlymore attempts have been made to identify genetic predictors of this disease. Wereviewed animal and human data on genes related to the development andincreased risk of erectile dysfunction.Materials and Methods: A literature search was performed using the PubMed®database. Articles addressing genes involved in erectile dysfunction were evalu-ated.Results: The majority of studies used a candidate gene approach to investi-gate genetic polymorphisms of known pathways mediating erection/detumes-cence. Studies in human and animal models are available. Human studiesoften compared the frequency of a specifically predetermined genetic polymor-phism in men with erectile dysfunction to that in matched controls in whomfew genes were persistently replicated. Several gene expression profilingstudies are available that targeted specific erectile dysfunction models. Cur-rently, there are few human genome wide association studies of erectiledysfunction.Conclusions: Studies investigating the genetics of erectile dysfunction aremostly derived from animal models and candidate gene approaches. Candidategene studies omit the greater portion of the genome, a problem that can be solvedusing a genome wide association study approach. The lack of persistently repli-cated results of candidate gene studies may be related to different patient ethnicbackgrounds, variations in erectile dysfunction etiology and small sample sizes.Using strict inclusion/exclusion criteria for erectile dysfunction etiology andethnicity in human studies may lead to improved understanding of the geneticsof erectile dysfunction in specific populations.

Abbreviations

and Acronyms

ACE � angiotensin convertingenzyme

Ang � angiotensin

CSMC � cavernous smoothmuscle cell

D � deletion

ED � erectile dysfunction

eNOS � endothelial NOS

GWAS � genome wideassociation study

Hcy � homocysteine

I � insertion

IGF � insulin-like growth factor

IGFBP � IGF binding protein

NO � nitric oxide

NOS � NO synthase

PDE5i � phosphodiesterase 5inhibitor

PR � progesterone receptor

SHR � sex hormone receptor

SMR � submandibular rat gene 1

SNP � single nucleotide

Key Words: penis, erectile dysfunction, genetics, genome, ethnology

5456; FAX: 206-897-5442; e-mail: kanchanc@uw.edu).

1676 www.jurology.com

ACCORDING to the MassachusettsMale Aging study, more than 50% ofmales 40 years old or older will haveED of various severities.1 The prev-alence of complete impotence triplesin men between ages 40 and 70years, affecting multiple domains ofquality of life of patients and theirpartners. While ED is more commonin the aging population, patientswith metabolic syndrome, diabetes,hypertension and obesity are also at

increased risk.2

0022-5347/12/1885-1676/0THE JOURNAL OF UROLOGY®

© 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES

Improved understanding of penileerection and detumescence has pro-vided us with the mainstay of EDpharmaceutical therapy, PDE5is. Theseagents, initially introduced in the mid1990s, enhance NO induced signalingand are generally the first line treat-ment for ED. Other common treat-ments, such as intracavernous injec-tions of prostaglandin or �-adrenergicantagonists, induce CSMC relaxation.While these pharmaceuticals improve

polymorphism

VEGF � vascular endothelialgrowth factor

VNTR � variable number tandemrepeat

vsca1 � variable codingsequence protein A1

* Correspondence: 815 Mercer St, Box 358050,Seattle, Washington 98109 (telephone: 206-897-

erection in some men, they do not

http://dx.doi.org/10.1016/j.juro.2012.07.008Vol. 188, 1676-1683, November 2012

EARCH, INC. Printed in U.S.A.

GENETICS OF ERECTILE DYSFUNCTION 1677

cure the underlying problem and men must oftencontinue medication, usually increasing the dosewith time.

Recently, effort has been directed toward identi-fying the genetic origin of impotence. InvestigatingED in twins suggested a heritability component of atleast 35%.2 To date most studies have focused on theNOS pathway and proteins composing ion channels.The first human trial of gene therapy was performedto attempt to increase the expression of ion channelsin penile smooth muscle.3 This therapy represents afirst attempt at curing the disease by modifyinggenetic material, rather than improving symptoms.

The role of genes in ED presentation and severityis not completely understood. Most groups have useda candidate gene approach, identifying genetic poly-morphisms in a pathway known to be involved inpenile erection. Several groups have looked at geneexpression in specific ED models. Significantly fewergroups have investigated novel gene polymorphismsor compared whole genomes of patients with ED tothose of matched controls. The primary goal of thisreview was to discuss findings relating to the geneticbasis of ED and establish possible directions forfuture research in this area.

