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NDT Advance Access published online on June 13, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm360
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphisms in the B-type natriuretic peptide (BNP) gene are associated with NT-proBNP levels but not with diabetic nephropathy or mortality in type 1 diabetic patients

Maria Lajer1, Lise Tarnow1, Anders Jorsal1 and Hans-Henrik Parving2,3

1520, Steno Diabetes Center, Gentofte, Denmark, 2Faculty of Health Science, University of Aarhus, Aarhus, Denmark and 3Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark

Correspondence and offprint requests to: Maria Lajer, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Email: mlaj{at}steno.dk



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are elevated in patients with diabetic nephropathy and independently predict excess cardiovascular morbidity and mortality. Therefore, we investigated the association between two polymorphisms –381T/C and 1551G/A of the BNP gene, plasma NT-proBNP levels and mortality prognosis in 380 type 1 diabetic patients with and without diabetic nephropathy.

Methods. In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy {121 men, age [mean (SD)] 41 ± 9.5 years, duration of diabetes 28 ± 8.0 years, glomerular filtration rate 67 ± 28 ml/min/1.73 m2}, and a matched control group of 183 patients with longstanding type 1 diabetes and persistent normoalbuminuria (111 men, age 43 ± 10.0 years, duration of diabetes 27 ± 8.3 years) were followed for 12.6 (0.0–12.9) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline. The BNP genotypes were determined by TaqMan chemistry based assays.

Results. The two polymorphisms were in almost complete linkage disequilibrium (r2 = 0.883) and thus only the results of the –381T/C promoter polymorphism are shown. There was no significant difference between cases and controls in either genotype distributions (cases TT 32%, TC 53%, CC 15%; controls TT 28%, TC 52%, CC 20%) or allele frequencies (cases T/C 0.58/0.42; controls T/C 0.54/0.46) for the –381T/C polymorphism. Among the 164 normoalbuminuric patients without antihypertensive treatment and previous major cardiovascular disease (CVD), the –381T/C polymorphism was associated with circulating levels of NT-proBNP [median (interquartile range) 21 (5–32), 34 (12–67) and 32 (12–58) ng/l for TT, TC and CC, respectively (P = 0.041)] persisting after adjustment for covariates (P = 0.018). During follow-up, the –381T/C polymorphism did not predict all-cause or cardiovascular mortality among type 1 diabetic patients with or without diabetic nephropathy.

Conclusions. The BNP –381T/C and 1551G/A polymorphisms are associated with circulating levels of NT-proBNP but not with prevalent overt diabetic nephropathy. These polymorphisms do not predict all-cause or cardiovascular mortality in Caucasian type 1 diabetic patients with or without diabetic nephropathy.

Keywords: BNP; diabetic nephropathy; N-terminal pro-B-type natriuretic peptide; polymorphism; type 1 diabetes



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Diabetic nephropathy is characterized by persistent albuminuria, raised arterial blood pressure, a relentless decline in glomerular filtration rate (GFR) and is associated with high cardiovascular morbidity and mortality, which cannot be explained by abnormalities in well-known cardiovascular risk factors alone. Familial clustering of diabetic nephropathy suggests genetic predisposition to play a role in the pathogenesis of this complication [1].

In the systemic circulation, the B-type natriuretic peptide (BNP) mediates a variety of physiological effects including natriuresis/diuresis, peripheral vasodilation and inhibition of the sympathetic nervous system as well as the renin-angiotensin-aldosterone system [2].

By translation of the BNP gene, (also named NPPB) a precursor protein is synthesized and constitutively released predominantly in response to cardiac myocyte stress as the active hormone BNP and the N-terminal fragment, N-terminal pro-brain natriuretic peptide (NT-proBNP). BNP is metabolized by natriuretic peptide receptors and degraded by plasma endopeptidases whereas NT-proBNP is mainly cleared by renal excretion. Recently, the overall correlation with renal function has been shown to be similar for BNP and NT-proBNP in patients with renal disease indicating a similar diagnostic performance of both markers [3].

