AJCN Cancer Health Disparities Conference
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Related articles in AJCN
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.
Agricola
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.
American Journal of Clinical Nutrition, Vol. 88, No. 2, 392-397, August 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Blood pressure and interactions between the angiotensin polymorphism AGT M235T and sodium intake: a cross-sectional population study1,2,3

Teresa Norat, Richard Bowman, Robert Luben, Ailsa Welch, Kay Tee Khaw, Nick Wareham and Sheila Bingham

1 From the MRC Dunn Human Nutrition Unit, Cambridge, United Kingdom (TN, RB, and SB), and the Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (RB, RL, AW, KTK, NW, and SB)

See corresponding editorial on page 255.

2 Supported by the Food Standards Agency and the Medical Research Council, United Kingdom.

3 Reprints not available. Address correspondence to SA Bingham, MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom. E-mail: sab{at}mrc-dunn.cam.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Intervention studies have indicated an interaction between the blood pressure response to a low-sodium or a low-fat and high-fruit and -vegetable diet and the angiotensinogen gene (AGT) polymorphisms G-6A and M235T.

Objective: We investigated whether this interaction is also present in a large free-living population.

Design: Urinary sodium, potassium as biomarkers of intake, and blood pressure were measured in 11 384 men and women aged 45–79 y participating in the Norfolk arm of the European Prospective Investigation of Nutrition and Cancer (EPIC). The M235T polymorphism was assessed by pyrosequencing.

Results: Highly significant associations between sodium and blood pressure were shown for all genotypes (P < 0.001), but the regression coefficient for systolic blood pressure associated with each unit of sodium for each of the MT and TT genotypes was approximately double that for the MM homozygotes (P < 0.001 for heterogeneity between genotypes). Differences were evident at high exposures to sodium but not at low exposures. There were no significant associations between blood pressure and dietary or urinary potassium.

Conclusions: This large cross-sectional study supports public health recommendations to reduce salt consumption in the population as a whole, and it confirms intervention trial data showing the greatest response to intervention in persons with the AA and TT genotype in the AGT G-6A and M235T polymorphisms. Genotype effects in populations at low exposure to sodium are not likely to be seen.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is extensive evidence that dietary sodium intake plays a role in regulating blood pressure and that a reduction in salt intake lowers blood pressure not only in hypertensive persons but also in normotensive persons (1-6). Several genes have also been shown to be linked to blood pressure, and the gene encoding angiotensinogen has met relatively stringent criteria supporting its role in the pathogenesis of essential hypertension. Secreted by the liver, angiotensinogen undergoes sequential cleavage by renin and angiotensin I–converting enzyme to produce the active hormone angiotensin II, which promotes a rise in blood pressure (7-10).

An A-to-G nucleotide substitution in the promoter region on the angiotensinogen gene (AGT) 6 nucleotides upstream from the start site of transcription is a functional mutation (11). Some evidence indicates that this polymorphism may affect the response to dietary interventions to reduce blood pressure. In a large low-fat, high-fruit and -vegetable intervention study [the Dietary Approaches to Stop Hypertension (DASH) study], blood pressure responses were greatest in persons with the AA genotype of the AGT G-6A polymorphism and lowest in those with the GG genotype (12). In the Hypertension Prevention Phase II (TOHP) study, the AA genotype was associated with a larger reduction in blood pressure than were the GA and GG genotypes after dietary salt reduction and weight loss (13).

In addition, there is a methionine-to-threonine transition, caused by a T->C single-nucleotide polymorphism (SNP) at codon 235 (M235T) in the proximal promoter. Although this polymorphism has been definitively excluded as the functional variant by biochemical analysis of recombinant M235 and T235 molecules (14), it is in very tight linkage equilibrium with AGT G-6A and is associated with higher concentrations of angiotensinogen, (7), with hypertension phenotypes (9, 10, 15-18), and with identical associations in intervention trials (13, 19).