MATERIALS AND METHODS

In July 2011 a PubMed database search was performed forarticles published between 1970 and the present. Theterms used were “genes,” “erectile dysfunction,” “GWAS,”

Table 1. Genetic polymorphisms previously investigated in ED

References Polymorphism, Allele

eNOS:Erol et al5 7G894T, 4VNTRLee et al6 7G894TSinici et al4 T-786CAndersen et al7 7G894TErkan et al9 4VNTRRosas-Vargas et al12 7G894TSafarinejad et al16 T786C, 7G894TSerrano et al10 T786C, 7G894TPark et al15 4VNTR

Slo (Davies et al17) SVcytVcsa1 (Tong et al34) Not applicableACE:

Park et al15 II, DI, DDMazo et al23 II, DI, DDAndersen et al25 II, DI, DDEisenhardt et al13 II, DI, DD

PR (Andersen et al28) PROGINSAndrogen receptor (Andersen et al29) CAG repeatHcy (Safarinejad et al30) C677T, A1298CIGFBP-3: Not applicable

Pu et al45

Soh et al46

Transforming growth factor-�1 (Peters et al42) Various

* Most studies were done in specific animal model or in cohort of men of specific ethni

“genetic polymorphism,” “microarray,” “impotence” andcombinations. The search primarily focused on originalarticles.

CANDIDATE GENE STUDIES

In 1975 one of the first studies was published todemonstrate that many proteins have various heri-table isoforms, showing that common genetic varia-tions could lead to a change in protein structure andbiological function. These genetic polymorphismscan be tested for their association with a disease bydetermining the genotype of these variants in af-fected individuals vs those without the disease. If agenotype of interest is present at a higher frequencyin cases, it is taken as evidence that the variation isassociated with an increased risk of the disease.

The majority of studies published in the field ofED genetics are candidate gene studies that take theapproach from known to unknown and allow for afocus on a particular gene with a known pathologicalinvolvement in the disease (table 1).

Nitric Oxide Synthase

One of the better studied candidate genes in thepenile smooth muscle relaxation pathway is eNOS.To date 3 forms of NOS, originally labeled after theirlocation, have been recognized, including neuronalNOS, eNOS and inducible NOS. It was hypothesizedthat rapid activation of neuronal NOS initiates theerectile process, whereas phosphorylation and acti-vation of eNOS lead to sustained erection.4 The en-

pment

Variant Rat Model* Ethnic Group*

Not applicable TurkishNot applicable TaiwaneseNot applicable TurkishNot applicable BrazilianNot applicable TurkishNot applicable Mexican MestizoNot applicable IranianNot applicable ColombianNot applicable KoreanDiabetic Not applicableDiabetic, aging � neurogenic Not applicable

Not applicable KoreanNot applicable RussianNot applicable BrazilianNot applicable GermanNot applicable BrazilianNot applicable BrazilianNot applicable Iranian

Not applicableAgingDiabeticNot applicable Various

develo

, Splice

, 4a/4b, 4VNTR

, G1793A

city.

GENETICS OF ERECTILE DYSFUNCTION1678

dothelial and neuronal forms of the NOS enzyme areencoded by different genes with eNOS mapped tochromosome 7q35 and consisting of 26 exons span-ning 21 kb of DNA.

Several polymorphisms of eNOS have been inves-tigated. More frequently, investigated regions of thisgene include a variable number of 27 bp tandemrepeats in intron 4 (4VNTR), G894T (rs1799983)polymorphism in exon 7 and a T-786C (rs2070744)polymorphism in the promoter region.4–7 The eNOSgene has 2 common alleles containing 4 VNTRs (al-lele a) and 5 VNTRs (allele b), which make 3 possiblegenotypes (aa, ab and bb). The biological function ofthe 4a/4b polymorphism is controversial. In the pastit was associated with decreased eNOS concentra-tion and activity, although no decrease in plasmaNO levels was reported.8 Also, eNOS aa, ab and bbgenotypes have a similar distribution in patientswith ED and controls.9 The eNOS G894T polymor-phism, which corresponds to a substitution of gluta-mate by aspartate at amino acid position 298, re-sults in the disturbance of eNOS activity and NOproduction.7 The T-786C region results in a signifi-cant decrease in eNOS gene promoter activity.10

