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Association of a CYP4A11 Variant and Blood Pressure in Black Men

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Association of a CYP4A11 Variant and Blood Pressure in Black Men JASN Express. Published on April 2, 2008 as doi: 10.1681/ASN.2008010063 CLINICAL RESEARCH www.jasn.org Association of a CYP4A11 Variant and Blood Pressure in Black Men ʈ James V. Gainer,*† Michael S. Lipkowitz,‡ Chang Yu,§ Michael R. Waterman, Elliott P. Dawson,¶ Jorge H. Capdevila,** Nancy J. Brown,* and the AASK Study Group Divisions of *Clinical Pharmacology and **Nephrology, Department of Medicine, and Departments of §Biostatistics ʈ and Biochemistry, Vanderbilt University Medical Center, and †Veterans Administration Hospital, Nashville, Tennessee; and ¶BioVentures, Inc., and the ‡Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York ABSTRACT CYP4A11 arachidonic acid monooxygenase oxidizes endogenous arachidonic acid to 20-hydroxyeicosa- tetraenoic acid, a renal vasoconstrictor and natriuretic. Cyp4a deficiency causes hypertension in male mice, and a loss-of-function variant (T8590C) of CYP4A11 is associated with hypertension in white individuals. Hypertension and hypertensive renal disease are more common among black than white individuals, but the relationship between genetic variation at CYP4A11 and hypertension in black individuals is not known. This study tested the hypothesis that the CYP4A11 T8590C polymorphism is associated with higher BP or clinical outcomes in 732 black Americans with hypertensive renal disease participating in the African American Study of Kidney Disease (AASK). Men with the 8590CC genotype had significantly higher systolic BP (CC 156.5 Ϯ 22.6 versus 148.4 Ϯ 24.3 mmHg in CT and TT combined; P ϭ 0.04) and pulse pressure (P ϭ 0.04) at baseline; this association was not observed among women. In addition, this genotype was associated with higher systolic and diastolic BP at 36-mo follow-up among those randomly assigned to the lower BP arm of the AASK. Among all participants (or men but not women) with proteinuria, the 8590CC genotype was associated with an increased cumulative incidence of ESRD or death, controlling for randomization and clinical characteristics. In summary, the CYP4A11 8590CC genotype is associated with increased BP in black men with hypertensive nephrosclerosis and is associated with adverse clinical outcomes in those with baseline proteinuria. These data support a role for renal monooxygenases and 20-hydroxyeicosatetraenoic acid in the regulation of BP and renal function in men. J Am Soc Nephrol ●●: –, 2008. doi: 10.1681/ASN.2008010063 Hypertension is a significant independent risk for ase, expressed in the human kidney, catalyzes the the development and progression of chronic kidney conversion of endogenous arachidonic acid to 20- disease.1 Studies in men and women have demon- hydroxyeicosatetraenoic acid (20-HETE). The 20- strated a strong, graded relationship between in- HETE metabolite regulates salt and water ho- creasing hypertension severity and declining renal meostasis at multiple