URINARY KALLIKREIN AND HYPERTENSION: A PROSPECTIVE STUDY The presence of a previously reported dominant major gene inferred from segregation analysis of total urinary kallikrein activity (TUK) in selected pedigrees will be verified on already collected frozen urine specimens from all 2500 persons in 98 pedigrees screened from 1980-1983, from 2284 pedigree members rescreened from 1983-1985 and from 391 twins. These subjects will be rescreened during this grant to get measured 9-year followup blood pressure data. Individuals will be classified by assigned baseline TUK genotype and it will be tested whether low TUK is prospectively associated with new hypertension onset or elevated blood pressures. If so, this would be their first major gene trait associated with hypertension that is also shown to predict future essential hypertension. Because a major gene effect has been implicated, available probes for the structural kallikrein gene or other related products that regulate kallikrein will be tested for genetic linkage to TUK levels. In addition, correlations with over 600 variables measured at baseline in pedigrees and twins will be tested to analyze the strong familiarity of environment, refine the genetic analyses to better assign genotypes, and detect gene environment interactions. All baseline variables except kallikrein, aldosterone, and prostaglandin measurements on frozen urine, and followup blood pressure have already been collected. TUK may be a marker for a renal, cellular or other physiological abnormality that influences both TUK expression and susceptibility to hypertension. Therefore the relationship of TUK to urinary aldosterone, prostaglandin E2 and F2a excretion, and already measured urinary electrolytes, plasma renin activity, and baseline and reactive blood pressures will also be determined. Genetic segregation analyses of the urinary variables and other variables closely associated with TUK will be performed. Urine will be received from 400 metabolic ward subjects in Utah and Boston already studied for renal blood flow response to angiotensin II infusion on high and low salt protocols. TUK will be measured and cortisol, and urinary electrolytes to test for salt sensitivity in those with low TUK, and to help define the physiology relating TUK to hypertension and blood pressure. Demonstration of a longitudinal association between TUK and hypertension, and cosegragation of TUK trait with genetically linked markers, would define a major gene susceptibility to essential hypertension for which specific treatment or prevention protocols may be developed to reduce or prevent the morbidity associated with this susceptibility to hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044738-02
Application #
3363569
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1990-07-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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