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We tested the hypothesis that genetic variation in the beta-2 adrenoceptor gene is associated with a genetic predisposition to hypertension. Offspring of two hypertensive parents were compared with offspring of two normotensive parents. The subjects were participants of the Bergen Blood Pressure Study, where couples were recruited in 1963 to 1964 and re-examined in 1990. We studied offspring of those couples in which both partners were either hypertensive or normotensive in both examinations. Twenty-three hypertensive and 22 normotensive families met the inclusion criteria. DNA samples from the first born of hypertensive family-history offspring and normotensive family-history offspring were analyzed. We used multiplex sequencing and specifically examined the promoter and the N-terminal portion of the beta-2 adrenoceptor gene. We found four genetic variants: at position -47, a C-->T substitution in the 5' leader cistron causing an Arg-->Cys exchange, at -20, a T-->C substitution, at +46 an A-->G substitution leading to an Arg16-->Gly exchange, and at +79, a C-->G substitution leading to a Gln27-->Glu exchange. The frequency of the Arg16 allele was significantly higher in the hypertensive family-history offspring compared to normotensive family-history offspring (58% vs. 28% P < 0.011). We constructed haplotypes for the four intragenic variants and found significant linkage dysequilibrium. In particular, the 5' leader cistron mutant with the wild type alleles at the other loci was significantly more frequent in offspring of hypertensive parents, compared to offspring of normotensive parents. We also performed a relative risk analysis comparing the Gly/Gly, Arg/Gly, and Arg/Arg alleles, which implicated the Arg-containing allele. Finally, we analyzed the effect of genotype on blood pressure in the offspring. We found a significant step-wise effect for all four polymorphisms examined. Our data suggest that the Arg variant of the Arg-->Gly exchange is associated with parental hypertension and higher blood pressure values in this northern European population.

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