Published online before print August 23, 2004, doi: 10.1161/01.HYP.0000141440.02210.da
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(Hypertension. 2004;44:448.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Genetic Risk of Atherosclerotic Renal Artery Disease
The Candidate Gene Approach in a Renal Angiography Cohort
From the Departments of Internal Medicine (M.v.O., A.A.K., A.J.H.M.H., L.H.G.H., P.W.d.L.) and Radiology (D.K.), University Hospital Maastricht and Cardiovascular Research Institute Maastricht (CARIM); Departments of Epidemiology (M.P.A.Z.) and General Practice (A.W.P., H.E.J.H.), Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands; Department of General Practice (M.P.A.Z.), Katholieke Universiteit Leuven, Leuven, Belgium.
Correspondence to Peter W. de Leeuw MD, PhD, FAHA, Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands. E-mail p.deleeuw{at}intmed.unimaas.nl
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Abstract |
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It is largely unknown to what extent genetic abnormalities contribute to the development of atherosclerotic renal artery disease. Among the potential candidate genes, those of the renin-angiotensin system and the endothelial nitric oxide synthase (eNOS) rank high because of their importance in the atherosclerotic process. We investigated the association of polymorphisms in these genes (the angiotensinogen Met235Thr, the angiotensin-converting enzyme insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp) with the presence or absence of atherosclerotic renovascular disease in 456 consecutive hypertensive patients referred for renal angiography on the suspicion of renovascular hypertension. Nondiseased normotensive (n=200) and hypertensive (n=154) patients from a family practice served as external controls. Renal artery disease was present in 30% of our angiography group. The Asp allele of the eNOS Glu298Asp polymorphism was associated with atherosclerotic renal artery stenosis with an odds ratio of 1.44 (95% confidence interval 1.00 to 2.09) versus hypertensives with angiographically proven patent arteries, of 1.89 (1.24 to 2.87) versus hypertensive family practice controls, and of 2.09 (1.29 to 3.38) versus normotensive family practice controls. However, this allele also differed significantly between patients with patent renal arteries and normotensive and hypertensive controls. No differences were found with respect to the other genetic polymorphisms. We hypothesize that the Asp allele of the Glu298Asp polymorphism may predispose to the development of atherosclerotic lesions but that renal artery involvement depends on other factors, also.
Key Words: hypertension, renovascular • renal artery • polymorphism • nitric oxide synthase • renin-angiotensin system • case-control studies
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Introduction |
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Atherosclerotic renal artery stenosis (ARAS) is a relatively common cause of secondary hypertension.1 Today, most investigators consider this abnormality to be part of a generalized atherosclerotic complex with an etiological background similar to extrarenal atherosclerosis.
Although it is still largely unknown if and to what extent genetic abnormalities contribute to the development of this disease, polymorphisms in genes of the renin-angiotensin system rank high among the potential candidates. For instance, the D allele of the insertion/deletion variant of the angiotensin-converting enzyme (ACE) gene has been associated with atherosclerotic disease,2,3 and it is conceivable that this is true also for ARAS. Another genetic variant that could have a bearing on the renal vasculature is the angiotensin II type 1 receptor A1166C (AT1R A1166C) polymorphism. Patients homozygous for the C allele of this polymorphism have increased sensitivity to angiotensin II4 and may, in combination with the DD genotype of the ACE gene, have an increased risk of cardiovascular complications.5 Finally, the angiotensinogen Met235Thr (AGT Met235Thr) polymorphism is of interest because the Thr allele of this polymorphism is associated with high plasma levels of AGT and increased responsiveness to angiotensin II.6
In addition to studies of angiotensin II and its precursors, many studies have highlighted the importance of endothelium-derived nitric oxide (NO) in inhibiting atherosclerotic disease and the possibility that impairment of endothelial NO production promotes atherosclerosis. NO is produced by endothelial nitric oxide synthase (eNOS). The gene encoding eNOS has a G-to-T polymorphism at position 894 leading to substitution of Glu by Asp at codon 298 of the eNOS protein. The mutant allele is associated with a reduced response to the eNOS inhibitor L-NMMA in healthy volunteers7 and may be related to the occurrence of atherosclerotic complications.
