The influence of two megsin polymorphisms on the progression of IgA nephropathy.

The clinical course of chronic renal diseases and their progression to ESRD is highly variable. The strongest predictors of poor outcome of IgAN involve hypertension, severe proteinuria and elevated serum creatinine level. Different candidate gene polymorphisms have been advocated as possible modulators of the progression of IgAN. Megsin belongs to the serpin superfamily and was mapped to chromosome 18q21.3. Megsin plays a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Overexpression of Megsin might lead to mesangial dysfunction, and impair degradation of the mesangial matrix and disposal of immune complexes. The expression of Megsin is upregulated in a variety of glomerular diseases with mesangial injury in humans and in animal models. We investigated a possible association of two C2093T, C2180T polymorphisms of the megsin gene with the progression of IgAN towards ESRD, as well as the haplotype reconstruction of megsin gene polymorphisms and clinical manifestation of IgAN. We examined a group of 197 pts with histologically proven IGAN (84 pts with normal renal function, 113 pts with progressive renal insufficiency); as a control group we used 61 genetically unrelated healthy subjects. DNA samples from collected blood were genotyped for two singlenucleotide polymorphisms of megsin C2093T, C2180T by means of PCR with defined primers, electrophoresis on 2% agarose gel, UV light visualization and direct sequencing. The megsin genotype distribution showed no differences among the groups of IgAN with normal renal function, progressive renal insufficiency and the control group. According to haplotype analysis, the TT haplotype (defined as T-2093, T-2180 alleles) was substantially more frequent in pts with IgAN and normal renal function (Table 1, P = 0.025; Table 3, P = 0.062). Pts in the progressive group showed significantly higher levels of 24-h UP (3.53 +/- 2.80 vs 2.06 +/- 2.06, P = 0.042; Table 10), diastolic blood pressure (92.89 +/- 15.66 vs 84.93 +/- 10.43, P = 0.047; Table 10) and almost significantly systolic blood pressure (150.79 +/- 32.88 vs 135.21 +/- 14.88, P = 0.058; Table 10). We confirmed the negative prognostic influence of hypertension and proteinuria on the progression of IgAN in Czech pts. We found out that the TT haplotype (defined as T-2093, T-2180 alleles) could play a protective role in the progression of IgAN. In our Czech population, we excluded the negative influence of the 2093C-2180T haplotype, which was proposed by Chinese studies.