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      Genetic variation in the SIM1 locus is associated with erectile dysfunction

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          Significance

          Erectile dysfunction is a common condition of men in middle and older ages. Twin studies suggest that about one-third of the risk is due to genetic factors, independent of other known erectile dysfunction risk factors. However, studies that have searched for specific genetic contributors have been limited due to small sample sizes, candidate gene approaches, and weak phenotyping. As a result, there are no confirmed genetic risk factors for erectile dysfunction. This study finds a specific genetic cause for 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.

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          Most cited references31

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          Erectile dysfunction.

          T F Lue (2000)
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            Ethnic disparities in diabetic complications in an insured population.

            Higher rates of microvascular complications have been reported for minorities. Disparate access to quality health care is a common explanation for ethnic disparities in diabetic complication rates in the US population. Examining an ethnically diverse population with uniform health care coverage may be useful. To assess ethnic disparities in the incidence of diabetic complications within a nonprofit prepaid health care organization. Longitudinal observational study conducted January 1, 1995, through December 31, 1998, at Kaiser Permanente Medical Care Program in northern California. A total of 62 432 diabetic patients, including Asians (12%), blacks (14%), Latinos (10%), and whites (64%). Incident myocardial infarction (MI), stroke, congestive heart failure (CHF), and nontraumatic lower extremity amputation (LEA), defined by primary hospitalization discharge diagnosis, procedures, or underlying cause of death; and end-stage renal disease (ESRD), defined as renal insufficiency requiring renal replacement therapy or transplantation for survival or by underlying cause of death. Patterns of ethnic differences were not consistent across complications and frequently persisted despite adjustment for a wide range of demographic, socioeconomic, behavioral, and clinical factors. Adjusted hazard ratios (relative to that of whites) were 0.56, 0.68, and 0.68 for blacks, Asians, and Latinos, respectively (P<.001), for MI; 0.76 and 0.72 for Asians and Latinos, respectively (P<.01), for stroke; 0.70 and 0.61 for Asians and Latinos, respectively (P<.01), for CHF; 0.40 for Asians (P<.001) for LEA; and 2.03, 1.85, and 1.46 for blacks, Asians, and Latinos, respectively (P<.01), for ESRD. There were no statistically significant black-white differences for stroke, CHF, or LEA and no Latino-white differences for LEA. This study confirms previous reports of elevated incidence of ESRD among ethnic minorities, despite uniform medical care coverage, and provides new evidence that rates of other complications are similar or lower relative to those of whites. The persistence of ethnic disparities after adjustment suggests a possible genetic origin, the contribution of unmeasured environmental factors, or a combination of these factors.
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              Incidence and Prevalence of Sexual Dysfunction in Women and Men: A Consensus Statement from the Fourth International Consultation on Sexual Medicine 2015.

              The incidence and prevalence of various sexual dysfunctions in women and men are important to understand to designate priorities for epidemiologic and clinical research.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                23 October 2018
                8 October 2018
                8 October 2018
                : 115
                : 43
                : 11018-11023
                Affiliations
                [1] aDivision of Research, Kaiser Permanente Northern California , Oakland, CA 94612;
                [2] bDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco , CA 94158;
                [3] cInstitute for Human Genetics, University of California, San Francisco , CA 94158;
                [4] dDivision of Medical Genetics, University of Washington School of Medicine , Seattle, WA 98195;
                [5] eDepartment of Epidemiology and Biostatistics, University of California, San Francisco , CA 94158;
                [6] fDepartment of Surgery (Urology), University of Utah School of Medicine , Salt Lake City, UT 84132;
                [7] gDeparment of Urology, University of Washington School of Medicine , Seattle, WA 98195
                Author notes
                1To whom correspondence may be addressed. Email: eric.jorgenson@ 123456kp.org or Stephen.vandeneeden@ 123456kp.org .

                Edited by Martin R. Pollak, Harvard Medical School, Beth Israel Deaconess Medical Center, Brookline, MA, and approved September 11, 2018 (received for review June 7, 2018)

                Author contributions: E.J., J.M.H., G.P.J., H.W., and S.K.V.D.E. designed research; E.J., N.M., T.J.H., X.Z., N.A., and S.K.V.D.E. performed research; M.R.P. and N.A. contributed new reagents/analytic tools; E.J., N.M., M.R.P., J.Y., J.S., T.J.H., K.K.T., X.Z., N.A., and S.K.V.D.E. analyzed data; and E.J., N.M., M.R.P., T.J.H., J.M.H., N.A., H.W., and S.K.V.D.E. wrote the paper.

                Author information
                http://orcid.org/0000-0002-5829-8191
                Article
                201809872
                10.1073/pnas.1809872115
                6205494
                30297428
                8e7ec826-3af6-417e-8d5d-c1c05c9fd04d
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 6
                Funding
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: R01 DK104764
                Award Recipient : Eric Jorgenson Award Recipient : Melody R Palmer Award Recipient : Jun Shan Award Recipient : James M Hotaling Award Recipient : Nadav Ahituv Award Recipient : Hunter Wessells Award Recipient : Stephen K Van Den Eeden
                Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
                Award ID: R01 EY027004
                Award Recipient : Eric Jorgenson
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: 1R01DK090382
                Award Recipient : Eric Jorgenson Award Recipient : Melody R Palmer Award Recipient : Jun Shan Award Recipient : James M Hotaling Award Recipient : Nadav Ahituv Award Recipient : Hunter Wessells Award Recipient : Stephen K Van Den Eeden
                Funded by: HHS | NIH | National Human Genome Research Institute (NHGRI) 100000051
                Award ID: 1UM1HG009408
                Award Recipient : Nadav Ahituv
                Funded by: HHS | NIH | National Institute of Mental Health (NIMH) 100000025
                Award ID: 1R01MH109907
                Award Recipient : Nadav Ahituv
                Funded by: HHS | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD) 100000055
                Award ID: 1P01HD084387
                Award Recipient : Nadav Ahituv
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100000050
                Award ID: 1R01HL138424
                Award Recipient : Nadav Ahituv
                Categories
                Biological Sciences
                Genetics
                From the Cover

                genome-wide association,erectile dysfunction,sim1,genetic,melanocortin

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