Although a few earlier studies have addressed the possible role of candidate genes such as the ones described in renovascular disease,8–11 none of these has been performed in patient populations that were primarily selected for their risk for ARAS. This is important because of the complex yet unresolved relation between anatomical abnormalities and clinical symptoms of renovascular disease.12 In the present study, therefore, we have examined the distribution of the alleles of the aforementioned 4 candidate genes in a group of patients in whom renovascular hypertension was clinically suspected and who all underwent renal angiography for this reason.
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Methods |
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Patients
Between January 1995 and December 2002, 456 patients referred to our outpatient clinic for evaluation of their hypertension underwent renal angiography. Hypertension was defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg on at least 3 occasions. All patients fulfilled 1 or more of the following criteria: persistent elevation of blood pressure despite the use of 2 or more antihypertensive drugs, accelerated hypertension, documented atherosclerotic vascular disease in 2 or more vascular beds, the presence of an abdominal bruit, or unexplained impairment of renal function in response to antihypertensive treatment.
Since mid 1996, we ask for written permission from all newly referred patients to draw a 3-mL blood sample for genetic analysis, as approved by the local Medical Ethics Committee. Patients who had undergone angiography between January 1995 and June 1996 were sent a letter with the request to visit our laboratory to donate a blood sample. Medical history and risk factor profiles were derived from the clinical files.
Two experienced readers evaluated all angiographic films and reported on the site and nature of the aberration and the (maximum) percent stenosis via standardized forms. If the 2 estimates of the degree of stenosis differed by >10%, then a third opinion was decisive. Because there is no consensus on what degree of renal artery narrowing is hemodynamically significant and because atheromatous renal artery abnormalities are likely to progress in time,13 we divided our study participants into 2 groups: (1) patent renal arteries and (2) (any grade of) atheromatous renal artery disease. Patients with nonatheromateous renal artery disease (mainly fibromuscular dysplasia) were excluded from analysis.
Control Populations
Hypertensive (n=154) and normotensive (n=200) subjects from the HIPPOCRATES study, which is an ongoing study on cardiovascular risk and genetics in a general practice in Kerkrade, the Netherlands, served as control groups for the ACE insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp genotype distributions. The details of the enrollment of the study participants have been published previously.14
Genetic Analysis
Genetic analysis was performed as previously described14 (the primers used for detection of the angiotensinogen Met235Thr, the ACE insertion/deletion, the angiotensin II type 1 receptor A1166C, and the eNOS Glu298Asp polymorphisms can be found in an online supplement available at http://www.hypertensionaha.org.).
Statistical Analysis
Statistical significance for differences in quantitative variables was tested by unpaired t tests or Mann–Whitney tests when appropriate. Allele and genotype frequencies and other qualitative data were analyzed using 
2 tests. Hardy–Weinberg equilibrium was tested using standard methods.15 Genetic models were further evaluated by logistic regression analysis to "correct" for those variables (confounders), which would alter the interpretation of the relationship between genotype and presence of renal artery abnormalities when not included in the model.16 We regarded age, sex, body mass index, pulse pressure, and renal function as potential confounders. We choose to regard only pulse pressure of the blood pressure parameters in our analysis because imputing systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well would inevitably lead to collinearity (Pearson correlation coefficients were 0.83 for pulse pressure versus SBP, 0.28 for pulse pressure versus DBP, and 0.76 for SBP versus DBP; P<0.0001 for all). We introduced the potential confounders independently into a model that contained genotype and assessed the change of the regression coefficient of the central determinant (genotype). The variable that led to the greatest change was retained in the model, provided that this change was at least 10%. The remaining potential confounders were then introduced again into the new model (containing genotype and the confounder). This was repeated until no more variables had to be retained. Interactions between 2 polymorphisms were tested in models that included the alleles (risk allele present or not present), the interaction between the 2, and confounders when applicable. We assumed that both groups from the family practice contained no subjects with renal artery stenosis. However, previous studies suggest that secondary hypertension is present in 
5% of hypertensive patients and renovascular hypertension in 1%.17–20 To the best of our knowledge, no such data are available on the presence of incidental renal artery stenosis in subjects without hypertension, but conceivably this value is much lower. We tested the robustness of statistically significant results in the hypertensive group by a sensitivity analysis21 by modeling odds ratios after deleting 5% of the subjects in this group with all possible alleles. Data are expressed as mean±SD or median (interquartile range) or odds ratio (95% confidence interval) unless indicated otherwise. A 2-sided P<0.05 was considered statistically significant. Statistical analyses were performed with SPSS 10.0 for Windows (SPSS Inc).
