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A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation.

ABSTRACT: BACKGROUND: Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population. METHODS: To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men. RESULTS: Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor ? receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer. CONCLUSIONS: The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor ? signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels.

SUBMITTER: Dalgaard MD

PROVIDER: S-EPMC3284313 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation.

Dalgaard Marlene D MD Weinhold Nils N Edsgärd Daniel D Silver Jeremy D JD Pers Tune H TH Nielsen John E JE Jørgensen Niels N Juul Anders A Gerds Thomas A TA Giwercman Aleksander A Giwercman Yvonne L YL Cohn-Cedermark Gabriella G Virtanen Helena E HE Toppari Jorma J Daugaard Gedske G Jensen Thomas S TS Brunak Søren S Rajpert-De Meyts Ewa E Skakkebæk Niels E NE Leffers Henrik H Gupta Ramneek R

Journal of medical genetics 20111203 1

<h4>Background</h4>Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population.<h4>Methods</h4>To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide associ ...[more]

PMID: 22140272

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Project description:Importance:Diet may play a role in testicular function, but data on how adherence to different diet patterns influences human testicular function are scarce. Objective:To determine whether adherence to specific dietary patterns is associated with testicular function in young men. Design, Setting, and Participants:This cross-sectional study included 2935 young Danish men unselected regarding fertility status who were enrolled from April 1, 2008, through May 31, 2017. Data were analyzed from July 1, 2017, to January 30, 2019. Exposures:Dietary patterns identified with principal component analysis based on responses to a validated food frequency questionnaire. Main Outcomes and Measures:Standard semen quality assessment; serum concentrations of testosterone, free testosterone, estradiol, inhibin B, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin; and testicular volume measured with ultrasonography. Results:Among the 2935 participants included in the analysis, median age was 19 (interquartile range, 19-20) years and 2290 (78.0%) had normal body mass index. The 4 dietary patterns identified included Western, prudent, open-sandwich (a traditional Danish eating pattern), and vegetarianlike. The greatest adherence to the prudent pattern was associated with the highest total sperm count (median, 167 [95% CI, 146-183] million), followed by adherence to vegetarianlike (median, 151 [95% CI, 134-168] million) and open-sandwich (median, 146 [95% CI, 131-163] million) patterns. Adherence to the Western pattern was associated with the lowest total sperm count (median, 122 [95% CI, 109-138] million), which was significantly lower than sperm count in the other 3 diet patterns. After adjusting for confounders, the median total sperm count for men in the highest quintile of adherence to the Western pattern was 26 million lower (95% CI, -42 to -9 million) than for men in the lowest quintile of adherence to this pattern. Conversely, the median total sperm count of men in the highest quintile of adherence to the prudent pattern was 43 million (95% CI, 23-63 million) higher than that of men in the lowest quintile. Men with the highest adherence to the Western pattern had a lower median ratio of inhibin B to follicle-stimulating hormone (-12 [95% CI, -20 to -3]) and higher median ratio of free testosterone to luteinizing hormone (10 [95% CI, 2-19]) compared with men with lowest adherence to this pattern. Conclusions and Relevance:In this cross-sectional study, adherence to generally healthy diet patterns was associated with better semen quality, with potentially more favorable fertility potential among adult men.

Dataset Information

A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation.

Publications

A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation.

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