We investigated whether the AGT M235T polymorphism influences the cross-sectional relation of blood pressure with sodium in a large, free-living population of 11 384 men and women participating in the Norfolk arm of the European Prospective Investigation of Nutrition and Cancer (EPIC-Norfolk). Because there is evidence that potassium intake is related to blood pressure (5, 19-22), potassium was also investigated. In contrast to invention trials, this study was sufficiently large to differentiate gene effects at different levels of exposure to sodium and potassium. Sodium and potassium in casual spot urine samples were used as sources of biomarkers of intake together with a medium-throughput genotyping technique, pyrosequencing. For operational reasons, the functional AGT G-6A polymorphism could not be identified with the use of this technique, and thus the tightly linked AGT M235T polymorphism using the reverse complement strand was assessed as a surrogate for the G-6A polymorphism.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The EPIC-Norfolk study
This cross-sectional analysis took place in the EPIC-Norfolk, which is an exclusively white prospective cohort of men and women recruited at age 45–79 y between 1993 and 1997. At the baseline survey, 30 445 participants completed detailed health and lifestyle questionnaires that included questions on smoking, alcohol consumption, usual physical activity, socioeconomic status, occupational history, use of medication, dietary changes, history of disease, and, for women, reproductive history (23).

Between 1993 and 1997, 25 639 participants attended a health check, at which trained nurses collected data on height, weight, and blood pressure and took blood samples and urine specimens. Nonfasting serum total cholesterol, HDL-cholesterol, and triacylglycerol concentrations were measured with an RA 1000 Technicon analyzer (Bayer Diagnostics, Basingstoke, United Kingdom). Casual urine specimens collected at the health check were frozen without preservative at –20 °C. Between 1998 and 2002, the urine samples were thawed and assayed for creatinine on a Roche Cobas Mira Plus analyzer (Roche, Welwyn, United Kingdom), and assayed for sodium and potassium concentrations by flame photometry (IL 943; Instrumentation Lab, Warrington, United Kingdom). Urinary electrolyte ratios [sodium-to-creatinine (Na:Cr) and potassium-to-creatinine (K:Cr)] were calculated.

Blood pressure was measured by using a noninvasive oscillometric blood pressure monitor (Acutorr; Datascope Medical, Huntingdon, United Kingdom) after the participant had been seated in a comfortable environment for 5 min. The arm was horizontal and was supported at the level of the midsternum; the mean of 2 readings was used for analysis. Acutorr readings were checked against those from sphygmomanometers every 6 mo. Participants also completed a 7-d diary and a food-frequency questionnaire, but, because these methods do not measure discretionary salt consumption, the ratio of dietary sodium to potassium (Na:K) was <1.0, and these data are not included in this report (24-26).

All participants are followed up for their health status, and, as part of follow-up, all baseline participants were invited back for a second health check at the beginning of 1998. At that time, an additional 9 mL blood was collected in EDTA for DNA extraction and genotyping; 15 783 persons attended, of whom 14 937 gave blood.

The participants provided written informed consent for the use of their medical records, to attend a health check, and for blood samples to be used at a later date. Approval of the study was granted by the Norfolk and Norwich Hospital Ethics Committee.

Genotyping
A contract laboratory (Whatman International, Maidstone, United Kingdom) used the phenol-chloroform method to extract genomic DNA from the blood samples collected at the second health check. The DNA was then robotically arrayed into 96-well plates at the EPIC laboratory, which were stored at –20 °C until genotyping.

The genotyping was performed on a PSQ 96MA pyrosequencing platform (Pyrosequencer; Biotage, Uppsala, Sweden). Full details of the pyrosequencing sample-preparation procedure were provided elsewhere (27-30). Test runs with the AGT G-6A were variable on the Pyrosequencer, possibly because the hairpin loop formation interfered with the pyrosequencing assay. The AGT M235T single-nucleotide polymorphism (SNP) (rs699), which was in very tight linkage disequilibrium with G-6A, was used instead, because of its robustness. AGT M235T genotypes were obtained by using polymerase chain reaction (PCR) to amplify 12-ng EPIC DNA samples to produce a 156-bp product, by using the primers 5'-biotin GAACTGGATGTTGCTGCTGA-3' and 5'-AGAG-CCAGCAGAGAGGTTTG-3'. These primers were designed in-house with the use of the Biotage PSQ Primer design software (Biotage). The PCR mix was 1x PCR Buffer, 2 mmol MgCl2/L, 1.5 U Taq Gold (Applied Biosystems, Warrington, United Kingdom), and 0.125 mmol/L of each dNTP (Amersham Biosciences, Amersham, United Kingdom). DNA (3 µL; 12 ng) was added to make a final volume of 25 µL. The PCR thermocycling profile was 95 °C for 5 min (95 °C for 20 s, 57 °C for 20 s, 72 °C for 20 s) x 49 and 72 °C for 10 min; it was performed on MJ PTC-200 DNA Tetrad DNA Engines (MJ Research, Waltham, MA).

