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(Hypertension. 2001;37:1416.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Polymorphisms in the hANP (Human Atrial Natriuretic Peptide) Gene, Albuminuria, and Hypertension
From the Department of Internal Medicine and Metabolism Unit of the CNR Institute of Clinical Physiology, University of Pisa School of Medicine (M.N., M.M., E.F.); and the Division of Medicine, General Hospital (A.P., A.D.B., G.S.), Pistoia, Italy.
Correspondence to Dr Monica Nannipieri, CNR Institute of Clinical Physiology, Via Savi, 8, 56100 Pisa, Italy. E-mail nannipi{at}ifc.pi.cnr.it
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Abstract |
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Abstract—Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP (hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (P<0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the ScaI mutated allele (A1) was significantly lower in hypertensive than in control subjects (11% versus 19%, P=0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%; P<0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the A1 allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59; P=0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele (T708) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59; P<0.001). We conclude that the mutated genotypes of the ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.
Key Words: atrial natriuretic factor • diabetes • albuminuria • hypertension, genetic
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypertension and kidney disease are well-known complications of diabetes mellitus. Raised blood pressure is a commonly associated factor in the early stages of diabetic renal disease.1 2 However, although blood pressure and albuminuria are unquestionably interrelated,3 there is still controversy as to whether increases in blood pressure result in kidney damage, whether albuminuria precedes the rise in blood pressure, or whether in fact each of these abnormalities is a risk factor for the other.4 Several lines of evidence indicate that familial predisposition to hypertension increases the susceptibility to diabetic nephropathy,5 thus implying that inherited factors distinct from hyperglycemia play a part in the development and progression of kidney damage.6 Moreover, studies in populations, families, and twins suggest that both diabetic nephropathy and hypertension have a significant genetic basis.7 8 9 10 However, the number and the kind of genes involved in the pathogenesis of kidney damage and hypertension are still unknown.
Atrial natriuretic peptide (ANP)11 12 13 is an endogenous vasoactive peptide, produced mainly in cardiac atria, which plays a central role in the regulation of blood pressure by modulating sodium homeostasis and the renin-angiotensin-aldosterone system. ANP also affects renal hemodynamics14 15 16 and microvascular permeability to macromolecules.17 The ANP gene has thus been included in the list of candidate genes for familial susceptibility to hypertension18 19 20 21 and diabetic nephropathy.22 Disruption of the ANP gene leads to salt-sensitive hypertension in transgenic animals23 24 ; this finding, together with the availability of reported genetic markers at the ANP gene locus,25 26 27 has prompted intense investigation. However, the results of association studies between DNA polymorphisms at the human ANP (hANP) locus and hypertension28 29 30 31 32 33 34 or diabetic nephropathy35 36 have been conflicting.
In a recent study in a large, ethnically homogeneous cohort of type 1 diabetic subjects,36 we reported a higher frequency of a mutated allele (T708, revealed by the BstXI restriction enzyme) in patients with microalbuminuria. The aim of this study was to examine the simultaneous association of two (ScaI and BstXI) polymorphisms of hANP with hypertension and proteinuria in a large cohort including patients with type 2 diabetes and nondiabetic subjects with essential hypertension.
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Methods |
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Patients
We screened a clinical cohort of 1033 subjects (497 men and 536 women). The group was enriched with cases of microalbuminuria (n=174 or 17%), macroalbuminuria (n=154 or 15%), and hypertension (n=424 or 41%) by including patients with type 1 diabetes (n=423), type 2 diabetes (n=384), and nondiabetic patients with essential hypertension (n=121). A group of healthy control subjects was also included in the study (n=105) (Table 1). In the type 1 diabetic group, all patients were older than 18 years, and age at diagnosis was under 31 years; the diagnosis was based on the continual need for insulin treatment since the onset of the disease (allowing for a short remission of up to 6 months during the first year) and on the current need for at least 2 insulin injections daily. Type 2 diabetes was defined according to the World Health Organization (WHO) criteria, that is, diagnosis after the age of 35 years, no need for insulin in the first year after diagnosis, and no history of ketosis.37 The duration of diabetes was longer than 1 year in all patients. All subjects were white Europeans residing in north-central Italy (Tuscany).
