Renin–Angiotensin–Aldosterone System Loci and Multilocus Interactions in Young‐Onset Essential Hypertension

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Abstract
Renin-angiotensin-aldosterone system component genes have been associated to essential hypertension. Thus, we studied the association of singe locus or multilocus interactions with young-onset essential hypertension. This is a case-control study based on a population sample of adolescent at an inner city. We studied 54 adolescents with hypertension and 121 age-matched normotensives, recruited from a high-school student population of 934 interviewed individuals. Resting blood pressure was measured on three different days and normalized (Z-score) by sex and age. Genotypes of ACE (I/D) angiotensinogen (T174M and M235T), ATIR (A1166C), and CYP11B2 (C-344T) were determined by PCR/RFLP or ASO. Although genotype frequencies were not different in both groups, we found a significant dominant effect of ACE D and angiotensinogen 235T alleles on normalized systolic arterial blood pressure in males. This effect was confirmed by sib-pair linkage analysis taking normalized blood pressure as a quantitative trait. We independently analyzed multilocus interactions in normotensive and hypertensive adolescents searching for multiple locus deviation from Hardy-Weinberg or linkage equilibrium. We found that from 63 multilocus combinations, 4 deviated significantly from equilibrium in hypertensive adolescents but none in the normotensives. Deviations from equilibrium may indicate that the combination of alleles at different loci affects susceptibility or resistance to the disease. In addition to the angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) gene variants, gene-gene interactions may be important causative factors in a complex disease such as young-onset essential hypertension.