Association of the tissue kallikrein gene promoter with ESRD and hypertension

Background. Kallikreins have long been implicated in human essential hypertension and associated complications. In particular, low urinary kallikrein excretion has been associated with hypertension and renal disease in African Americans. In an effort to identify the source of differential kallikrein excretion, we investigated the promoter of KLK1, the tissue kallikrein gene. The KLK1 promoter is uniquely polymorphic with a poly-G length polymorphism coupled with multiple single base substitutions. In this report, we genetically evaluated the association of KLK1 gene promoter alleles with end-stage renal disease (ESRD) in African Americans. Methods. A total of 15 haplotypes were identified in the KLK1 promoter region through detailed DNA sequence analysis. This polymorphic region was then genetically evaluated for association with ESRD in African Americans with diabetic and non-diabetic etiologies of ESRD. Results. The complex polymorphic nature of the promoter presents challenges to determining the alleles. We have redefined the region as six separate loci: five substitution loci and one length locus. The length locus was defined as G repeats starting at position -130 and ending at - 121 on the gene. Among four relevant substitution loci for this study, one at position -131, just outside the G repeats, is an A-to-G substitution. The other three variant positions are - 129, -128, and - 127, all G-to-C substitutions within the G repeats. This region was genotyped in African American subjects with and without ESRD using semiautomated sequencing. Four different G repeat alleles ranging from 11.8% for 12 Gs to 52.3% for 10 Gs were observed in 86 control subjects. The C substitution of Gs ranges from 2.9% at position -127 to 8.2% at -129. When affected probands from each of 76 hypertensive ESRD families were genotyped, an association for the 12 G allele, the longest of the length locus alleles, was detected (allele specific P = 0.004 and locus total P = 0.02). When all ESRD affected individuals with hypertension from each family (107 patients in total) were used in the analysis, an even stronger association was observed for this allele (allele specific P = 0.003, locus total P = 0.01). This allele was more frequent in the hypertensive (non-diabetic) patients (0.20 in probands and 0.19 in all ESRD cases) than in the controls (0.12). No evidence of association in diabetic ESRD patients was observed (P = 0.93). Conclusions. The KLK1 promoter is uniquely polymorphic. The observed genetic association suggests an etiologic effect of the KLK1 promoter on hypertension and/or hypertension associated ESRD.