Circulating BNP and NT-proBNP levels have been shown to be a prognostic marker of increased mortality due to chronic heart failure and acute coronary syndromes in non-diabetic populations [4] and in various disease states such as hypertension [5] and end-stage renal disease (ESRD) [6]. Furthermore, recent studies report plasma NT-proBNP to be elevated and to be an independent marker of excess overall and cardiovascular mortality in both type 1 [7] and type 2 [8,9] diabetic patients with diabetic nephropathy. In addition to the contribution from unrecognized cardiovascular disease (CVD), the gene coding for BNP and NT-proBNP could be involved in the genetic susceptibility to the increased cardiac and vascular damage accompanying diabetic nephropathy. Therefore, the aim of the present study was to investigate whether the two genetic polymorphisms –381T/C and 1551G/A of the BNP gene were associated with DN, circulating NT-proBNP levels as well as overall and cardiovascular mortality among patients with or without diabetic nephropathy in a prospective observational design.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Study population
During 1993, all Caucasian type 1 diabetic patients with diabetic nephropathy (n = 242) attending the out-patient clinic at Steno Diabetes Center, in whom GFR had been measured by 51Cr-EDTA during the same year, were invited to participate in a case-control study [10]. A total of 199 patients fulfilling the clinical criteria for diabetic nephropathy [persistent macroalbuminuria (>300 mg 24 h–1) in at least two out of three consecutive 24 h urine collections, in the presence of diabetic retinopathy and the absence of other kidney or urinary tract disease] were recruited.

Simultaneously, a group of 192 patients with long-lasting type 1 diabetes [≥15 years, mean (SD) 27 ± 8.5 years] and persistent normoalbuminuria were recruited as controls. Regarding the normoalbuminuric patients, GFR was estimated by the MDRD formula [11].

Plasma NT-proBNP was measured and BNP genotypes determined in 197 patients with nephropathy and in 183 patients with normoalbuminuria [7]. At baseline, none of the included patients were diagnosed with heart failure corresponding to NYHA class III or IV or received medical treatment for heart failure. Patients were interviewed using the WHO cardiovascular questionnaire, and, based on these major cardiovascular events, were diagnosed as having a history of stroke and/or myocardial infarction. The included patients were not further examined for congestive or coronary heart disease.

Follow-up
In a prospective, observational study design, the patients were followed until the 1st September 2006 or until death (n = 79) or emigration (n = 3). Endpoints were all-cause mortality and cardiovascular mortality. If a patient died before 1 September 2006, the date of death was recorded and information on cause of death was obtained from the death certificate. Two observers reviewed all death certificates independently and the primary cause of death was recorded. Additional available information from necropsy reports was included. All deaths were classified as cardiovascular deaths unless an unequivocal non-cardiovascular cause was established [12].

The study was approved by the local ethics committee, in accordance with the Helsinki Declaration, and all patients gave their informed written consent.

Genotyping
Publicly available single nucleotide polymorphisms (SNP) databases (http://www.snpper.chip.org) and (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=4879) were used for selecting SNPs covering the relatively small BNP gene on chromosome 1.

Two SNPs located in the promoter region (rs198389, –381T/C) and the 3'UTR (rs198388, 1551G/A) with a reported heterozygosity of 0.5 were selected. None of the reported SNPs positioned between the two SNPs flanking the three exons of the BNP gene had an expected minor allele frequency >0.05 and were therefore not examined in this study.

Genomic DNA was extracted from human leucocyte nuclei isolated from peripheral blood by standard techniques. Genotyping of the –381T/C and 1551G/A polymorphisms was performed using commercially available fluorogenic 5'nuclease-based allelic discrimination assays (TaqMan®) (c_8861289_20 and c_2482614_1, respectively) combined with the ABI Prism® 7900 Sequence Detection System according to manufacturer's protocol (Applied Biosystems, Foster City, CA, USA).