Human studies correlating these polymorphismswith ED prevalence are controversial. A limitation isthat most available studies were performed in smallgroups of patients of various ethnic backgrounds.While the 7G894T polymorphism was noted to be anindependent factor for ED in Mexican, Turkish andTaiwanese populations,5,6,11,12 findings do not sup-port a role of this polymorphism in the Brazilian orGerman population.7,13 A recent meta-analysis byWang et al showed a significant association of EDand the G894T polymorphism (generalized OR 1.64,95% CI 1.30–2.61) but failed to demonstrate thesame correlation with 4VNTR (OR 0.96).14 4VNTR(allele a) and the distribution of eNOS genotypes inED was first investigated in the Korean populationin 1999 by Park et al.15 They found no significantdifference in the distribution in the ED group com-pared to controls. Consistently, 4VNTR has not pre-disposed men to ED in a Turkish or Iranian popu-lation.5,16 T-789C is an independent predisposingfactor for ED in Iranian and Turkish men.4,16 How-ever, data supporting its role in other populationsare lacking.

eNOS polymorphisms occur at different frequen-cies among various ethnic groups.10 This differencein distribution could contribute to the lack of wellreplicated results across patient populations of dif-ferent ethnicities. In the future it could potentiallybe improved by comparing the distribution of eNOSpolymorphisms in larger cohorts of patients with ED

vs controls across various ethnic backgrounds.

Ion Channels

Penile erection and detumescence are partly a func-tion of the smooth muscle cells of the cavernosumand arterial wall, which are regulated by changes infree cytosolic calcium. Ca2� channels can be regu-lated by currents generated through K� channels.17

These channels allow K� to flow down its gradientand out of the smooth muscle cell. The hyperpolar-ization that occurs limits intracellular Ca2� entryand results in smooth muscle relaxation.

The Maxi-K or BK channel (large performance,calcium sensitive K channel) is the most studied ionchannel in the field of ED genetics and physiologythat was previously shown to have a role in penileerection.18 However, there are limited data on in-trinsic expression of the Maxi-K gene or its variantsin men with ED. The pore forming subunit of thischannel is encoded by the slo gene. In slo knockoutmice cavernous tissue relaxation was decreased by50% and intracavernous pressure was attenuated inresponse to nerve stimulation.18 The slo gene isknown to undergo alternative splicing triggered byvarious stimuli, including hormones, leading to sev-eral different isoforms.19 In streptozotocin induceddiabetic animals alternative splicing led to up-regu-lation of the SV0 channel forming transcript com-pared to controls. Also, a higher proportion of SV0was reported in men with vs without diabetes, sug-gesting that alternative splicing of the slo gene mayhave a role in diabetic ED.17

Angiotensin Converting Enzyme I/D

The presence of ACE, Ang II and Ang II receptor inthe corpora cavernosa has been confirmed. The cor-pus cavernosum produces physiologically relevantamounts of Ang II and tissues with higher Ang IIlevels appear to have a decreased response to papav-erine and prostaglandin E-1.20 Increased Ang II incavernous blood was noted during penile detumes-cence vs rigidity and in patients with organogenicED vs controls.20 ACE, which converts Ang I intoAng II, is encoded by the ACE gene containing apolymorphism based on the presence (I) or absence(D) in an intron of a 287 bp nonsense DNA domain(rs4646994). This results in 3 possible genotypes,including DD, DI or II.15 An ACE polymorphismaccounts for 47% of the total phenotypic variance ofserum ACE levels with a higher concentration in theII genotype.21 Identification of homologous sequences ingene ontology annotated databases suggested thatthe DD genotype lacks molecular and biologicalfunction.22

One of the first studies of ACE polymorphismsrelated to ED was reported by Park et al.15 Theyexamined the relationship between gene polymor-phism and organic ED. In the ED group the propor-

tion of the DD genotype was significantly higher

GENETICS OF ERECTILE DYSFUNCTION 1679

than in controls (54% vs 24%, p �0.01). Consistentfindings were published in Russian men with meta-bolic syndrome, with a higher frequency of the Dallele and the DD genotype in the ED group vscontrols (81.3% vs 63.8%, p �0.001, and 68.3% vs38.2%, respectively).23 The opposite was seen in theBrazilian population with increased frequency of theI allele in individuals complaining of ED.21 In astudy of German patients with ED compared withcontrols there was no difference in the ACE I/Dgenotype.13 However, that study included patientswith ED attributable to various causes, includingvascular, neurogenic, psychogenic, hormonal andmixed etiologies, as well as 11% of men for whom nospecific ED etiology could be identified. A lack ofassociation was also noted between ACE genotypesin the Korean population.24

It is possible that the lack of consistent replica-tion in the reports outlined is due to the study ofdiverse ethnic backgrounds, ED etiologies and co-morbidities. Potentially, a larger sample size of pa-tients with a single ED etiology would shed morelight on the genetic correlation of polymorphismsand the predisposition to ED.