The samples were then genotyped by using the PSQ 96MA Operating Software (version 2.1; Biotage) with a sequencing primer (5'- CCACACTGGCTCCC-3') and a dispensation order of CGAGTCAGA. The actual SNP for M235T is a T->C substitution; however, the pyrosequencing was done by using the reverse complement strand, which resulted in an allele call of A->G. To avoid confusion with existing literature, M and T allele calls have been used in subsequent results and tables.

The AGT M235T assay was validated by using 48 samples and a restriction protocol using TthIII restriction endonuclease (31). Here, a 165-bp product yields a digest 141-bp product in the presence of the T235 variant. Samples from the control set of DNA were genotyped with the Pyrosequencer, and the process was repeated with the respective restriction fragment length polymorphism (RFLP) assays, with full concordance between the Pyrosquencing assays and the RFLP assays.

All genotyping was carried out blind at the Dunn Human Nutrition Unit. The finished data were sent to the EPIC-Norfolk coordinating center, where they were combined with the first-health-check data from the main EPIC database. The combined database was then issued for statistical analysis.

Statistical analysis
Baseline characteristics of cohort participants according to AGT M235T genotype and sex were summarized in means and SDs for quantitative variables and in number and percentages for qualitative variables. Mean values across genotypes were compared by using analysis of variance for continuous variables and chi-square tests for categorical variables.

We examined the relation of systolic (SBP) and diastolic (DBP) blood pressure with urinary excretion of Na:Cr and K:Cr by regression analysis. Regression coefficients (b) were standardized to show the change of blood pressure for every 1-SD change of sodium or potassium. Age (continuous), sex, smoking status (never, former smoker, or current smoker), BMI (continuous), and use of antihypertensive medication at health check were included as covariates in the models. These covariates were defined a priori. We tested the change of the estimates after the inclusion of FFQ alcohol intake, weight, socioeconomic status, educational level, physical activity, total serum cholesterol concentration, and serum cholesterol fractions (instead of total cholesterol) in the model. Only alcohol intake (<5, 5–10, 10–20, 20–40, or >40 g/d), physical activity (5 categories), and total serum cholesterol concentrations (continuous) were included in the final models. The inclusion of other covariates did not substantially modify the results (because they altered <10% of variation in the regression coefficient estimate). We wished to examine the independent relation of sodium with blood pressure, and therefore we adjusted the analyses of sodium by potassium when appropriate.

We examined whether the AGT M235T polymorphism modified the relation between blood pressure and urinary excretion of sodium and potassium in analyses stratified by AGT M235T genotype. Heterogeneity was examined by chi-square tests based on the inverse variance method (32).

We also estimated least-square means of SBP and DBP across quintiles of urinary excretion by using linear regression with the same covariates included in the previous analyses. Linear trend was tested by scoring the categories according to an ordinal variable and entering the variable as a continuous term in the analysis of variance. Differences across genotypes were tested by adding an interaction term for the genotype and the exposure variable.

