Association of the T8590C Polymorphism of CYP4A11 With Hypertension in the MONICA Augsburg Echocardiographic Substudy

Abstract

Abstract-Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (nϭ1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 . Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function. Key Words: genetics Ⅲ polymorphism Ⅲ hypertension, arterial Ⅲ echocardiography A variety of gene variants has shown association with arterial hypertension. However, only small or inconsistent effects on blood pressure were observed for most of the frequent polymorphisms of hypertension-related genes. 1 On the other hand, mutations with profound implications for blood pressure regulation were found predominantly in exceptional families. 2 Thus, despite extensive research, genetic testing for risk assessment in hypertension is not yet advisable for routine patient evaluation. A major challenge for this field will be the identification of genetic variants with reproducible and clinically as well as epidemiologically relevant effects on blood pressure regulation that, in addition, offer the potential of therapeutical intervention.The CYP4A arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicostatetraenoic acid (20-HETE). Depending on its expression at renovascular or tubular sites, the 20-HETE metabolite can act in a prohypertensive or antihypertensive manner. [3][4][5][6] Holla et al characterized a CYP4A14 (Ϫ/Ϫ) knockout mouse as a model of gender-specific severe hypertension. 7 Evaluation of human homologues as potential novel genetic determinants in hypertension revealed 2 candidate genes: CYP4A11 and CYP4A22 from the CYP4A gene family. 8,9 Recently, CYP4A11 but not CYP4A22 was identified as the functional active protein that catalyzes the metabolism of arachidonic acid to 20-HETE in humans. 10 Screening for genetic variants revealed a cytosine for thymidine transition at nucleotide 8590 in exon 11, which results in a nonsynonymous phenylalanine to serine substitution at residue 434 of CYP4A11. The less frequent 8590C genotype, which corresponds to the 434S variant on protein

A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure

“…Both the CYP4A11 F434S and CYP4F2 V433M genotype frequencies observed in the present study were in agreement with previous studies examining these mutations. 3,11,20 Gainer et al 11 had demonstrated previously an in vitro loss of function as a result of the CYP4A11 TC/CC genotype. The lack of an effect of the TC/CC genotype on BP in this cohort is intriguing.…”

“…11 Although Mayer et al 20 observed a tendency toward elevated BP in the CC genotype compared with TT/TC genotypes (recessive effect model), when the CC/TC genotypes were combined (dominant effect model), the association with high BP was lost. 20,21 Both of these studies suggest that the CYP4A11 isoform is found at a location in the kidney where 20-HETE functions as a natriuretic, such that loss of production causes elevations in BP. The lack of a relationship between BP and individuals with the TC or CC genotype in our study could be because of the relatively small number of individuals with these genotypes.…”

“…3,4 Animal studies have previously shown that disruption of the murine Cyp450 4a14 gene results in hypertension, possibly via increased expression of Cyp4a12. 5 20-HETE has been shown to play a role in vasoconstriction and renal salt handling in the spontaneously hypertensive rat. 2,6 -8 In humans, 20-HETE has been shown to play a role in regulation of natriuresis in salt-sensitive and salt-resistant hypertension, 9 and we have previously demonstrated a significant association between urinary 20-HETE excretion and both hypertension and endothelial dysfunction.…”

“…5 20-HETE has been shown to play a role in vasoconstriction and renal salt handling in the spontaneously hypertensive rat. 2,6 -8 In humans, 20-HETE has been shown to play a role in regulation of natriuresis in salt-sensitive and salt-resistant hypertension, 9 and we have previously demonstrated a significant association between urinary 20-HETE excretion and both hypertension and endothelial dysfunction. 10 Paradoxically, within the kidney, 20-HETE can have either prohypertensive or antihypertensive actions, depending on its site of production.…”

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

“…Selective disruption of the murine Cyp4a10 (6) and Cyp4a14 (7) genes leads to hypertensive phenotypes that are thought to reflect changes in renal 20-HETE production arising through distinct mechanisms. Interestingly, an allelic variant encodes a human CYP4A11 with reduced catalytic activity that is associated with an increased risk for hypertension in studies of three independent cohorts (8,9). P450s 4F2 and 4F3B are highly similar in amino acid sequence and display overlapping catalytic activity profiles.…”