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Results |
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Patient Characteristics
Of the 456 patients who underwent angiography, genotyping was available in 401 (88%). The remainder did not differ from the genotyped patients regarding demographics or important potential confounders. Thirty-three of the 401 patients had fibromuscular dysplasia diagnosed and, therefore, were excluded from analysis. Thus, the present report is based on the remaining 368 subjects. In 109 (30%) of these, atherosclerotic renal artery abnormalities were present, among which there were 70 (19%) with a renal arterial lumen reduction of >50%.
General characteristics of the 4 study groups are presented in Table 1. As expected, normotensive and hypertensive controls from the general practice had lower SBP, DBP, and pulse pressures in comparison to the subjects with renal artery stenosis. In addition, they were more often female and had higher body mass index (although not statistically significant in the normotensive group). Normotensive controls were slightly older than the angiography group, whereas the hypertensive controls were a bit younger. In the angiography group, patients with renal artery stenosis (ARAS+) presented with a worse cardiovascular risk profile than individuals with nondiseased renal arteries (ARAS–). They were older, more often male, and had a longer history of hypertension (6 [2 to 17] versus 4 [4 to 11] years; P=0.014). In addition, they had higher pulse pressure, a lower estimated creatinine clearance (56±22 versus 87±32 mL/min; P<0.001), and were more often hypercholesterolemic (45% versus 29%, P=0.003) and diabetic (16% versus 9%, P=0.043). Finally, they more often had atherosclerotic manifestations in other vascular beds (43% versus 22%; P<0.001).
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Genetic Analyses
The distribution of the polymorphisms in the control populations was compatible with the Hardy–Weinberg equilibrium, whereas this was not the case in the angiography group with respect to the eNOS Glu298Asp (only ARAS–) and the AGT Met235Thr polymorphisms. (Table 2). No differences in either genotype or allele frequencies were found between the normotensive and the hypertensive control group.
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Normotensive Controls Versus Patients With ARAS+
The distribution of the eNOS Glu298Asp polymorphism was different between normotensive controls and subjects with renal artery disease (2=17.6; P<0.0001). When the presence of renal artery disease was taken as a dependent variable in logistic regression and the Glu/Glu as reference category, the odds ratios of the Glu/Asp and Asp/Asp genotypes were 1.33 (0.79 to 2.26) and 4.45 (2.13 to 9.30), respectively. After correction for pulse pressure, sex, and age, the odds ratios were 1.39 (0.61 to 3.16) and 5.08 (1.61 to 16.0), respectively. To allow comparison with data from the angiography group, we also performed analysis of allele frequencies, which yielded comparable results (Table 3). The frequency of the ACE insertion/deletion and the ATR1 A1166C polymorphisms did not differ between controls and patients with renal artery stenosis. There were no interactions between the polymorphisms.
