Hypertensive Nephropathy and the Gene for Angiotensin-Converting Enzyme

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Genes and Gene Therapy

High Blood Pressure

Kidney Diseases
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:252-256.)
© 1997 American Heart Association, Inc.
Articles
Hypertensive Nephropathy and the Gene for Angiotensin-Converting Enzyme
Kazuomi Kario; Nobuyuki Kanai; Shinichi Nishiuma; Takeshi Fujii; Ken Saito; Takefumi Matsuo; Masafumi Matsuo; Kazuyuki Shimada
the Departments of Cardiology (K.K., K. Shimada) and Pathology (N.K., T.F., K. Saito), Jichi Medical School, Tochigi, the Department of Internal Medicine (T.M.), Hyogo Prefectural Awaji Hospital, Sumoto, Hyogo, and the Division of Genetics (S.N., M.M.), International Center for Medical Research, Kobe University School of Medicine, Kobe, Japan.
Correspondence to Dr Kazuomi Kario, MD, Department of Cardiology, Jichi Medical School, 3311-1, Yakushiji, Minamikawachi, Kawachi, Tochigi, 329-04, Japan.

Abstract

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To investigate the genetic determinants for microalbuminuria, we studied an insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene, which influences the plasma ACE level, in 333 consecutive hypertensive patients and 113 normotensive control subjects. The urinary albumin excretion rate was calculated by using a 12-hour urine collection (mean for two consecutive nights from 7 PM to 7 AM) in all 333 hypertensive patients. The ACE D allele frequency did not differ significantly between the hypertensive patients and the normotensive control subjects (0.37 and 0.33, respectively). Among the hypertensive patients, nephropathy (microalbuminuria and albuminuria) was more common (P<.001) in those with the ACE DD genotype than in those with other genotypes. The D allele frequency in the nephropathy group was significantly higher than that in the normoalbuminuric group (0.45 versus 0.32,

2=10.8, P<.001). These results indicate that ACE I/D polymorphism is a genetic determinant for hypertensive renal disease in hypertensive patients. This polymorphism might be a confounding factor involved in the association between hypertensive nephropathy and cardiovascular events.
Key Words: angiotensin-converting enzyme gene • hypertension • hypertensive nephropathy • microalbuminuria • Japanese

Introduction

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Microalbuminuria, defined as increased UAE, is often present in patients with essential hypertension and is the earliest manifestation of hypertensive nephropathy.1234 Microalbuminuria is associated with increased cardiovascular mortality and morbidity in both nondiabetic and diabetic subjects.567 Microalbuminuria is reported to be related to lipid abnormalities, left ventricular hypertrophy, hyperinsulinemia, endothelial cell damage, and hypercoagulability,48910 although the genetic determinants of microalbuminuria in hypertension remain unclear.
Genes that influence the renin-angiotensin system are potentially etiological candidates for renal disease because their products exert a profound effect on the vasoconstriction of the kidney and because ACE inhibitors reduce the UAE rate and delay end-stage renal failure in patients with hypertension.11 The ACE I/D polymorphism has been reported to be associated with the development of cardiac hypertrophy and with increased risk for myocardial infarction and cerebrovascular disease in Caucasians and Japanese.1213141516 In diabetes, this polymorphism reportedly tends to be related to microalbuminuria,17 but negative findings have also been reported.18 However, there have been no reports as to the association of this polymorphism with hypertensive renal disease.
The purpose of the present study was to clarify the association between ACE I/D polymorphism and hypertensive nephropathy.

Methods

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Subjects
We studied 333 consecutive outpatients with essential hypertension, which we defined as a mean systolic BP

