Accumulating evidence from clinical studies suggest that renal diseases of different etiologies are more prevalent among men than age-matched women. Furthermore, non-diabetic chronic renal diseases progress more rapidly in men than women, independently of blood pressure. These observations suggest that genetic and/or hormonal male-specific factors may adversely affect renal function and structure in humans. However, a joint analysis of the relationships between the Y chromosome and androgens with respect to renal phenotypes has not been performed in men. Based on our preliminary and previously reported studies, we hypothesize that genetic variation within the human Y chromosome acting, at least in part, through modulation of circulating concentrations of androgens have detrimental effects on renal function and structure in men. 1. Using two well-phenotyped cohorts of Polish men, we will determine the association of polymorphisms in the non-recombining region of the Y chromosome (NRY) with androgen levels and renal function in humans (Specific Aim 1). Genotyping of the Hindlll(+/-) bi-allelic marker within the NRY will be performed using the polymerase chain reaction - restriction fragment length polymorphisms (PCR-RFLP) method. Serum concentrations of free testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and dihydrotestosterone will be assessed by radioimmunoassay. Renal function will be evaluated using creatinine clearance and urinary albumin-to-creatinine ratio. 2. Using renal tissue from the unaffected part of the human kidney of men undergoing unilateral elective nephrectomy due to renal cancer, we will examine the association of the NRY with androgen Ievels and renal structure (Specific Aim 2). Renal structural changes will be assessed by light microscopy. Cell proliferation and death will be determined by proliferating cell nuclear antigen and Terminal Deoxynucleotidyl Transferase Biotin-dUTP Nick End labeling (TUNEL), respectively. Extracellular matrix deposition will be assessed by immunohistochemistry and Western analysis of collagen types I and IV localization and expression. Determination of the association among NRY, androgens and human renal function and structure proposed in this application will improve our understanding of sexual dimorphism in prevalence and progression of chronic renal disorders and development of preventive and therapeutic regimens for these disease processes.
| International Consortium for Blood Pressure Genome-Wide Association Studies (see original citation for additional authors) (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-9 |
| Tomaszewski, Maciej; Charchar, Fadi J; Nelson, Christopher P et al. (2011) Pathway analysis shows association between FGFBP1 and hypertension. J Am Soc Nephrol 22:947-55 |
| Marques, Francine Z; Campain, Anna E; Tomaszewski, Maciej et al. (2011) Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertension 58:1093-8 |
| Tomaszewski, Maciej; Debiec, Radoslaw; Braund, Peter S et al. (2010) Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array. Hypertension 56:1069-76 |
| Kaess, Bernhard M; Barnes, Timothy A; Stark, Klaus et al. (2010) FGF21 signalling pathway and metabolic traits - genetic association analysis. Eur J Hum Genet 18:1344-8 |
| Tomaszewski, Maciej; Charchar, Fadi J; Barnes, Timothy et al. (2009) A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol. Arterioscler Thromb Vasc Biol 29:1316-21 |
| Tomaszewski, Maciej; Charchar, Fadi J; Maric, Christine et al. (2009) Inverse associations between androgens and renal function: the Young Men Cardiovascular Association (YMCA) study. Am J Hypertens 22:100-5 |
| Tomaszewski, Maciej; Charchar, Fadi J; Maric, Christine et al. (2009) Association between lipid profile and circulating concentrations of estrogens in young men. Atherosclerosis 203:257-62 |
| Charchar, Fj; Zimmerli, Lu; Tomaszewski, M (2008) The pressure of finding human hypertension genes: new tools, old dilemmas. J Hum Hypertens 22:821-8 |
| Tomaszewski, Maciej; Charchar, Fadi J; Lynch, Mark D et al. (2007) Fibroblast growth factor 1 gene and hypertension: from the quantitative trait locus to positional analysis. Circulation 116:1915-24 |
Showing the most recent 10 out of 12 publications
