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Third International Chronic Prostatitis Network

Single nucleotide polymorphism studies in patients with CPPS: Preliminary Results

J. Dimitrakov
Justus-Liebig University, Urology Clinic, Giessen, Germany and
Higher Medical Institute, Departments of Urology and Pathology, Plovdiv, Bulgaria
BACKGROUND
Information about the genome of our species is accumulating along two dimensions: While the latitudes of our chromosomes are being charted, crudely at first, but with the expectation of a complete nucleotide sequence of one reference human genome early this millennium, the longitudes of sequence variation at specific locations in the genome are also explored, revealing how different we all are. This variation consists mostly of sequence differences in single nucleotide positions, referred to as single nucleotide polymorphisms or SNPs. An expanding panel of known sequence variants, along with greatly improved methods to monitor them, now promise to offer fresh insights into human biology and pathophysiology.
MATERIAL & METHODS
Expanding on our previous experience with linkage analysis in patients with autosomal dominant polycystic kidney disease (ADPKD), we performed linkage analysis on a total of 228 male patients affected with CPPS and used as controls in a previously published linkage analysis study and 59 unaffected individuals, and 54 spouses using eight polymorphic markers linked to PKD1 which has been mapped to chromosome 16. Since the interleukin(IL)-4 receptor gene (IL4R) shown to be abnormal in inflammatory diseases, is also located on chromosome 16 it is thus both a positional and functional candidate for a susceptibility gene for CPPS. We screened this gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with CPPS.
RESULTS
Associations were observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) with a lod score of 5.8. Evidence for association was found even when the four markers were analyzed individually. The results indicate that these variants are important in determining genetic predisposition to CPPS and that the IL4R gene is a likely candidate for a target gene in CPPS. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants were in linkage disequilibrium with each other which is underscored by the fact that they are separated by only about 21 kilobases of genomic DNA.
CONCLUSIONS
For the majority of human diseases, there is no single, highly penetrant mutation that is responsible for disease. Instead it is likely that common polymorphisms (> 1 % frequency) within one or more pathways directly influence the expression of disease, Often, the phenotype is subtle or not apparent at all. Yet, in combination with and against a vulnerable background, the wrong set of variable could cumulatively undermine one or more biological functions and lead to disease. Our findings underscore the importance of further studies into the SNPs in a large cohort of CPPS patients.
Dr. Dimitrakov was supported by the European Consortium for Concerted Action Against Polycystic Kidney Disease

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