140 mm Hg and/or a mean diastolic BP

90 mm Hg on three or more occasions spanning 2 months or the use of antihypertensive drugs. BP was measured in the sitting position by using an automated sphygmomanometer (BP103N-II, Nippon Colin Co, Ltd) after the subject had rested for at least 5 minutes. All the subjects were ambulant and had normal appetite. Patients with diabetes mellitus, primary renal disease, or secondary hypertension were excluded from this study. We also studied a control group of 113 healthy normotensive subjects (50% male) who participated in an annual examination whose mean (SD) age was 65 (14) years. Body mass index was calculated as weight in kilograms divided by height in meters squared.
No antihypertensive therapy was administered in 97 of the 333 hypertensive patients for at least 1 month before examination. All the remaining treated patients were asked to discontinue their antihypertensive treatment 7 to 14 days before examination, but 38 of them were not able to do so. Forty-seven (23%) and 29 (22%) in the normoalbuminuric and nephropathy groups, respectively, were or had been taking an ACE inhibitor.
PCR for Detection of ACE I/D Polymorphism
Genomic DNA was extracted from citrated whole blood by using salt/chloroform in a modification of one of our previous methods.19 Enzymatic amplification of DNA was performed by using PCR with 0.1 mg of the DNA extract and thermostable Taq polymerase (Takara Biochemical, Kyoto, Japan) according to the manufacturer's instructions. PCR was performed in a thermal reactor (MJ Research)2021 according to the method of Rigat et al22 by using the PCR primers of the oligonucleotide sequences of 5' CTG CAG ACC ACT CCC ATC CTT TCT 3' and 5' GAT GTG GCC ATC ACA TTC GTC AGA T 3'.16 All samples were studied in a blind manner at the Department of Pathology at the Jichi Medical School, Tochigi, Japan.
To avoid mistyping, in the 58 samples identified as DD genotype by the above method we conducted an insertion-specific second amplification using the insertion-specific primer of the oligonucleotide sequences of 5' TGG GAC CAC AGC GCC CGC CAC TAC 3' and 5' TCG CCA GCC CTC CCA TGC CCA TAA 3'23 and confirmed that five samples with ID genotype were misclassified as DD by the first identification. This confirmation was conducted at the Division of Genetics, International Center for Medical Research, Kobe University School of Medicine, Kobe, Japan.
Assay Procedures
The levels of total cholesterol, glucose, urea, and creatinine were measured by using routine chemical methods. HDL cholesterol was determined by using an enzymatic procedure after precipitation with phosphotungstic acid. The urinary albumin concentration was assayed by using a nephelometric method, and the UAE rate was expressed in micrograms per minute.102425
Patient Classification by UAE
To control for the influence of fluctuation in daily physical activity and to standardize urine collection, we asked the patients to collect urine on two consecutive nights between 7 PM and 7 AM for urinary albumin measurement.102425 The 333 hypertensive patients were divided into three groups on the basis of UAE rate: normoalbuminuric (UAE <15 µg/min; n=200), microalbuminuric (UAE

15 but <300 µg/min; n=123), and albuminuric (UAE

300 µg/min; n=10). In the analysis, we combined the data for those with microalbuminuria and albuminuria to examine the hypertensive nephropathy group (UAE

15 µg/min).
Statistical Analysis
Data are shown as mean (SD). Data for UAE rates were log10 transformed and are shown as the geometric mean (SD range). Allele frequencies in different groups were compared by gene counting and

2 analysis. The unpaired t test was used for comparing the mean values for the control and patient groups. Pearson's correlation coefficient was calculated to examine the relation between BP and UAE. Differences with a probability value <.05 were considered significant.

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Hypertension
The ACE genotypes and gene frequencies in the 333 hypertensive patients and 113 normotensive control subjects are shown in Table 1

. Age (P<.0001) and prevalence of male gender (P<.05) in the hypertensive group were significantly higher than those in the control group. Neither the ACE genotype distribution nor the derived ACE D allele frequency in the hypertensive patients differed significantly from that in the normotensive group. To match for age and gender in the two groups, we excluded those aged <50 years (n=16) from the normotensive control group. The mean (SD) age of the remaining subjects was 69 (10) years, and 48% were male in this age- and gender-matched normotensive group (n=97). Neither the ACE genotype distribution (II=38%, ID=56%, and DD=6%) nor the derived ACE D allele frequency (0.34) in the age- and gender-matched control group was significantly different from that in the hypertensive patients.
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Table 1. Genotype Distribution and Allele Frequencies of ACE Gene in Hypertensive Patients and Normotensive Control Subjects

Hypertensive Nephropathy
When we classified the 333 hypertensive patients into normoalbuminuric (n=200), microalbuminuric (n=123), and albuminuric (n=10) groups by UAE rate, it became apparent that the number of albuminuric patients was small. Thus, we combined the microalbuminuric and albuminuric groups into a single nephropathy group (n=133). The clinical and metabolic characteristics of the patients in the normoalbuminuric and nephropathy groups are listed in Table 2

. There was no difference between the two groups in the prevalence of the patients who were unable to discontinue antihypertensive treatment (11% for the normoalbuminuric group and 12% for the nephropathy group), nor were there any significant differences between them for the levels of any listed parameters except urea and creatinine. There was also no difference between the two groups in the prevalence of patients who were or had been taking ACE inhibitors (23% in the normoalbuminuric group and 22% in the nephropathy group).
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Table 2. Comparison of Characteristics in Hypertensive Groups With and Without Nephropathy

There was a marked difference between the ACE genotype distributions in the normoalbuminuric and nephropathy groups; the ACE D allele frequency was much higher in the latter group (P=.001) (Table 3

). The frequency of this allele in the normoalbuminuric hypertensive patients (0.32) was almost identical to that in the normotensive control group (0.33).
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Table 3. Genotype Distribution and Allele Frequencies of ACE Gene in Hypertensive Groups With and Without Nephropathy

Microalbuminuria
Table 4

shows, for the studied hypertensive patients, the relationships of ACE genotype with hypertensive nephropathy and its subtypes. The frequency of microalbuminuria was significantly higher in the patients with the ACE DD genotype than in those with other genotypes; this was associated with a higher frequency of nephropathy in the DD genotype.
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Table 4. ACE Genotypes and Microalbuminuria in Hypertensive Subjects

Relationships Between BP and UAE
A positive correlation between systolic BP and UAE was found in the 295 hypertensive patients who were able to discontinue their antihypertensive therapy for at least 7 days (Table 5

and the Figure

). This positive correlation was found in all the ACE genotypes. There was only a slight correlation between diastolic BP and UAE in the entire group of patients.
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Table 5. ACE Genotypes and Relationships Between UAE and BP in Hypertensive Patients Who Discontinued Antihypertensive Therapy

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Figure 1. Semilogarithmic plots show correlations of BP and UAE in hypertensive subjects with ACE II or DD genotypes. Dotted lines indicate range of cutoff values for microalbuminuria.