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In accordance with the criteria set by the Joint National Committee (JNC-VI), hypertension was defined as a blood pressure level >140 mm Hg (systolic) and/or 90 mm Hg (diastolic) on at least 3 different visits over the 3 months preceding the study or by current antihypertensive treatment.38 Patients with clinical signs, symptoms, or laboratory findings suggestive of hypertension secondary to renal or endocrine diseases other than diabetes were excluded. Diagnosis of diabetic nephropathy was made as described elsewhere.36 Irrespective of diabetes, the large majority of hypertensive individuals with albuminuria in the normal range were treated with antihypertensive agents such as ACE inhibitors or angiotensin II receptor antagonists in monotherapy. Approximately 80% of microalbuminuric and 10% of macroalbuminuric patients were receiving monotherapy with ACE inhibitors or angiotensin II receptor antagonists. Macroalbuminuric patients generally required adjunctive treatment (calcium antagonists, ß-blockers, clonidine, diuretics, and combinations thereof). The study protocol was approved by the institutional ethics committee, and all participants gave their informed consent to the genetic studies.
Procedures
Participants were seen at the metabolism
unit at 8:00 AM after an
overnight fast and were asked to refrain from smoking for at least 1
hour before the visit. Body mass index (BMI) was calculated as the
ratio of weight to the square of height
(kg/m2). Sitting arterial blood
pressure (Korotkoff phase I to V) was measured twice to the nearest
2 mm Hg after a 10-minute rest and with a 10-minute interval, and
the arithmetic mean of the 2 readings was recorded. Venous blood
was sampled for routine blood chemistry and genetic analysis.
Serum glycosylated hemoglobin (HbA1c) and
creatinine levels and urinary albumin concentration
were measured as described
elsewhere.36
Microalbuminuria was defined as a urinary albumin
excretion (AER) between 30 and 300 mg/d and
macroalbuminuria as an AER >300 mg/d on 3 successive
24-hour urine collections over a period of 
6 months. In hypertensive
patients, any treatment with ACE inhibitors,
angiotensin II receptor antagonists, or calcium
antagonists was withdrawn at least 15 days before
collecting urine. In these patients, 3 urine collections were obtained
over a 2-week period. However, other antihypertensive medication (
-
or ß-blockers or clonidine and/or diuretics) was allowed to
preserve blood pressure control.
Genetic Study
Leukocytes were isolated from peripheral
blood, and DNA was extracted by standard
techniques.39
ScaI and
BstXI polymorphisms of the
hANP gene were determined by
polymerase chain reaction (PCR)/restriction fragment length
polymorphism as previously
described.36 For
ScaI polymorphism, a
fragment of 133 bp was amplified in the region overlapping intron 2 and
the 3' flanking region of the
ANP
gene,40 with the sense
primer (5'-GGCACACTCATACATGAAGCTGACTTTT-3') from
nucleotides 2158 to 2185 and the antisense primer
(3'-GCAGTCTGT- CCCTAGGCCCA-5') from
nucleotides 2270 to 2289. A single, 2-allele
polymorphism was detected by first digesting with
ScaI and then size-separating
the PCR products on a 15% polyacrylamide gel; detection
was by silver staining. In the presence of the polymorphic site
(allele
A2),
2 fragments corresponding to size 77 and 56 bp were generated; in the
absence of the site, a fragment of 133 bp was observed (allele
A1).
The loss of that site caused by mutation leads to an extension of ANP
by 2 additional arginine residues, so that the original peptide of 28
amino acids is extended to 30 amino acids.
For BstXI polymorphism, a fragment of 640 bp extending from exon I to exon II was amplified as previously described,36 by using the following primers: sense primer 5'-AGACAG-AGCAGCAAGCAGTG-3', complementary to nucleotides 527 to 544; antisense primer 5'-CATTTCCATCCCCAGTTCC-3', complementary to nucleotides 1148 to 1166 of the published sequence.40 After incubation with BstXI enzyme, the amplicons were separated on a 10% polyacrylamide gel and stained with silver. In wild-type samples (C708), BstXI identified a single restriction site inside the PCR products and gave origin to 2 fragments of 442 and 198 bp. If the point mutation was present, two restriction sites were identified: BstXI classed 3 fragments of 262, 198, and 180 bp in homozygote (T708).
Statistical Analysis
Data are presented as arithmetic mean±SD.