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Hypertensive Controls Versus Patients With ARAS+
Genotype frequencies of the eNOS Glu298Asp polymorphism were different between hypertensive controls and subjects with renal artery disease (2=10.2, P=0.006). When the presence of renal artery disease was taken as a dependent variable in logistic regression and the Glu/Glu as reference category, the odds ratios of the Glu/Asp and Asp/Asp genotypes were 1.22 (0.69 to 2.18) and 2.88 (1.33 to 6.23), respectively. After correction for pulse pressure and sex, the odds ratios were 1.29 (0.66 to 2.53) and 4.17 (1.73 to 10.05), respectively. Analysis of allele frequencies yielded comparable results (Table 3). This association remained even when one would assume that 5% of the hypertensive controls had incidental renal artery stenosis (and therefore would have had to be excluded from analyses). For details, please see the online supplement. The frequencies of the ACE insertion/deletion and the ATR1 A1166C polymorphisms did not differ between controls and patients with renal artery stenosis. There were no interactions between the polymorphisms.
Angiography Group: ARAS– Versus ARAS+
The genotype frequency distribution was not different with regard to the polymorphisms undergoing study. Because there was no Hardy–Weinberg equilibrium with respect to the eNOS Glu298Asp and the AGT Met 235 Thr polymorphisms, we also tested differences in allele frequency. Again, this did not yield significant results. However, logistic regression analysis showed that the Asp allele had an odds ratio of 1.44 in comparison to the Glu allele on ARAS, conditionally on estimated creatinine clearance (Table 3). There were no interactions between the polymorphisms.
ARAS Versus Controls
When the ARAS– group was contrasted with the 2 general care control groups, the Asp allele appeared to be significantly more frequent in ARAS– than in both control groups. For details, see the online supplement.
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Discussion |
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The objective of our study was to investigate the association of several candidate genes with ARAS in a population of patients with hypertension and clinical clues suggesting the presence of renal artery stenosis. All patients were subjected to angiography and the prevalence of renal artery abnormalities in this group was 30%. We found that patients with ARAS (ARAS+) were more often carriers of the Asp allele with regard to the eNOS Glu298Asp polymorphism. Because this association only just reached statistical significance, we sought for additional evidence that the association was a genuine one. Therefore, we compared ARAS+ to 2 sets of nondiseased controls: 1 of hypertensive and 1 of normotensive subjects, who were drawn from a family practice. Again, the Asp allele had a significantly higher prevalence in patients with renovascular disease. Nevertheless, even the use of these control groups is not free of assumptions. The prevalence of renal artery stenosis among hypertensive patients in population samples is, reported to be low,
1%.17–20 Still, we remain uncertain about the true prevalence of ARAS in controls. However, model analysis showed that our results are robust to a low prevalence of this condition in the control group. Furthermore, the Maastricht hospital is the nearest academic center, but it is not the closest hospital. This implies that patients from Kerkrade with a moderate severe clinical picture have a lower probability of undergoing renal angiography in Maastricht than patients with similar symptoms from the Maastricht region and will therefore be underrepresented in this study. Yet, we have no clues indicating that our current controls from a general care practice are any different from a random selection of subjects from a general practice in Maastricht. Positive findings in an association study can be attributed to 3 situations. First, the allele itself directly affects the expression of the phenotype. Second, the allele is in linkage disequilibrium with another allele that is responsible for the effect. Third, the association is brought about by confounding or selection bias.22 Whereas the first 2 situations do not hamper the use of a polymorphism for predicting the presence of a condition, the third obviously does. One of the major concerns in this respect is the presence of selection bias. The routine use of the Hardy–Weinberg equilibrium test has been advocated to reduce false-positive findings.23 Hardy–Weinberg equilibrium was absent in ARAS–. We can only speculate about the explanation for this phenomenon, but it is very likely to be related to the fact that these patients are not truly healthy controls. The under-representation of heterozygotes in ARAS– especially suggests that the presence or absence of the Asp allele itself may have influenced the chance for an individual being selected for angiography according to our criteria.
