ABSTRACT
OBJECTIVE: 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. SETTING AND DESIGN: This is a case-control study based on a population sample of adolescent at an inner city. PARTICIPANTS: We studied 54 adolescents with hypertension and 121 age-matched normotensives, recruited from a high-school student population of 934 interviewed individuals. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Angiotensinogen/genetics , Hypertension/genetics , Oxidoreductases Acting on CH-NH Group Donors/genetics , Peptidyl-Dipeptidase A/genetics , Receptors, Thyrotropin-Releasing Hormone/genetics , Renin-Angiotensin System/genetics , Adolescent , Case-Control Studies , Chromosome Mapping , Female , Gene Frequency , Humans , Linear Models , Male , Methylenetetrahydrofolate Reductase (NADPH2) , Polymorphism, GeneticABSTRACT
Leptin, an adipocyte-released hormone, modifies food intake and energy expenditure regulating hypothalamic-pituitary-thyroid axis function. We previously reported that thyrotropin-releasing hormone (TRH) precursor gene overexpression induces hypertension in the normal rat and that spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In both models, intracerebroventricular antisense (AS) treatment against the TRH precursor produced a dose-dependent reduction of the increased diencephalic TRH content while normalizing high arterial blood pressure. In this article, we report that male Wistar rats that were made hypertensive by intracerebroventricular injection of a eucaryotic expression plasmid containing the pre-TRH cDNA showed decreased leptin plasma levels and that pre-TRH AS treatment reversed this phenomenon. In addition, male and female spontaneously hypertensive rats showed lower levels of circulating leptin than did sex-matched Wistar-Kyoto control rats. This difference also was abated by the pre-TRH AS treatment. Conversely, 20 microg ICV leptin induced a long-lasting pressor effect (18 +/- 5 mm Hg, n=6, P<0.01, >60 minutes) that was not observed in pre-TRH AS pretreated rats (2 +/- 3 mm Hg, n=6) but persisted in rats used as controls that were treated with inverted oligonucleotide (20 +/- 6 mm Hg, n=4, P<0.01). These data suggest that in rats with TRH-induced hypertension, leptin is decreased, inducing compensatory adiposity. We propose that because leptin produces central TRH synthesis and release, obesity may induce hypertension through TRH system activation and that the TRH-leptin interaction may thus contribute to the strong association between hypertension and obesity.
