Sex and Body Mass Index Specific Regulation of Blood Pressure by CYP19A1 Gene Variants

Abstract

Abstract-Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3ЈUTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT) Key Words: essential hypertension Ⅲ body mass index Ⅲ polymorphism Ⅲ genetics Ⅲ estrogens Ⅲ gender E ssential hypertension (EH) is the most common cardiovascular disease, with a prevalence of nearly 27% worldwide. 1 EH is a major risk factor for stroke, heart disease, and end-stage renal disease. High arterial blood pressure is a complex and multifactorial disorder that results from the interaction of multiple genetic and environmental influences. 2 Genetic factors account for 30% to 50% of interindividual variability in blood pressure (BP), [3][4][5] and there is evidence suggesting that each of the polygenes contributing to hypertension has only a modest effect.Sexual dimorphism in the regulation of BP has been demonstrated in several population studies 3,6 and in experimental animal models. 7 Age-adjusted BP is consistently higher in men than women, but these differences are attenuated when women enter menopause. 8 These findings suggest the presence of distinct mechanisms of BP regulation in males and females, emphasizing the importance of the sex hormonal levels in determining BP. Thus, genes involved in testosterone-estradiol shunt are strong candidates to explain, at least in part, the genetic influence on hypertension. The aromatase cytochrome P450 is the enzyme responsible for catalyzing the final step of conversion of androgens into estrogens. 9 The importance of this enzyme in BP regulation has been highlighted in animal studies. Aromatase inhibitors have antihypertensive effects in rats with genetic and experimental hypertension. 10,11 Thus, genetic variations in CYP19A1, the gene encoding aromatase, might contribute to alterations in aromatase expression and enzyme activity,

A genetic polymorphism in the CYP19A1 gene and the risk of hypertension among midlife women

“…Ramirez et al[9] evaluated polymorphisms within the CYP19A1 gene, IVS4 (rs11575899), and 3′UTR (rs10046); findings from this study suggested that the CYP19A1 gene may be involved in the regulation of blood pressure in women only (independent of menopausal status). Specifically, the 3′UTR_11 and IVS4_22 genotypes were associated with an increased risk of diastolic hypertension and the IVS4_11 and 3′UTR_22 genotypes were associated with a decreased risk of systolic hypertension in non-obese women (body mass index; BMI<30 kg/m 2 ) and not in obese women.…”

“…Only a few studies have tested whether genetic variations in CYP19A1 are associated with blood pressure and hypertension [1,9–11] and the results of these studies are inconsistent. Ramirez et al[9] evaluated polymorphisms within the CYP19A1 gene, IVS4 (rs11575899), and 3′UTR (rs10046); findings from this study suggested that the CYP19A1 gene may be involved in the regulation of blood pressure in women only (independent of menopausal status).…”

An aromatase polymorphism modulates the relationship between weight and estradiol levels in obese men

“…(36, 39) These polymorphisms have been linked to various clinical conditions with conflicting results. (40) The deletion/insertion polymorphism [-/TCT] has been suggested to affect the relation between TTTAn polymorphism and estrogen levels. We have screened a group of men from the same population for the deletion/insertion polymorphism [-/TCT] and found that it did not strengthen the relation between the TTTA polymorphism and estradiol levels (data not shown).…”

“…There are 2 coding SNPs that have been described, Arg264Cys and Val80Val (G/A), these polymorphism were not associated estrogen-dependent end points. (40) Another coding SNP, Trp39Arg, was associated with less active aromatase protein in a Japanese population. (14) A recent report found that the (rs2470152) SNP (G→A) located in intron 1 of the CYP 19A1 gene to be highly correlated to estrogen levels in in two populations of 1041 young and 4490 older men.…”

Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene‐Smoking Interactions

“…Genome-wide association studies have identified dozens of variants associated with BP, but they collectively explain less than 3% of BP variability (Ehret, GB 2010). Among the factors hypothesized to contribute to this ‘missing heritability’ are interactions between genes and other clinical factors (Manolio, TA et al 2009) known to influence BP, including age (Shi, G et al 2009), sex (Ramirez-Lorca, R et al 2007), BMI (Ramirez-Lorca, R et al 2007), alcohol consumption (Simino, J et al 2013), and diet (Zhang, RR et al 2013). …”