Our finding of an association between the presence of renal artery stenosis and the eNOS Glu298Asp polymorphism should be interpreted cautiously because the prevalence of Asp carriers was also higher in the ARAS– group than in the control groups. This implies that the ARAS– group differed from controls by a (unmeasured) variable (or possibly variables) that coincides with the differences in genotype distribution of the eNOS Glu298Asp polymorphism. Although we cannot rule out that the mutant gene polymorphism is associated with more severe hypertension, because both ARAS– and ARAS+ patients had substantially higher blood pressure than controls, this option does not fully explain the data either, because we accounted for blood pressure differences by logistic regression analysis. Although the introduction of pulse pressure in the logistic regression analysis may seem debatable because we cannot rule out causality (via the possible scenario that the Asp allele leads to a high pulse pressure, which subsequently causes angiographically detectable ARAS), we found that the odds ratio on renal artery stenosis increased when pulse pressure was accounted for. In case of causality, we would have expected a decrease of the odds ratio in the adjusted model. Moreover, all reports regarding blood pressure or presence of hypertension and the eNOS Glu298Asp polymorphism in whites are negative.24–28 Alternatively, (differences in) the total burden of atherosclerosis may account for our findings. Other investigators previously found the eNOS Glu298Asp polymorphism to be related to the presence of atherosclerotic manifestations such as coronary artery disease29–31 and carotid atherosclerotic plaques,32 although negative reports have also been published.28 Because atherosclerotic renovascular disease is generally viewed as a local manifestation of systemic atherosclerotic disease, at least our data in ARAS+ are in line with these earlier observations. Even the results in ARAS– patients may be compatible with more severe atherosclerosis in these individuals. The absence of atherosclerotic lesions in renal arteries does not at all exclude the presence of atherosclerosis elsewhere in the vascular system, and 22% of the ARAS– patients had experienced signs of extrarenal atherosclerosis. Moreover, it is likely that normotensive and hypertensive patients with relatively mild forms of hypertension in a general care practice have lower amounts of (extrarenal) atherosclerosis than patients in an outpatient clinic of a tertiary referral hospital who are suspected of having renal artery stenosis. In this respect, the difference between ARAS– and ARAS+, namely proven renal artery atherosclerosis, may just be a marker of more widespread atherosclerosis. Indirectly, this hypothesis is supported by the differences between the groups regarding pulse pressure, which is commonly associated with the severity of atherosclerosis, although it cannot be ignored that ARAS+ had a far worse risk profile. Yet, because the extent of extrarenal atherosclerosis was not investigated in our study, we cannot exclude other explanations.22,23,33
The most obvious candidate genes to look at when renal artery disease is the object of study, the ones of the renin-angiotensin system, were evenly distributed among all groups, at least with respect to the polymorphisms in the genes that we studied. Only a few studies have focused on the association between ARAS and genetic polymorphisms, and all have addressed the ACE insertion/deletion polymorphism.8–11 Two groups compared the distribution of the ACE insertion/deletion genotypes between ARAS and normotensive groups and found the D allele to be more prevalent in ARAS.9,11 The AGT Met 235T and the ATR1 A1166C polymorphisms were not found to be associated with ARAS.11 When, however, patients with ARAS were compared with patients with diffuse atherosclerotic disease who underwent angiography on the suspicion of aortic aneurysm, no association was found with the ACE genotype.8 The only study that compared hypertensive patients with renal artery stenosis to hypertensive patients without renal artery stenosis found an overrepresentation of DD homozygotes in the renal artery stenosis group,10 but it must be emphasized that in only 38% of the patients angiography of the renal arteries was performed on the suspicion of renovascular hypertension. Our study is the first to our knowledge to examine 3 different polymorphisms of the renin-angiotensin system in hypertensive patients who were all selected according to the same criteria for angiography. With our standardized approach, we did not find an association between these genotypes and ARAS.