Categorical variables were compared by the
2 test. Associations were tested by using
general linear models including both continuous and categorical
variables. Logistic regression was carried out by standard methods;
results are expressed as the odds ratio with 95% confidence
intervals.
Genetic data are presented according to both
genotype and allele frequency.
2 analysis was used to test for
Hardy-Weinberg equilibrium within the 4 main groups of study subjects
(type 1 diabetics, type 2 diabetics, nondiabetic hypertensive patients,
nondiabetic control subjects). Differences in genotype and
allele frequency across study groups were tested by
2
analysis.
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Results |
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The clinical characteristics of the study groups are reported in Table 1. Type 2 diabetic patients, who were older and heavier than type 1 diabetic patients, also had a higher prevalence of hypertension (
2=86.1,
P<0.0001),
microalbuminuria (2=16.8,
P<0.0001), and
macroalbuminuria (2=16.0,
P<0.0001). In the whole
cohort, the prevalence of hypertension was 31%, 58%, and 61% in
normoalbuminuric, microalbuminuric, and
macroalbuminuric subjects, respectively
(2=75.3,
P<0.0001)
(Figure).
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The distribution of the
ScaI and
BstXI genotypes were in
Hardy-Weinberg equilibrium in the 4 groups of subjects (in healthy
control subjects 2=2.05,
P=NS and
2=2.5,
P=NS, respectively, for
ScaI and
BstXI; in type 1 diabetic
patients 2= 3.5,
P=NS and
2=0.13,
P=NS; in type 2 diabetes
2=0.23,
P=NS and
2=0.003,
P=NS; in hypertensives
2=0.26,
P=NS and
2=0.07,
P=NS). In the whole cohort,
Hardy-Weinberg equilibrium also prevailed for both polymorphisms
across degrees of albuminuria;
ScaI and
BstXI genotypes were in
linkage dysequilibrium (2=64.3,
P<0.0001).
The genotype distributions and allele
frequencies of both polymorphisms in subjects grouped according to
the clinical diagnosis (control subjects, type 1 or type 2 diabetes,
hypertension) are shown in
Table 2. The frequency of the
A1
allele was significantly lower in the presence of hypertension
(2=6.19,
P=0.012) or type 2 diabetes
(2=15.98,
P<0.0001) compared with
healthy control subjects and was lower in type 2 diabetic patients than
in type 1 diabetic patients (2=33.6,
P<0.0001). When analyzing
ScaI polymorphism according
to severity of albuminuria, the frequency of the
A1
allele was lower in macroalbuminuric subjects compared with
normoalbuminuric subjects in the whole cohort
(Table 3) as well as in the diabetic group alone
(Table 4). In contrast, analysis of the
BstXI polymorphism
according to albuminuria showed an higher frequency of the
T708
allele in the presence of microalbuminuria in the whole
cohort
(Table 3) as well as in the diabetic group alone
(Table 5).
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To test for independent associations between genotypes and hypertension or albuminuria, we set up a nominal logistic model in which presence of hypertension (or, alternately, micro/macroalbuminuria) was the dependent variable, age was a simple regressor, and genotype, gender, and presence of obesity, diabetes or micro/macroalbuminuria (or hypertension) were main effects. In these models, the influence of age, obesity, and diabetes was accounted for; in addition, the models also accounted for the strong association between hypertension and micro/macroalbuminuria (OR, 2.81; CI, 2.01 to 3.92; P<0.0001). With this approach, the mutated ScaI genotypes were not found to be independently associated with hypertension (OR, 0.87; CI, 0.61 to 1.23; P=NS), whereas they were strongly associated with micro/macroalbuminuria in an inverse fashion (OR, 0.57; CI, 0.38 to 0.82; P=0.003).