Measurement of NT-proBNP
BNP and NT-proBNP can be detected in serum and plasma using commercially available assays, however, the half-life of BNP is much shorter (20 min) compared with NT-proBNP (120 min), and therefore NT-proBNP were selected for this study from a clinical diagnostic perspective.

After the patient had been at rest in the supine position for at least 20 min, blood samples for determination of NT-proBNP were collected in EDTA tubes, centrifuged and plasma stored at –80°C until analysis. Although the stability of NT-proBNP after 15+ years of storage is not known, all samples only underwent one freeze–thaw cycle for out-portioning and were otherwise treated and stored under the same conditions. Plasma concentrations of NT-proBNP were measured by a sandwich immunoassay on an Elecsys 2010 (Roche Diagnostics, Basel, Switzerland). The intra-assay variation is <3.0% and the total coefficient of variation ranges from 2.2 to 5.8% for low and high ranges of NT-proBNP, respectively.

Statistical analysis
Comparisons between groups were performed with Chi-square test for categorical variables. Student's t-test and ANOVA were used for continuous variables. Non-normally distributed variables were log transformed before analysis including plasma NT-proBNP, which followed normal distribution when log transformed. Relations between BNP genotype and plasma NT-proBNP levels were adjusted for covariates in a linear regression analysis. Time-to-death variables were analysed according to genotype using a log rank test. A Cox-proportional hazards regression model was used to evaluate the relative contributions of covariates to mortality correcting for duration of follow-up given as hazard ratios with 95% confidence intervals. All calculations were performed using SPSS, Version 13.0 for Windows (SPSS, Chicago, IL, USA). Pairwise linkage disequilibrium was estimated and expressed in terms of r2-value.

Assuming a multifactorial minor gene effect, we sought to detect an expected and clinically relevant effect size of a difference in allele frequency of 5% and 10% at the 0.05 significance level. With the given number of patients, we had a power of 30% and 80% to detect differences of 5 and 10% corresponding to odds ratios of ~1.2 and 1.5, respectively, using the PS power and sample size program available for free at: http://www.mc.vanderbilt.edu/prevmed/ps/index.htm.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
The clinical characteristics of the 380 type 1 diabetic patients with and without diabetic nephropathy are summarized in Table 1. The two groups were closely matched with respect to gender, age and duration of diabetes. Patients with diabetic nephropathy had elevated blood pressure, HbA1c levels and serum cholesterol, and a lower GFR (P < 0.0001) as compared with the normoalbuminuric type 1 diabetic patients. NT-proBNP levels were higher in patients with diabetic nephropathy, P < 0.001.


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  		Table 1. Baseline clinical and laboratory characteristics of 380 type 1 diabetic patients with and without diabetic nephropathy

 
The distributions of allele and genotype frequencies of the two polymorphisms 381T/C and 1551G/A were compatible with the Hardy–Weinberg equilibrium. The two variants were in almost complete linkage disequilibrium (r2 = 0.883). Statistical analysis of both –381T/C and 1551G/A were performed, however, no differences in results were observed and thus only data on the –381T/C promoter polymorphism are shown.

The allele and genotype distributions of the –381T/C polymorphism in cases and controls are shown in Table 1. There was no significant difference between cases and controls in either genotype distributions or allele frequencies. Exclusion of 19 normoalbuminuric patients on antihypertensive treatment and previous major CVD from the analysis did not change the result of the case-control study.

Among the 164 normoalbuminuric patients without antihypertensive/diuretic treatment, a history of previous major CVD, or clinical symptoms of heart failure, the –381T/C polymorphism was associated with circulating levels of NT-proBNP (P = 0.041) (Table 2). This association is further strengthened when adjusted for age, systolic blood pressure, estimated GFR and body mass index (BMI) (P = 0.018). In contrast, no statistically significant differences were found in gender distribution, age, duration of diabetes, BMI, HbA1c, blood pressure, urinary albumin excretion rate or GFR levels across the three groups of genotypes (Table 2).