sites within the kidney.12 function.2 Differences in the incidence and progres- sion of chronic kidney disease among ethnic groups Received January 17, 2008. Accepted February 26, 2008. have been reported,3–5 and black Americans are Published online ahead of print. Publication date available at four times as likely to develop ESRD as white Amer- www.jasn.org. icans.6 Animal7–9 and human studies10,11 support a Correspondence: Dr. Nancy J. Brown, 550 Robinson Research causal role for genetic factors, but the genetic deter- Building, Vanderbilt University Medical Center, Nashville, TN minants of hypertension-associated renal disease in 37232-6602. Phone: 615-343-8701; Fax: 615-343-2551; E-mail: humans are largely unknown. [email protected] The CYP4A11 arachidonic acid monooxygen- Copyright ᮊ 2008 by the American Society of Nephrology J Am Soc Nephrol ●●: –, 2008 ISSN : 1046-6673/●●00- 1 CLINICAL RESEARCH www.jasn.org Experimental models of hypertension indicate that 20-HETE can act in either a pro- or antihypertensive manner, depending on its site-specific expression in the renal vasculature or tubule, respectively.13–16 In previous work, we showed that knockout of Cyp4a14, a murine homologue of CYP4A11, caused gender- specific and androgen-sensitive hypertension.17 Several studies supported the involvement of 20-HETE, CYP4A, and omega hydroxylase activity in animal models of renal injury.18–20 In humans, we21 previously reported an association of a functional CYP4A11 variant, T8590C, characterized by re- duced 20-HETE synthase activity, with hypertension in two independent white American cohorts. Mayer et al.22 also demon- strated an association of the T8590C variant with hypertension and systolic BP (SBP) in a German-based white population co- hort. In our original study, we did not detect an association of CYP4A11 T8590C genotype with hypertension in an black Amer- ican cohort, but the study was limited by a small sample size. The primary goal of this study was to determine whether genetic variation in CYP4A11 (i.e., T8590C variant) influences hemodynamic indices or the progression of renal disease in hypertensive black Americans and whether gender-dependent genotype effects are detectable. To this end, we genotyped 732 participants of the African American Study of Kidney Disease (AASK), a trial designed to evaluate the effect of two different BP goals and three different treatment regimens on progres- sion of hypertensive kidney disease. We assessed the effect of the CYP4A11 T8590C variant on BP and on clinical end points. Figure 1. Relationship between CYP4A11 T8590C genotype RESULTS and prerandomization SBP, DBP, and pulse pressure (PP) in men and women. *P Ͻ 0.05 versus CT and TT groups. Baseline Characteristics previously in black individuals (Table 1).21 There were no sig- CYP4A11 T8590C genotype and allele frequencies were in nificant differences among genotype groups in age, gender dis- Hardy-Weinberg equilibrium and similar to those reported tribution, body mass index (BMI), baseline renal function, his- Table 1. Patient characteristicsa P (65 ؍ CC (n (322 ؍ CT (n (345 ؍ Characteristic TT (n Age (yr) 53.6 Ϯ 10.9 53.9 Ϯ 10.2 53.7 Ϯ 10.9 0.90 Women (%) 40.0 41.0 35.4 0.70 BMI (kg/m2) 30.9 Ϯ 6.3 31.4 Ϯ 6.9 29.6 Ϯ 6.3 0.12 GFR (ml/min per 1.73 m2) 47.6 Ϯ 13.5 47.7 Ϯ 13.9 46.1 Ϯ 13.5 0.66 Serum creatinine (mg/dl)b 2.02 Ϯ 0.73 1.98 Ϯ 0.69 2.05 Ϯ 0.79 0.60 UP/Cr† 0.32 Ϯ 0.53 0.31 Ϯ 0.49 0.27 Ϯ 0.48 0.74 History of heart disease (%) 48.4 50.3 50.8 0.87 Years of hypertension 13.5 Ϯ 10.3 13.9 Ϯ 9.3 15.4 Ϯ 11.3 0.38 Antihypertensive meds 2.5 Ϯ 1.2 2.5 Ϯ 1.1 2.7 Ϯ 1.1 0.23 Antihypertensive use (%) angiotensin-converting enzyme inhibitor 44.6 38.9 35.6 0.21 ␤ blocker 27.4 30.6 40.7 0.11 calcium channel blocker 65.8 60.5 71.2 0.18 dihydropyridine calcium channel blocker 48.2 43.6 54.2 0.24 diuretic 62.2 69.4 72.9 0.08 Randomization to ramipril:metoprolol:amlodipine (%) 43.8:38.3:18.0 39.4:41.0:19.6 27.7:43.1:29.2 0.10 Randomization to low BP group (%) 50.4 53.7 46.2 0.46 aData are means Ϯ SD unless otherwise indicated. UP/Cr, urine protein to creatinine ratio at baseline. bTo convert creatinine mg/dl to ␮ mol/L, multiply by 88.4. To convert urine protein g/d to mg/d, multiply by 1000. 2 Journal of the American Society of Nephrology J Am Soc Nephrol ●●: –, 2008 www.jasn.org CLINICAL RESEARCH Table 2. CYP4A11 genotype and BP during follow-upa Genotype 3Mo 36Mo Parameter TT CT CC P TT CT CC P (57 ؍ n) (292 ؍ n) (314 ؍ n) (65 ؍ n) (322 ؍ n) (345 ؍ n) Usual BP medications, n men 1.7 Ϯ 1.3b 2.1 Ϯ 1.5 1.8 Ϯ 1.2 0.18 2.1 Ϯ 1.5b 2.3 Ϯ 1.7b 2.0 Ϯ 1.2b 0.46 women 1.5 Ϯ 1.3 1.3 Ϯ 1.1b,c 1.8 Ϯ 1.5 0.32 2.0 Ϯ 1.5 2.0 Ϯ 1.5b 2.4 Ϯ 1.7 0.72 all 1.6 Ϯ 1.3b 1.8 Ϯ 1.4b 1.8 Ϯ 1.3 0.48 2.1 Ϯ 1.5b 2.2 Ϯ 1.6b 2.1 Ϯ 1.4 0.74 SBP (mmHg) men 139.1 Ϯ 16.5b 143.4 Ϯ 16.1b 146.3 Ϯ 12.0b 0.07 140.2 Ϯ 13.7b 142.3 Ϯ 17.1b 143.3 Ϯ 9.0 0.58 women 139.4 Ϯ 17.7b 145.7 Ϯ 19.0 145.3 Ϯ 14.7b 0.12 141.7 Ϯ 15.9b 143.9 Ϯ 20.6b 135.2 Ϯ 12.5 0.36 all 139.3 Ϯ 17.0b 144.3 Ϯ 17.3b,d 145.9 Ϯ 12.8b,d 0.01 140.9 Ϯ 14.7b 142.9 Ϯ 18.5b 140.5 Ϯ 10.9 0.54 DBP (mmHg) men 87.7 Ϯ 9.8b 89.4 Ϯ 10.9b 88.7 Ϯ 11.5b 0.53 86.8 Ϯ 10.5b 87.2 Ϯ 10.5b 87.1 Ϯ 9.5 0.97 women 87.3 Ϯ 11.2b 84.8 Ϯ 11.0† 90.4 Ϯ 10.8b 0.21 84.8 Ϯ 9.3b 82.1 Ϯ 11.6c 87.2 Ϯ 8.8b 0.23 all 87.5 Ϯ 10.4b 87.7 Ϯ 11.2b 89.3 Ϯ 11.1b 0.66 85.9 Ϯ 10.0b 85.2 Ϯ 11.2b 87.1 Ϯ 9.1 0.66 Lower BP medications, n men 2.5 Ϯ 1.4 2.3 Ϯ 1.1 2.2 Ϯ 1.3 0.55 2.9 Ϯ 1.5 3.1 Ϯ 1.5 2.9 Ϯ 1.2 0.57 women 1.7 Ϯ 1.3c 1.8 Ϯ 1.3c 1.5 Ϯ 0.9 0.71 2.4 Ϯ 1.6 2.7 Ϯ 1.5 2.0 Ϯ 1.1 0.31 all 2.2 Ϯ 1.4 2.1 Ϯ 1.2 1.9 Ϯ 1.2 0.52 2.7 Ϯ 1.5 2.9 Ϯ 1.5 2.6 Ϯ 1.2 0.36 SBP (mmHg) men 128.2 Ϯ 17.2 126.8 Ϯ 19.9 131.7 Ϯ 20.2 0.55 124.6 Ϯ 17.0 123.3 Ϯ 17.0 139.1 Ϯ 24.0d,e 0.004 women 132.2 Ϯ 23.6 138.9 Ϯ 24.2c 125.6 Ϯ 15.2 0.10 126.4 Ϯ 15.2 135.5 Ϯ 22.8c,d 124.1 Ϯ 19.3 0.03 all 129.6 Ϯ 19.7 132.0 Ϯ 22.6 129.5 Ϯ 18.5 0.52 125.2 Ϯ 16.3 128.5 Ϯ 20.5 133.5 Ϯ 23.2 0.08 DBP (mmHg) men 80.2 Ϯ 12.7 80.1 Ϯ 12.9 80.0 Ϯ 14.9 1.00 76.8 Ϯ 10.6 75.9 Ϯ 12.2 83.8 Ϯ 16.4e 0.048 women 81.3 Ϯ 14.0 82.8 Ϯ 14.2 78.9 Ϯ 9.2 0.61 76.4 Ϯ 10.4 78.6 Ϯ 11.5 77.8 Ϯ 9.8 0.57 all 80.5 Ϯ 13.1 81.3 Ϯ 13.5 79.6 Ϯ 12.9 0.76 76.7 Ϯ 10.5 77.1 Ϯ 11.9 81.6 Ϯ 14.4 0.13 aData are means Ϯ SD.
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