For the mutated BstXI genotypes, the same statistical model did not yield a significant association with micro/macroalbuminuria (OR, 1.37; CI, 0.88 to 2.12; P=NS) or hypertension (OR, 1.2; CI, 0.77 to 1.88; P=NS). When separate analyses were run for microalbuminuria and macroalbuminuria, the independent associations were positive for BstXI and microalbuminuria (OR, 2.25; CI, 1.39 to 3.59; P=0.0008) and negative for ScaI and macroalbuminuria (OR, 0.46; CI, 0.26 to 0.76; P=0.004). These results were not changed when both polymorphisms were included in the model. When the analysis was repeated after excluding normoalbuminuric type 1 diabetic patients with a diabetes duration <10 years, the independent association between ScaI and micro/macroalbuminuria was still statistically significant (OR, 0.55; CI, 0.37 to 0.80; P=0.002).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The hANP gene has long been on the list of candidate genes for familial susceptibility to hypertension and diabetic nephropathy.18 19 20 21 22 28 Evidence for the involvement of this gene in the pathogenesis of hypertension comes from studies in transgenic animals, in which disruption of the gene is associated with salt-sensitive hypertension.23 24 In humans, despite the fact that molecular genetic studies at this locus have been facilitated by the various polymorphisms so far identified,25 26 27 there is no clear evidence that the hANP gene is significantly involved either in the pathogenesis of hypertension or in the initiation and progression of diabetic renal damage.29 30 31 32 33 34 35 36 Ramasawmy et al,25 who reported the presence of the ScaI polymorphism in the third exon of the hANP gene, found that allele frequencies varied widely, depending on ethnic background. In our control subjects, the A1 allele frequency was 0.19, a value that is slightly lower than that reported by Ramasawmy et al25 in French whites (0.26) but higher than that observed in Mauritian Indians (0.11). The prevalence of the A1 allele in hypertensive (0.42) and normotensive (0.39) individuals of black origin, previously investigated by Rutledge et al,32 is higher than that reported here; in this ethnic group, there was no association between this polymorphism and hypertension.
To enhance the likelihood of establishing an association between polymorphisms of the hANP gene and hypertension or albuminuria, we screened a large group of white subjects enriched with diabetic patients (both type 1 and type 2) with micro/macroalbuminuria and nondiabetic patients with essential hypertension. Predictably, hypertension was strongly associated with both microalbuminuria and macroalbuminuria (Figure). Whether by single or compound polymorphism analysis, we found that the ScaI polymorphism of the hANP gene was clearly associated with both albuminuria and essential hypertension. In particular, the A1 (mutant) allele was less frequent in macroalbuminuric patients as compared with normoalbuminuric subjects and in nondiabetic patients with essential hypertension as compared with control subjects. On the other hand, the T708 (mutant) allele, identified by the BstXI polymorphism, was only associated with microalbuminuria and no other clinical phenotype (type 1 or type 2 diabetes, hypertension). In this case, the T708 allele was more frequent in subjects with microalbuminuria.
The question arises whether the association between ScaI genotype and high blood pressure was driven by the underlying kidney disease, in which case the A1 allele would be rather a marker of renal protection than one related to blood pressure. The fact that a significant reduction of the A1 allele frequency was found in individuals with macroalbuminuria but not in those with microalbuminuria despite a similar prevalence of hypertension suggested that the genotype was linked with overt nephropathy. In the present series, we had sufficient statistical power to test whether the association between genotype and high blood pressure was independent of albuminuria. After including age, gender, obesity, diabetes, and micro/macroalbuminuria as independent variables in the regression of hypertension on genotype, hypertension was no longer related to the A1 genotypes. In contrast, when albuminuria was used as the dependent variable and hypertension as a covariate, the A1 genotypes were significantly associated with macroalbuminuria. In the same model, the T708 allele of the BstXI polymorphism was significantly associated with microalbuminuria but not with overt nephropathy; again, no association emerged between this polymorphism and hypertension.
It is commonly held that microalbuminuria heralds clinical nephropathy with a positive predictive value >80%.41 42 This view has recently been questioned in patients with duration of diabetes >30 years,43 in whom microalbuminuria may persist without progressing to overt nephropathy. Recent epidemiological findings, in fact, have shown that after 30 years of diabetes, the cumulative prevalence of nephropathy plateaus at 30%, whereas the cumulative prevalence of microalbuminuria without diabetic nephropathy is 28%.44 45 The cross-sectional nature of the present study cannot provide conclusive evidence that ANP polymorphisms have predictive value for the natural history of microalbuminuria. The finding that the observed associations between the polymorphisms and micro/macroalbuminuria were still present when the analysis of type 1 diabetic patients was restricted with those with a relatively long disease duration is compatible with the possibility that polymorphisms in the ANP gene may impact on the prognosis of renal disease. Only longitudinal studies can resolve this issue.
