Dataset Information

Genetic variation in the SIM1 locus is associated with erectile dysfunction.

ABSTRACT: Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.

SUBMITTER: Jorgenson E

PROVIDER: S-EPMC6205494 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Genetic variation in the <i>SIM1</i> locus is associated with erectile dysfunction.

Jorgenson Eric E Matharu Navneet N Palmer Melody R MR Yin Jie J Shan Jun J Hoffmann Thomas J TJ Thai Khanh K KK Zhou Xujia X Hotaling James M JM Jarvik Gail P GP Ahituv Nadav N Wessells Hunter H Van Den Eeden Stephen K SK

Proceedings of the National Academy of Sciences of the United States of America 20181008 43

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the disc ...[more]

PMID: 30297428

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Project description:BackgroundThe causal relationship between certain lifestyle factors and erectile dysfunction (ED) is still uncertain.AimThe study sought to investigate the causal effect of 9 life factors on ED through 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR).MethodsGenetic instruments to proxy 9 risk factors were identified by genome-wide association studies. The genome-wide association studies estimated the connection of these genetic variants with ED risk (n = 223 805). We conducted SVMR, inverse variance-weighting, Cochran's Q, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MVMR analyses to explore the total and direct relationship between life factors and ED.OutcomesThe primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED.ResultsIn SVMR analyses, suggestive associations with increased the risk of ED were noted for ever smoked (odds ratio [OR], 5.894; 95% confidence interval [CI], 0.469 to 3.079; P = .008), alcohol consumption (OR, 1.495; 95% CI, 0.044 to 0.760; P = .028) and body mass index (BMI) (OR, 1.177; 95% CI, 0.057 to 0.268; P = .003). Earlier age at first intercourse was significantly related to reduced ED risk (OR, 0.659; 95% CI, -0.592 to -0.244; P = 2.5 × 10-6). No strong evidence was found for the effect of coffee intake, time spent driving, physical activity, and leisure sedentary behaviors on the incidence of ED (All P > .05). The result of MVMR analysis for BMI (OR, 1.13; 95% CI, 1.01 to 1.25; P = .045) and earlier age at first intercourse (OR, 0.77; 95% CI, 0.56 to 0.99; P = .018) provided suggestive evidence for the direct impact on ED, while no causal factor was detected for alcoholic drinks per week and ever smoked.Clinical implicationsThis study provides evidence for the impact of certain modifiable lifestyle factors on the development of ED.Strengths and limitationsWe performed both SVMR and MVMR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry.ConclusionEver smoked, alcoholic drinks per week, BMI, and age first had sexual intercourse were causally related to ED, while the potential connection between coffee intake, physical activity, recreational sedentary habits, and increased risk of ED needs to be further confirmed.

Project description:Protein expression profiles in rat corporal smooth muscle tissue were compared between animal models of streptozotocin-induced diabetes mellitus (STZ-DM) and age-matched controls (AMCs) at 1 week and 2 months after induction of hyperglycemia with STZ treatment. At each time point, protein samples from four STZ-DM and four AMC rat corpora tissues were prepared independently and analyzed together across multiple quantitative two-dimensional gels using a pooled internal standard sample to quantify expression changes with statistical confidence. A total of 170 spots were differential expressed among the four experimental groups. A subsequent mass spectrometry analysis of the 170 spots identified a total of 57 unique proteins. Network analysis of these proteins using MetaCore suggested altered activity of transcriptional factors that are of too low abundance to be detected by the two-dimensional gel method. The proteins that were down-regulated with diabetes include isoforms of collagen that are precursors to fibril-forming collagen type 1; Hsp47, which assists and mediates the proper folding of procollagen; and several proteins whose abundance is controlled by sex hormones (e.g. CRP1 and A2U). On the other hand, proteins seen or predicted to be up-regulated include proteins involved in cell apoptosis (e.g. p53, 14-3-3-gamma, Serpinf1, Cct4, Cct5, and Sepina3n), proteins that neutralize the biological activity of nerve growth factor (e.g. anti-NGF 30), and proteins involved in lipid metabolism (e.g. apoA-I and apoA-IV). Subsequent Western blot validation analysis of p53, 14-3-3-gamma, and Hsp47 confirmed increased p53 and 14-3-3-gamma and decreased Hsp47 levels in separate samples. According to the results from the Western blot analysis, Hsp47 protein showed a approximately 3-fold decrease at 1 week and was virtually undetectable at 2 months in diabetic versus control. Taken together, our results identify novel candidate proteins playing a role in erectile dysfunction in diabetes resulting from STZ treatment.

Dataset Information

Genetic variation in the SIM1 locus is associated with erectile dysfunction.

Publications

Genetic variation in the <i>SIM1</i> locus is associated with erectile dysfunction.

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