Perspectives
Taking all data together, we hypothesize that the Asp allelle of the eNOS Glu298Asp polymorphism predisposes to (systemic) atherosclerosis but that the extent of the lesions, among which are those in the renal arteries, depends also on additional risk factors. Considering the importance of endothelium-derived nitric oxide in atherosclerosis, our findings fit very well in the theoretical framework of atherosclerotic disease and merit further research into the mechanisms whereby altered nitric oxide production in conjunction with other cardiovascular risk factors may cause systemic and/or renal atherosclerosis.
Received February 22, 2004; first decision March 10, 2004; accepted July 27, 2004.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. McLaughlin K, Jardine AG, Moss JG. ABC of arterial and venous disease. Renal artery stenosis. BMJ. 2000; 320: 1124–1127.
2. Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A. ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol. 2000; 20: 484–492.
3. Staessen JA, Wang JG, Ginocchio G, Petrov V, Saavedra AP, Soubrier F, Vlietinck R, Fagard R. The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. J Hypertens. 1997; 15: 1579–1592.[CrossRef][Medline] [Order article via Infotrieve]
4. Spiering W, Kroon AA, Fuss-Lejeune MM, Daemen MJ, de Leeuw PW. Angiotensin II sensitivity is associated with the angiotensin II type 1 receptor A(1166)C polymorphism in essential hypertensives on a high sodium diet. Hypertension. 2000; 36: 411–416.
5. Tiret L, Bonnardeaux A, Poirier O, Ricard S, Marques-Vidal P, Evans A, Arveiler D, Luc G, Kee F, Ducimetiere P, Soubrier F, Cambien, F. Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet. 1994; 344: 910–913.[CrossRef][Medline] [Order article via Infotrieve]
6. Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, Solorio D, Fisher NDL, Hollenberg NK, Williams GH. Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension. Circulation. 2002; 105: 1921–1927.
7. Veldman BA, Spiering W, Doevendans PA, Vervoort G, Kroon AA, de Leeuw PW, Smits P. The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide. J Hypertens. 2002; 20: 2023–2027.[CrossRef][Medline] [Order article via Infotrieve]
8. Losito A, Parente B, Cao PG, Jeffery S, Afzal AR. ACE gene polymorphism and survival in atherosclerotic renovascular disease. Am J Kidney Dis. 2000; 35: 211–215.[Medline] [Order article via Infotrieve]
9. Missouris CG, Barley J, Jeffery S, Carter ND, Singer DR, MacGregor GA. Genetic risk for renal artery stenosis: association with deletion polymorphism in angiotensin 1-converting enzyme gene. Kidney Int. 1996; 49: 534–537.[Medline] [Order article via Infotrieve]
10. Olivieri O, Grazioli S, Pizzolo F, Stranieri C, Trabetti E, Beltrame F, Girelli D, Pignatti PF, Corrocher R. Different impact of deletion polymorphism of gene on the risk of renal and coronary artery disease. J Hypertens. 2002; 20: 37–43.[CrossRef][Medline] [Order article via Infotrieve]
11. Olivieri O, Trabetti E, Grazioli S, Stranieri C, Friso S, Girelli D, Russo C, Pignatti PF, Mansueto G, Corrocher R. Genetic polymorphisms of the renin-angiotensin system and atheromatous renal artery stenosis. Hypertension. 1999; 34: 1097–1100.
12. Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med. 2001; 344: 431–442.
13. Caps MT, Perissinotto C, Zierler RE, Polissar NL, Bergelin RO, Tullis MJ, Cantwell-Gab K, Davidson RC, Strandness DE Jr. Prospective study of atherosclerotic disease progression in the renal artery. Circulation. 1998; 98: 2866–2872.
14. Henskens LH, Spiering W, Stoffers HE, Soomers FL, Vlietinck RF, de Leeuw PW, Kroon AA. Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population: first results of the Hippocrates study. J Hypertens. 2003; 21: 81–86.[CrossRef][Medline] [Order article via Infotrieve]
15. Sham P. Statistics in human genetics. Arnolds Applications of Statistics. London: Arnold; 1998.
16. Confounding and interaction in regression. In: Muller KE, eds. Applied Regression Analysis and Other Multivariable Methods, 2nd ed. Boston: PWS-KENT Publishing Company; 1988: 163–180.