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  		Table 2. Clinical and biochemical characteristics of 164 normoalbuminuric type 1 diabetic patients without antihypertensive treatment classified according to –381 T/C genotype E

 
The interaction between the –381T/C genotype and GFR was not significant, thus indicating that the effect of the –381T/C genotype on circulating levels of NT-proBNP is independent of GFR. Among the 125 patients with diabetic nephropathy pausing their AHT and with no history of major CVD patients carrying the –381 TT, CT or CC genotype had similar levels of NT-proBNP levels [median (interquartile range)] 98 (35–253) ng/l, 88 (30–234) ng/l and 187 (74–386), respectively (P = 0.88).

During the 12.6 (range: 0.0–12.9) years of follow-up, 79 (40%) of the patients with diabetic nephropathy died. There was a tendency towards a lower mortality among the TT carriers (31%) compared with the TC and CC genotype (44%), however, this was not significant (P = 0.10). The case was similar for cardiovascular mortality (P = 0.16). Plasma NT-proBNP independently predicts outcome of patients with diabetic nephropathy in this population, as published previously [7].

The normoalbuminuric patients were followed for 12.6 (range: 1.7–12.7) years during which 13 patients (8%) died. The same tendency towards a lower mortality among the TT carriers (4%) compared with the TC and CC genotype (10%) was seen, however, this was not significant (P = 0.25).



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Our genotype-phenotype study on 164 normoalbuminuric patients without antihypertensive or diuretic treatment revealed the –381T/C polymorphism to be associated with circulating plasma levels of NT-proBNP, with circulating levels being increased with ~50% among the patients carrying either the –381CC or CT genotype compared with TT-carriers. Patients with and without diabetic nephropathy carrying the TT-genotype tended to have a lower all-cause and cardiovascular mortality rate, however this was not statistically significant. Results were similar for the 1551G/A polymorphism. In our well-matched case-control study of 380 Caucasian type 1 diabetic patients with and without diabetic nephropathy, the –381T/C BNP polymorphism was not associated with prevalent diabetic kidney disease.

Several studies of diabetic populations at high cardiovascular risk have found circulating BNP or NT-proBNP levels to be increased in patients with left ventricular hypertrophy [13], diastolic and systolic dysfunction [14] as well as to predict future cardiovascular morbidity [15] and mortality [7,9]. Furthermore, in type 1 and type 2 diabetic patients with elevated urinary albumin excretion rate, circulating NT-proBNP levels are elevated [7,9]. Elevated BNP levels are considered a marker of general vasohumoral activity and as such are likely to represent underlying unrecognized cardiac and vascular disease. However, whether the increased BNP protein levels result from transcriptional or translational changes is not known. Since gene expression is regulated at many levels, the possibility still remains that, in addition to being a marker of unrecognized CVD, a genetic predisposition to higher BNP expression may be involved in the observed increase in BNP levels among patients with diabetic nephropathy. The –381T/C polymorphism is located just upstream of the BNP gene transcription site and reported to be within a suggestive consensus binding sequence of an E-box binding element (CAnnTG) of transcription factor {delta}–crystallin/E2-box factor 1 ({delta}-EF1; GGACACCTGGA) thereby influencing gene activation [16]. Additionally, the observation that regulation of BNP secretion takes place during gene expression rather than on release from storage granules supports a role for gene variants located in the BNP promoter region to influence circulating BNP and NT-proBNP levels [17].

To our knowledge, this is the first published association study of genetic variation within the BNP gene in relation to diabetes and its complications. To date, publicly available SNP databases only report the –381T/C and 1551G/A polymorphisms of the BNP gene as having an expected minor allele frequency >5%, and hence these were selected for analysis. However, despite our reasonably-sized, clinically well-characterized case-control study population, other yet unidentified genetic variants of the BNP gene could modulate the increased cardiovascular risk accompanying diabetic nephropathy.