Discussion

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ACE gene polymorphism has been reported to be unrelated to essential hypertension in Caucasians and Japanese,1226272829 but at least two reports do not support this conclusion.3031 One study30 reports that DD genotype frequency was decreased in hypertensive subjects, suggesting that the presence of the DD genotype increases the frequency of premature death,32 and the other31 shows increased DD genotype frequency in Japanese hypertensive subjects. However, no thorough evaluation of hypertensive target organ damage was performed in either of these studies. In our study neither the distribution of ACE genotypes nor the D allele frequency in the entire hypertensive group (combined normoalbuminuric and nephropathy groups) showed any difference from that in the normotensive control group (Table 1

). The ACE D allele frequencies of both these groups were lower than those reported for Caucasians. Since our normotensive control group consisted of healthy participants in annual health examinations, the lower ACE D allele frequency (0.33), which is similar to that reported for the Japanese general population in Kanazawa (0.32),31 is probably characteristic of our district.
We found a positive association between the ACE D allele and hypertensive nephropathy (Table

s 3 and 4). As only 10 of the patients in this study had albuminuria, the association between the ACE D allele and hypertensive nephropathy was due essentially to the association between ACE D allele and microalbuminuria (Table 4

). The cutoff UAE value of 10 to 20 µg/min has been proposed for microalbuminuria for prediction of cardiovascular disease, but it has not yet been established.533 In concordance with previous studies,10242534 we defined microalbuminuria as UAE

15 but <300 µg/min. We subsequently reexamined our data using a UAE cutoff value of 20 µg/min to define microalbuminuria, but the results were essentially identical to those presented herein.
The positive relationships between the ACE D allele and hypertensive nephropathy indicate the important contribution of the renin-angiotensin system to the pathogenesis of hypertensive renal disease, even in the early silent stage. However, the precise mechanism of its contribution remains unknown. The ACE I/D polymorphism is partially responsible for interindividual variations in plasma ACE levels, such that the subjects with the DD genotype have approximately twice the plasma levels of ACE as those with the II genotype.35 In the kidney, ACE mRNA is found in the endothelial, mesangial, and epithelial cells.36 The ACE concentration in the kidney would probably be increased with the DD genotype. ACE catalyzes activation of angiotensin I to angiotensin II and inactivates the vasodilator peptide bradykinin. Thus, an increase of ACE in the kidney leads to increased intraglomerular pressure and an increased glomerular filtration rate,36 and the increased UAE rate might accelerate hypertensive renal disease. The ACE I/D polymorphism is therefore associated with genetic variants that may contribute to an increased UAE rate. Hypertensive patients with this genotype may thus be more susceptible to hypertensive renal disease than patients with the other genotypes. In clinical practice, careful monitoring might be necessary for the prevention of renal disease in these patients.
A positive correlation between systolic BP and UAE rate was found in all ACE genotypes (Table 5

and the Figure

). High BP itself could essentially accelerate hypertensive nephropathy in all ACE genotypes, and long-term adequate antihypertensive therapy might be effective in preventing hypertensive nephropathy in all ACE genotypes. The administration of ACE inhibitors to hypertensive patients reduces the UAE rate, and progression to end-stage renal failure is delayed.11 Hypertensive patients with the DD genotype are reported to be resistant to renoprotective antihypertensive therapy with enalapril37 ; the DD group in that study showed no decrease in the degree of proteinuria, whereas the ID and II groups showed a significant reduction.37 In our study, there was no difference between the normoalbuminuric and nephropathy groups in the proportion of the patients who were or had been taking ACE inhibitors.
In conclusion, we found a positive association between the ACE D allele and early hypertensive renal disease (microalbuminuria) in our study of Japanese hypertensive patients. The ACE D gene might be a confounding factor for the increased incidence of cardiovascular disease in hypertensive patients with microalbuminuria. The consistency of our results in different populations and their pathological relevance still need to be assessed by larger prospective association studies or linkage-based family studies.

Selected Abbreviations and Acronyms
ACE = angiotensin-converting enzyme
BP = blood pressure
I/D = insertion/deletion
PCR = polymerase chain reaction
UAE = urinary albumin excretion

Acknowledgments
This work was supported by grants-in-aid awarded from the Foundation for the Development of the Community, Tochigi, Japan, from 1994 through 1997.
Received October 31, 1995; revision received August 29, 1996;

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Abstract

Introduction

Methods

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Discussion

References
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