17. Berglund G, Andersson O, Wilhelmsen L. Prevalence of primary and secondary hypertension: studies in a random population sample. BMJ. 1976; 2: 554–556.
18. Sigurdsson JA, Bengtsson C, Tibblin E, Wojciechowski J. Prevalence of secondary hypertension in a population sample of Swedish women. Eur Heart J. 1983; 4: 424–433.
19. Lewin A, Blaufox MD, Castle H, Entwisle G, Langford H. Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program. Arch Intern Med. 1985; 145: 424–427.
20. Detection, evaluation, and treatment of renovascular hypertension. Final report. Working Group on Renovascular Hypertension. Arch Intern Med. 1987; 147: 820–829.
21. Hollis S. A graphical sensitivity analysis for clinical trials with non-ignorable missing binary outcome. Stat Med. 2002; 21: 3823–3834.[CrossRef][Medline] [Order article via Infotrieve]
22. Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet. 2003; 361: 598–604.[CrossRef][Medline] [Order article via Infotrieve]
23. Tiret L, Cambien F. Departure from Hardy-Weinberg equilibrium should be systematically tested in studies of association between genetic markers and disease. Circulation. 1995; 92: 3364–3365.[Medline] [Order article via Infotrieve]
24. Karvonen J, Kauma H, Kervinen K, Rantala M, Ikaheimo M, Paivansalo M, Savolainen MJ, Kesaniemi YA. Endothelial nitric oxide synthase gene Glu298Asp polymorphism and blood pressure, left ventricular mass and carotid artery atherosclerosis in a population-based cohort. J Intern Med. 2002; 251: 102–110.[CrossRef][Medline] [Order article via Infotrieve]
25. Jachymova M, Horky K, Bultas J, Kozich V, Jindra A, Peleska J, Martasek P. Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. Biochem Biophys Res Commun. 2001; 284: 426–430.[CrossRef][Medline] [Order article via Infotrieve]
26. Markus HS, Ruigrok Y, Ali N, Powell JF. Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke. 1998; 29: 1908–1911.
27. Meyrier A, Dratwa M, Sennesael J, Lachaud-Pettiti V. Fixed low-dose perindopril-indapamide combination in hypertensive patients with chronic renal failure. Am J Hypertens. 1998; 11: 1087–1092.[Medline] [Order article via Infotrieve]
28. Jeerooburkhan N, Jones LC, Bujac S, Cooper JA, Miller GJ, Vallance P, Humphries SE, Hingorani AD. Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease. Hypertension. 2001; 38: 1054–1061.
29. Colombo MG, Andreassi MG, Paradossi U, Botto N, Manfredi S, Masetti S, Rossi G, Clerico A, Biagini A. Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298
Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart. 2002; 87: 525–528.
30. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O’Shaughnessy KM, Brown MJ. A common variant of the endothelial nitric oxide synthase (Glu298Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999; 100: 1515–1520.
31. Paolo Rossi G, Cesari M, Zanchetta M, Colonna S, Maiolino G, Pedon L, Cavallin M, Maiolino P, Pessina AC. The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study. J Am Coll Cardiol. 2003; 41: 930–937.
32. Lembo G, De Luca N, Battagli C, Iovino G, Aretini A, Musicco M, Frati G, Pompeo F, Vecchione C, Trimarco B. A common variant of endothelial nitric oxide synthase (Glu298Asp) is an independent risk factor for carotid atherosclerosis. Stroke. 2001; 32: 735–740.
33. Deng HW, Chen WM, Recker RR. Population admixture: detection by Hardy-Weinberg test and its quantitative effects on linkage-disequilibrium methods for localizing genes underlying complex traits. Genetics. 2001; 157: 885–897.
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