[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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 β 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.
The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor β 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.
Journal of Medical Genetics 12/2011; 49(1):58-65. DOI:10.1136/jmedgenet-2011-100174 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian stimulation carries a risk of either low or excessive ovarian response. The aim was to develop prognostic models for identification of standard (ovulatory and normal basal FSH) patients’ risks of low and excessive response to conventional stimulation for IVF/intracytoplasmic sperm injection. Prospectively collected data on 276 first-cycle patients treated with 150 IU recombinant FSH (rFSH)/day in a long agonist protocol were analysed. Logistic regression analysis was applied to the outcome variables:low (seven or less follicles) and excessive (20 or more follicles) response. Variables were woman’s age, menstrual cycle length, weight or body mass index, ovarian volume, antral follicle count (AFC) and basal FSH. The predictive performance of the models was evaluated from the prediction error (Brier score, %) where zero corresponds to a perfect prediction. Model stability was assessed using 1000 bootstrap cross-validation steps. The best prognostic model to predict low response included AFC and age (Brier score 7.94) and the best model to predict excessive response included AFC and cycle length (Brier score 15.82). Charts were developed to identify risks of low and excessive ovarian response. They can be used for evidence-based risk assessment before ovarian stimulation and may assist clinicians in individual dosage of their patients.