PubMed · 11026321
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T Ishigami, S Umemura. 2000. [Angiotensinogen gene].. https://pubmed.ncbi.nlm.nih.gov/11026321/
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AIMS: Angiotensinogen plays an essential role in maintaining circulatory homeostasis. AGT rs5050(T > G) has been identified as a regulator of the transcription of AGT mRNA, with differential expression between sexes. We sought to determine if rs5050(T > G), an estrogen response element, modifies the relationship between estrogen and angiotensinogen levels. METHODS: rs5050(T > G) was genotyped, and plasma angiotensinogen levels were measured in 4,831 MESA participants, including postmenopausal women, on hormone therapy (n = 709) or not (n = 1,551), and 2,581 men. Linear regression models were employed to determine the associations of angiotensinogen with rs5050(T > G) allele dosage; and to evaluate whether rs5050(T > G) modifies the association between estradiol and angiotensinogen, with a main effect term and interaction term between rs5050(T > G)*estradiol. Estimated marginal means (EMMs) were used to further evaluate the effect of estradiol on angiotensinogen across different rs5050 alleles (T > G). RESULTS: rs5050TT had the highest median levels of angiotensinogen, followed by TG and GG. Adjusted main effect model showed positive associations between estradiol and angiotensinogen, with each rs5050T allele associated with 0.329 SD higher log-angiotensinogen levels (CI 95% 0.293, 0.365). The interaction rs5050(T > G)*estradiol was not significant, with EMMs exhibiting overlapping slope confidence intervals across genotypes. The proportion of the variance in angiotensinogen explained by modeling increases from 47.9% to 51.6% when including rs5050(T > G) or interation rs5050(T > G)*estradiol in the model. CONCLUSIONS: rs5050(T > G) is associated with circulating angiotensinogen levels, but rs5050(T > G) alleles do not influence the relationship between estradiol and angiotensinogen. This suggests that estrogen's effect on angiotensinogen regulation occurs independently of rs5050(T > G), despite its location within an estrogen-responsive element.
Pharmacologic inhibition of the renin-angiotensin system (RAS) is a widely accepted and effective treatment for hypertension. However, in the past several years, much attention has been focused on additional roles of the RAS including the possibility that its end-product, angiotensin II, could elicit end-organ pathologies independent of its effect on blood pressure. The ability to selectively delete genes in mice (by homologous recombination or gene knockouts) has led to new--and sometimes surprising--insights into the roles of the RAS in the developmental modeling and pathologic remodeling of the heart and blood vessels.
The molecular basis of single-gene Mendelian disorders resulting from gain or loss of function is being clarified at a rapid pace. Progress in the genetics of common disease, by contrast, has been frustratingly limited, as we discuss by reference to essential hypertension (EH). The application of standard genetic paradigms to hypertension research has yielded remarkable findings. Arterial pressure (AP) variation in laboratory rats has been correlated with various genes. Likewise, rare Mendelian hypertension syndromes are increasingly understood in molecular terms. The implications of these findings for EH have proven to be modest, however. Genetic methods have been applied to investigate directly essential hypertension in humans, with mixed results. The power of such methods to identify genetic determinants of EH has been questioned. The issues confronting the genetic analysis of EH are discussed by drawing from our ongoing work along the hypothesis that molecular variants of the angiotensinogen gene may constitute inherited predispositions to the condition. Simply establishing correlation is already a daunting task. Far more challenging yet is to establish causation for a physiological phenotype, that is, to understand the mechanism by which a genetic factor may predispose to essential hypertension. Susceptibility imparted by genetic variation, modest and quantitative, modulates response to environmental exposure over time. The product of the gene under examination may be highly pleiotropic, being involved with multiple physiological processes in multiple tissues. Finally, as physiological phenotypes are defined at the level of the entire organism, ultimate demonstration of genetic determination may require specific genetic manipulations in entire organisms.