With regard to the functional significance of ANP variants, in a previous study in type 1 diabetes,36 we observed that the T708 allele was associated with lower plasma ANP concentrations and preserved microvascular permeability (as judged from the albumin transcapillary escape rate) independent of the presence of microalbuminuria. On these grounds, we hypothesized a protective role of the T708 allele in the progression of microvascular damage. The present data, obtained in a larger cohort enriched with patients with type 2 diabetes, confirm and extend the finding. Therefore, it is legitimate to propose that the BstXI polymorphism could play a role in the progression of nephropathy through effects of ANP on the microvasculature.
The functional significance of ScaI variant is currently unclear. The A1 allele has been reported to cause loss of the regular stop codon, leading to an extension of the human natriuretic peptide by 2 additional arginine residues25 32 ; this circulating form of ANP might have a different biological activity, playing a selective role in the regulation of glomerular filtration rate and the genesis of hyperfiltration.15 16 46 Available information is, however, scarce, nor is there evidence for an effect of T708 variant on the synthesis and/or activity of the mature peptide.
Overall, the present findings are compatible with a role of ANP gene variants in protecting against the development and progression of renal damage. The association between these polymorphisms and high blood pressure appears to be mediated by the presence of albuminuria.
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Acknowledgments |
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We are indebted to Drs Roberto Pedrinelli and Lamberto De Giorgio for referring some of the patients to us. We also wish to thank all the subjects who took part in this study.
Received June 26, 2000; first decision July 17, 2000; accepted November 22, 2000.
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  C. Vassalle and M. G. Andreassi Genetic Polymorphisms of the Natriuretic Peptide System in the Pathogenesis of Cardiovascular Disease: What Lies on the Horizon? Clin. Chem., May 1, 2009; 55(5): 878 - 887. [Abstract] [Full Text] [PDF]
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 D. Conen, R. J. Glynn, J. E. Buring, P. M Ridker, and R. Y.L. Zee Natriuretic Peptide Precursor A Gene Polymorphisms and Risk of Blood Pressure Progression and Incident Hypertension Hypertension, December 1, 2007; 50(6): 1114 - 1119. [Abstract] [Full Text] [PDF]
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C. Vassalle, M. G. Andreassi, C. Prontera, M. Fontana, L. Zyw, C. Passino, and M. Emdin Influence of ScaI and Natriuretic Peptide (NP) Clearance Receptor Polymorphisms of the NP System on NP Concentration in Chronic Heart Failure Clin. Chem., November 1, 2007; 53(11): 1886 - 1890. [Abstract] [Full Text] [PDF]
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 B. London Natriuretic Peptides and Cardiac Hypertrophy J. Am. Coll. Cardiol., August 1, 2006; 48(3): 506 - 507. [Full Text] [PDF]
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S. Rubattu, G. Bigatti, A. Evangelista, C. Lanzani, R. Stanzione, L. Zagato, P. Manunta, S. Marchitti, V. Venturelli, G. Bianchi, et al. Association of Atrial Natriuretic Peptide and Type A Natriuretic Peptide Receptor Gene Polymorphisms With Left Ventricular Mass in Human Essential Hypertension J. Am. Coll. Cardiol., August 1, 2006; 48(3): 499 - 505. [Abstract] [Full Text] [PDF]
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 S. Rubattu, R. Stanzione, E. Di Angelantonio, B. Zanda, A. Evangelista, D. Tarasi, B. Gigante, A. Pirisi, E. Brunetti, and M. Volpe Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans Stroke, April 1, 2004; 35(4): 814 - 818. [Abstract] [Full Text] [PDF]
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 A. K. Kiemer, N. C. Weber, R. Furst, N. Bildner, S. Kulhanek-Heinze, and A. M. Vollmar Inhibition of p38 MAPK Activation via Induction of MKP-1: Atrial Natriuretic Peptide Reduces TNF-{alpha}-Induced Actin Polymerization and Endothelial Permeability Circ. Res., May 3, 2002; 90(8): 874 - 881. [Abstract] [Full Text] [PDF]
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A. K. Kiemer, N. C. Weber, R. Furst, N. Bildner, S. Kulhanek-Heinze, and A. M. Vollmar Inhibition of p38 MAPK Activation via Induction of MKP-1: Atrial Natriuretic Peptide Reduces TNF-{alpha}-Induced Actin Polymerization and Endothelial Permeability Circ. Res., May 3, 2002; 90(8): 874 - 881. [Abstract] [Full Text] [PDF]
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