Type 2 Diabetes Could Be a Cause of Erectile Dysfunction

Liam Davenport

December 26, 2018

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.

The study was supported by the UK Biobank, Partners HealthCare Biobank, the Estonian Biobank of the Estonian Genome Center of the University of Tartu, and their participants. EGCUT received funding from the European Commission Horizon 2020 research and innovation program. Dr Holmes has collaborated with Boehringer Ingelheim in research. In accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), he did not accept any personal payment. Relevant financial relationships of other authors are listed in the original article.

Am J Hum Genet. Published online December 20, 2018. Full text

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