Hormone Receptors

Sex hormones have various effects on sexual func-tion, including NOS activity, erectile frequency andthe sexual behavior of male rodents.25,26 However,data are limited on possible genetic variations in sexhormone and SHR genes. Genetic expression of an-drogen, progesterone and estrogen receptor � de-creases dramatically in the penile crura of agingrats, suggesting that SHR may have a role in agerelated ED.26

However, no difference in SHR polymorphismswas found in 2 population based reports. In the firstreport a PROGINS polymorphism of the PR genewas investigated.27 It consists of a 306 bp Alu inser-tion in intron G, a silent point mutation in exon 5and a change at position 660 from valine to leucine(V660L) (rs1042838). In the past the PROGINS vari-ant has been associated with a decreased responseto progesterone due to reduced protein activity. De-creased PR activity could potentially alter erectilefunction. However, in the report by Andersen et althere was no difference in the frequency of PROGINS inan ED vs a nonED group.28 The limitation of thereport was that only 1.2% of subjects were homozy-gous for Alu insertion, possibly making the samplesize inadequate to detect a difference.

Another study of the CAG repeat sequence of theandrogen receptor gene was reported by Andersen etal.29 Longer CAG sequences were associated withdecreased transcriptional activity, presumably cor-relating with relatively reduced androgen feedback.

However, there was no association with increased

ED complaints. While sex hormones certainly havean important role in sexual function, currently thereis a lack of evidence that genetic polymorphisms ofSHR predispose to ED development.

Hcy Metabolism

Genes involved in the Hcy pathway have been in-vestigated in relation to ED. The methylenetetrahy-drofolate reductase gene, located on chromosome 1,is a key enzyme in folic acid metabolism. Threepolymorphisms of this gene are known, includingC677T (rs1801133), A1298C (rs1801131) and G1793A(rs2274976), which result in decreased enzyme ac-tivity and increased Hcy levels.30 An increase in Hcyis linked to impaired endothelial dysfunction andvascular disease. Recently it was reported that pa-tients with early onset vasculogenic ED had higherlevels of serum Hcy and a higher prevalence ofC677T polymorphism compared to controls (15.8%vs 22.4%, p � 0.01).30 Additionally, patients ho-mozygous for the C677T allele have a decreasedresponse to PDE5i alone but improve with combi-nation treatment of PDE5i, folate and vitamin B6.31

GENE EXPRESSION PROFILING

While the candidate gene approach provides thebenefit of knowing the function of the investigatedgene, it is unlikely to detect variation in gene ex-pression. For that purpose gene expression profilingbecomes useful. It is an effective tool for character-izing gene expression among various ED models andin ED vs healthy controls. Although they do notnecessarily directly relate to genetic heritability,methods of gene expression profiling allow us toacquire quantitative data on the level of activity ofmultiple genes. The majority of all reports availableare derived from rodents.

One of the first groups reported altered expres-sion of 126 genes in the neurogenic impotencemodel. One of the down-regulated genes was SMR1,a member of the opiorphin family, which is ex-pressed at a significantly higher level in male thanin female rats. Later, it was also suggested as an EDmarker in candidate studies.32 In humans othergenes from the same family, ProL1, hSMR3A andhSMR3B, are significantly down-regulated in menwith ED with and without diabetes.33

The rat homologue of opiorphin, sialorphin, whichis encoded by the vsca1 gene, was suggested as anED marker in diabetic, neurogenic and aging animalmodels.34 Its product is a neutral endopeptidase in-hibitor, which is a membrane bound peptidase thatdecreases peptide agonist action by removing themfrom membrane receptors. Substantial vsca1 up-reg-ulation was noted following intracorporeal injection

of the Slo gene containing vector, a pore forming

GENETICS OF ERECTILE DYSFUNCTION1680

subunit of the BK channel.32 It was hypothesizedthat Vcsa1 may improve CSMC relaxation by neu-tral endopeptidase inhibition, thus, prolonging pep-tide agonist action at the receptors.35

Using microarray technology in diabetic rats, 529genes were identified with differential expression.36