In our study, the –381T/C polymorphism is associated with plasma NT-proBNP levels in normoalbuminuric, type 1 diabetic patients, and it is possible that individuals carrying the CT and CC genotypes are prone to an increase in BNP gene expression at a given stimuli. Although none of these patients had clinical symptoms corresponding to NYHA III/IV or received medical treatment for heart failure, we cannot exclude that some patients had unrecognized, undiagnosed mild cardiac insufficiency. The observation that BNP protein levels, but not the investigated gene variants predict outcome in diabetic populations points towards other genetic or non-genetic mechanisms to be involved in the pathogenesis of diabetic nephropathy.

In conclusion, the –381T/C and 1551G/A polymorphisms in the BNP gene were in almost complete linkage disequilibrium and hence both associated with circulating levels of NT-proBNP but not with diabetic nephropathy. Furthermore, neither of the two investigated polymorphisms predicts all-cause mortality or cardiovascular mortality in Caucasian type 1 diabetic patients with or without diabetic nephropathy.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors acknowledge the work by Birgitte V. Hansen, Tina R. Juhl, Berit R. Jensen, Lotte Pietraszek and Ulla M. Smidt for technical assistance, Ingelise Holstein for secretarial support and Roche Diagnostics, Germany for providing the measurements of NT-proBNP.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Parving H-H. Renoprotection in diabetes: genetic and non-genetic risk factors and treatment. Diabetologia (1998) 41:745–759.[CrossRef][Web of Science][Medline]
  2. De Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Eng J Med (2001) 345:1014–1021.[Abstract/Free Full Text]
  3. Luchner A, Hengstenberg C, Löwel H, Riegger GA, Schunkert H, Holmer S. Effect of compensated renal dysfunction on approved heart failure markers: direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Hypertension (2005) 46:118–123.[Abstract/Free Full Text]
  4. Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J (2003) 24:1735–1743.[Abstract/Free Full Text]
  5. Olsen MH, Wachtell K, Tuxen C, et al. N-terminal pro-brain natriuretic peptide predicts cardiovascular events in patients with hypertension and left ventricular hypertrophy: a LIFE study. J Hypertens (2004) 22:1597–1604.[CrossRef][Web of Science][Medline]
  6. Madsen LH, Ladefoged S, Corell P, Schou M, Hildebrandt PR, Atar D. N-terminal pro brain natriuretic peptide predicts mortality in patients with end-stage renal disease in hemodialysis. Kidney Int (2007) 71:548–554.[CrossRef][Web of Science][Medline]
  7. Tarnow L, Hildebrandt P, Hansen BV, Borch-Johnsen K, Parving H-H. Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy. Diabetologia (2005) 48:149–155.[CrossRef][Web of Science][Medline]
  8. Gaede P, Hildebrandt P, Hess G, Parving H-H, Pedersen O. Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. Diabetologia (2005) 48:156–163.[CrossRef][Web of Science][Medline]
  9. Tarnow L, Gall MA, Hansen BV, Parving H-H. Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes. Diabetologia (2006) 49:2256–2262.[CrossRef][Web of Science][Medline]
  10. Tarnow L, Cambien F, Rossing P, et al. Insertion/deletion polymorphism in the angiotensin-I-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy. Diabetologia (1995) 38:798–803.[CrossRef][Web of Science][Medline]
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  13. Andersen NH, Poulsen SH, Knudsen ST, Heickendorff L, Mogensen CE. NT-proBNP in normoalbuminuric patients with Type 2 diabetes mellitus. Diabetic Med (2005) 22:188–195.[CrossRef][Web of Science][Medline]
  14. Epshteyn V, Morrison K, Krishnaswamy P, et al. Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care (2003) 26:2081–2087.[Abstract/Free Full Text]
  15. Gaede P, Hildebrandt P, Hess G, Parving HH, Pedersen O. Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. Diabetologia (2005) 48:156–163.[CrossRef][Web of Science][Medline]
  16. Sekido R, Murai K, Funahashi JI, et al. The delta;-crystallin enhancer-binding protein deltaEF1 is a repressor of E2- box-mediated gene activation. Mol cell Biol (1994) 14:5692–5700.[Abstract/Free Full Text]
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Received for publication: 12. 1.07
Accepted in revised form: 11. 5.07


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