Analyses of mutations in the human renal kallikrein (hKLK1) gene and their possible relevance to blood pressure regulation and risk of myocardial infarction.

The kallikrein-kinin system is involved in the maintenance of blood pressure (BP), and studies have shown an inverse correlation between BP and urinary kallikrein levels. These and other effects, make the human tissue kallikrein (hKLK1) gene a candidate gene with respect to BP regulation as well as risk of myocardial infarction (MI). By analysis for single-stranded conformation polymorphisms (SSCPs), patterns consistent with four different variants of the gene were detected and further characterized by DNA sequencing. Three of the variants have not been described before. Two of the polymorphisms changed the codon for an amino acid. Methods based on the polymerase chain reaction (PCR) were developed to analyze these polymorphisms at the hKLK1 locus. We found no evidence of association between any genotype in the polymorphisms and normal BP level in two series of healthy, unrelated individuals. In a third series, diastolic BP exhibited a weak association with genotypes in three of the four polymorphisms. Since no such association was detected in the other two series, we conclude that no effect on normal BP level is exerted by variants in the hKLK1 as expressed in these polymorphisms. In two series of monozygotic (MZ) twin pairs, there were no differences between genotypes in within-pair difference in systolic BP or diastolic BP. Finally, no differences in allele frequencies or genotype frequencies in the four polymorphisms at the hKLK1 locus were found between a series of young MI survivors and a series of controls. Thus, genes in the four polymorphisms at the hKLK1 locus detected by SSCP and DNA sequencing did not exhibit associations with MI, and had neither "level gene" nor "variability gene" effects on normal blood pressure.