That group took the study 1 step further and identifiedgenes that were previously reported to mediate vascu-lar dysfunction. One of these genes, ceruloplasmin,and its 2 splice variants were up-regulated in diabeticrat CSMCs and endothelium. Previous reports demon-strated that ceruloplasmin impairs aortic relaxation,possibly altering NO bioavailability in the penis.37

Aberrant regulation of growth factors is often im-plicated in vasculogenic ED. Several penile growthfactors have been identified. Originally IGF-1 andVEGF were found to promote CSMC proliferation inrats.38 One of the first groups to report these growthfactors in human CSMCs was Rajasekaran et al.39

Using reverse transcriptase-polymerase chain reac-tion they identified 4 splice variants of VEGF mRNA,including VEGFs 121, 145, 165 and 189, withVEGFs 121 and 165 most abundant. In that study atwofold proliferation of CSMCs was seen with expo-sure to VEGF. In hypercholesterolemic rats with EDsignificantly lower VEGF gene expression and lowerlevels of phosphorylated eNOS were shown.40 Im-proved intracavernous pressure in diabetic animalstransfected with the VEGF gene was also observed.41

In humans specific polymorphisms of VEGF andtransforming growth factor-�1 are related to ED de-velopment following radiation therapy for prostatecancer.42

IGF and its receptors have varied expression inED. IGF-1 is a polypeptide structurally homologousto proinsulin that facilitates the regeneration ofNOS containing nerve fibers.43 After pudendal ar-tery ligation in rats, up-regulation of IGFBP-1, 3and 5, and down-regulation of IGFBP-6 was seen.44

In the same report the most highly induced geneafter pudendal artery ligation was apolipoprotein D.IGFBP-3 mRNA expression levels were increased inaging and diabetic rat models.45,46 It is possible thatincreased expression levels of IGFBP-3 decrease theavailability of IGF-1 in penile tissue, contributing toED in patients with diabetes. This is consistent withthe report that IGF-1 injection improved erectilefunction in aging animals.45 While to our knowledgeit is unknown whether there is a difference in VEGFor IGF-1 gene expression in nondiabetic, nonvascu-logenic ED, they could possibly provide the basis forfuture gene therapy in specific patient populations.

Gene expression profiling studies, including mi-croarray analysis, permits analysis of the gene net-work interactions to identify the most highly af-fected components. However, frequently they are

used to confirm involvement of a gene of interest or

as a starting point for candidate gene studies. Thismethod of analysis also does not account for alter-native gene splicing, a major mechanism for gener-ating protein diversity, or for the protein expressionlevel, which may not correlate with gene expressionin a direct manner. An adjunct solution may beproteomic analysis to look at the expression of theprotein rather than the gene. While those limita-tions exist, these studies can still provide additionalinformation to the field of ED genetics.

GENOME WIDE

ASSOCIATION STUDIES/SNP

Candidate gene studies target pathways known tocontribute to ED. However, they ignore most of thegenome and are likely to miss many causal regionsof genes or show many false-positive associations.Results of candidate gene studies are also not ofteneasily and consistently reproduced. Gene expressionstudies investigate variations in gene transcriptionfor a given condition but do not identify specificpolymorphisms.

GWASs improve on those shortcomings, allowingcomparison of common genetic variants over theentire genome in a large number of cases to those inunaffected controls. However, there are still only afew reports available (table 2). Kerns et al identifiedSNPs associated with ED development in blackAmerican men.47 In the 27 men who qualified foranalysis Kerns et al identified SNP rs2268363 assignificantly associated with ED after multiple com-parison correction (unadjusted p � 5.46 � 10�8,Bonferroni p � 0.028) and an additional 4 SNPs thattrended toward a significant association (unadjustedp �10�6). SNP rs2268363 is located on chromosome2 in the follicle stimulating hormone receptor, whichis involved in testis development and function. Al-terations in the follicle stimulating hormone signal-ing pathway lead to improper gonad development inmice, and to small testis size and infertility in hu-mans. Since to our knowledge this is the only reportimplicating SNP rs2268363 as possibly involved inED, a candidate gene study may be warranted.

Two more abstracts were recently presented bygroups that investigated ED genetics using a GWAS

Table 2. SNPs identified in GWASs in patients with ED

References SNP PopulationUnadjustedp Value*

Kerns et al47 rs2268363 Black American men 5.46 � 10�8

Hotaling et al48 rs9810233, rs1920201 Diabetes Cohort �Complications Trial

7 � 10�7,9 � 10�7

Hotaling et al49 SNP on chromosome 14 Adult Changes inThought

1.1 � 10�6

* Standard GWAS significance criteria considered at p �5 � 10�8.

