A GENE-ENVIRONMENT INTERACTION BETWEEN INFERRED KALLIKREIN GENOTYPE AND POTASSIUM

Urinary kallikrein excretion has been shown statistically to be partia lly determined by a major gene in large Utah pedigrees with the use of segregation analysis. A previous twin analysis of environmental facto rs influencing urinary kallikrein level showed that urinary potassium twin differences were strongly related to differences in urinary kalli krein. The present study uses 769 individuals in 58 Utah pedigrees to analyze the association of urinary potassium with urinary kallikrein w ithin statistically inferred kallikrein genotypes. Fitting genotype-sp ecific curves relating urinary kallikrein level to 12-hour urinary pot assium amount within a major gene, polygene, and common environment mo del, we showed a significant statistical urinary potassium interaction with the inferred major gene for kallikrein (P=.0002). The heterozygo tes (with a frequency of 50%) had a significant association between ur inary kallikrein and potassium (slope, 0.5 +/- 0.04 SD). whereas there was no association with potassium in the low homozygotes, suggesting a genetic defect involving the kallikrein response to potassium. The m odel predicted that an increase in urinary potassium excretion of 0.8 SD above the mean in these pedigrees would be associated with high kal likrein levels in the heterozygotes similar to the high homozygotes. A decrease of 1.3 SD in urinary potassium excretion in heterozygous ind ividuals was associated with kallikrein levels similar to the homozygo us individuals with low kallikrein. Because in the steady state urinar y potassium represents dietary potassium intake, this study suggests t hat an increase in dietary potassium intake in 50% of these pedigree m embers, estimated to be heterozygous at the kallikrein locus, would be associated with an increase in an underlying genetically determined l ow kallikrein level. If kallikrein excretion is found to be a physiolo gical marker related to the risk of developing hypertension, that risk may be able to be modified by achievable increases in dietary potassi um intake in heterozygous individuals deficient in potassium intake.