A promoter polymorphism of the alpha 8 integrin gene and the progression of autosomal-dominant polycystic kidney disease.

Dysregulation of integrins is a feature of tissue remodeling in autosomal-dominant polycystic kidney disease (ADPKD). The alpha 8 beta 1 integrin (alpha8beta1) affects kidney development and the susceptibility to renal injury in mice. We investigated whether the -414 T/C polymorphism in the promoter region of the alpha 8 integrin chain gene (ITGA8) is associated with the progression of renal disease in ADPKD. Genotyping for the -414 T/C polymorphism was performed by allelic separation using RT-PCR in 294 patients with ADPKD. Alpha 8 integrin expression was detected by RT-PCR and immunohistochemistry. 41% of the study population reached end stage renal disease at a mean age of 51 +/- 12 years. The frequency of the -414 C allele was 0.194 in ADPKD. C allele carriers (CC and TC genotypes) were compared with patients homozygous for the T allele (TT genotype). Kaplan-Meier analysis revealed that end-stage renal failure occurred at a significantly younger age in TT homozygotes (median age, 47 years; 95% CI, 46-49 years) than in C allele carriers (median age, 51 years; 95% CI, 49-53 years; p = 0.046 by the log-rank test). When parameters of ADPKD patients were compared between genotype by analysis of variance, only age at onset of end-stage renal failure was significantly different (p = 0.026) whereas age at onset of hypertension, body surface area, 24-hour systolic and diastolic blood pressure did not differ. In kidneys of ADPKD, expression of alpha 8 integrin is increased and found de novo in cystic epithelia. A polymorphism of the ITGA8 promoter modifies the progression of renal failure in ADPKD.