GENETICS OF ERECTILE DYSFUNCTION 1681

approach. The first study specifically investigatedtype 1 diabetes related ED using the Diabetes Con-trol and Complications Trial cohort.48 Two SNPslocated on chromosome 3 near the activated leuko-cyte cell adhesion molecule gene were identified,approaching the standard GWAS significance crite-rion of p �5 � 10�8. Expression of activated leuko-cyte cell adhesion molecule, a member of the Igsuperfamily, was noted in various cultured humanendothelial cells and is also thought to have a role inthe inflammatory response. Another series includedmale patients with and without ED from the GroupHealth Adult Changes in Thought study.49 Afteradjustment for smoking, diabetes and hypertension,an SNP on chromosome 14 near the ADCK1 genewas identified to have the strongest association withED (p � 1.1E-06). ADCK1 is a highly conserved geneimplicated in coenzyme Q biosynthesis, a part of theelectron transport chain of the inner mitochondrialmembrane.

To our knowledge none of the mentioned findingsin human studies have been replicated to date. Al-though GWASs allow analysis of the entire genome,the identified SNPs mostly do not have an obviousassociation with ED, making the causal variantidentification challenging.50 The question then arises ofwhether the SNP identified represents an associa-tion as a proxy of a causal variant with a similarfrequency, or an association of the causal variant vialinkage disequilibrium. Linkage disequilibrium ispresent when some combination of alleles or geneticmarkers is present at a higher or lower frequency inthe population than would be expected based ontheir random combination frequency. Detectingsuch a synthetic association would require extensiveresequencing.50 While GWASs allow simultaneoustesting of thousands of SNPs, they raise a statisticalchallenge of accounting for multiple comparisons.Failure to do so results in decreased power, false-positive results and incorrect rejection of the nullhypothesis, also influencing the publication biasthat favors the dissemination of positive results. Inaddition to those statistical challenges, which arebeyond the scope of this report, GWASs require sam-ple sizes in the thousands to detect a modest asso-ciation. Achievement of this power is particularlychallenging while evaluating a multifactorial dis-ease such as ED in a population with a specificphenotype.

CONCLUSIONS

Multiple genetic variants potentially associatedwith ED have been found. Most of them are a prod-

uct of candidate gene studies stemming from the

pathophysiological basis of ED. Few results havebeen consistently replicated across various ED mod-els. Currently, the most commonly used ED modelsin the literature are vasculogenic, neurogenic andaging. What may work as a genetic marker in onemodel may not be applicable in another model.

Gene association studies have identified variousgene polymorphisms thought to be etiological con-tributors or genetic markers of ED. However, few ofthem have been successfully replicated across differ-ent populations, possibly due to variations in ethnicbackground, sample size, different study inclusioncriteria, confounding by the population substruc-ture, potential false-positive associations and under-powered, nonsignificant studies of real associations.ED is a complex disease and, like most diseases withcomplex traits, it likely results from the interactionof multiple genetic and environmental factors. Whilethe central goal of genetic ED research is to identifygenetic factors and their effect of ED development, itwould be most desirable to simultaneously considergene-gene and gene-environment interaction.

Gene expression profiling identifies variations inset ED models. However, it does not detect novelpolymorphisms or account for post-transcriptionalmodification. While it is currently a useful adjunct,it could potentially be supplemented further usingproteomic analysis.

The possible genetic associations that are over-looked by candidate gene studies could be investi-gated using a GWAS. However, currently only a fewreports are available that analyzed a limited num-ber of patients. To determine whether the result ofan association study represents a true associationwould require large sample sizes, an appropriatestatistical approach with correction for multiple hy-pothesis testing and replication of the results in aseparate but phenotypically close population.

The ultimate goal of the search for the geneticorigin or association of ED is the creation of bettertreatment and possibly cure. The search for geneticassociations of ED will likely lead to the discovery of2 groups of genes, including those that contribute tothe development of or protection from impotence andthose that are markers for it. Genes belonging to theformer group could lead to advances in treatmentand specifically tailored therapies based on the ge-netic makeup of the patient, such as local introduc-tion of a gene encoding for a specific enzyme or ionchannel. With the latter the prevention and identi-fication of ED before it is clinically evident and thedevelopment of preventive strategies will likely be

possible.

GENETICS OF ERECTILE DYSFUNCTION1682

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