All P values presented are 2-tailed, and P < 0.05 was considered statistically significant. Analyses were performed by using STATA software (version 9.2; Stata Corp, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Complete urinary electrolyte excretion, blood pressure, and genotype data were available for 11 384 persons aged 45–79 y (5202 M, 6182 F). The main characteristics of the study population by AGT M235T genotype and sex are shown in Table 1Go. The MM genotype was carried by 4000 persons (35% of the study participants), and the TT variant was carried by 16%. The distribution according to genotype was similar in men and women and similar to the distribution of AGT G-6A and M235T observed in other white populations (7). No significant differences across genotypes were observed in age, BMI, smoking status, physical activity level, socioeconomic status, serum cholesterol concentrations, urinary Na:Cr and K:Cr, or antecedents of disease in men and women. Mean SBP and DBP were significantly higher in women with the homozygous TT genotype than in women with heterozygous MT or homozygous MM genotype (P value = 0.001). Blood pressure levels did not vary across the AGT M235T genotype in men.


View this table:
[in this window]
[in a new window]

  		TABLE 1 Main characteristics at baseline of subjects aged 45–79 y by M235T angiotensinogen (AGT) genotype in the European Prospective Investigation into Nutrition and Cancer–Norfolk Cohort1

 
The results of the regression analyses of blood pressure levels on urinary excretion of electrolytes are shown in Table 2Go. SBP was positively related to urinary Na:Cr (β standardized = 0.12, P value < 0.001), as was DBP (β standardized = 0.09, P value < 0.001). Urinary K:Cr was not significantly related to SBP or DBP.


View this table:
[in this window]
[in a new window]

  		TABLE 2 Regression of systolic (SBP) and diastolic (DBP) blood pressure on urinary excretion of sodium and potassium according to M235T angiotensin (AGT) genotype in men and women aged 45–79 y in the European Prospective Investigation into Nutrition and Cancer–Norfolk

 
Regression analyses stratified by AGT M235T genotype are shown in Table 2Go. The regression coefficients were of similar magnitude in men and women, and results are presented for the 2 sexes combined. We tested the heterogeneity of the relations of urinary sodium and potassium with blood pressure levels by including an interaction term for sex and urinary concentrations of electrolytes in the regression models. None of the interaction terms was statistically significant (P > 0.10 in all models except the relation of DBP with urinary potassium, for which P = 0.06 in the strata of subjects with TT genotype).

In all genotypes, DBP and SBP were positive and significantly (P < 0.001) related to urinary sodium, with significant heterogeneity across AGT M235T genotype for sodium and SBP (P < 0.001). The regression coefficient for SBP for each unit of sodium for the MT and TT genotypes was approximately double than that for the MM genotype (P < 0.001). For DBP, there was also a significant interaction according to genotype for sodium (P = 0.02). There were no significant relations and no significant interactions for potassium.

The results of the categorical regression analyses were similar in trends to those obtained with the continuous regression analyses There was a 5-mm Hg difference in mean SBP between the lowest and the highest quintiles of sodium, which corresponded to a 3-fold mean Na:Cr (Table 3Go).


View this table:
[in this window]
[in a new window]

  		TABLE 3 Least-square adjusted means (SE) of systolic (SBP) and diastolic (DBP) blood pressure by quintile of urinary excretion according to angiotensinogen (AGT) genotype in 11 384 men and women aged 45–79 y in the European Prospective Investigation into Cancer and Nutrition–Norfolk1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this large study of 11 384 men and women, the interactions between SBP and DBP, angiotensinogen genotype, and urinary excretion of sodium and potassium have been examined. Biomarkers of sodium and potassium in urine were used, because of the underestimation of sodium intake from food diaries and FFQs. There were no associations with potassium intake and blood pressure with the use of these methods (data not shown).

Highly significant associations between blood pressure and sodium were shown in the population as a whole or when stratified by genotype. The associations with sodium and blood pressure were weakest in subject with the MM-homozygous AGT M235T genotype, and there were significant interactions for SBP in the continuous analysis. In this large population, we were able to show that the associations of genotype and blood pressure were most evident in the top quintile of sodium intake. However, there were no differences in SBP according to Na:Cr at the lowest quintile of intake. The differences in the association between genotype and blood pressure across different sodium intake levels show the importance of measuring not only genotype but also lifestyle exposures when attempting to assess the effect of genotypes on disease risk markers.

Trials have shown that changing sodium intake changes blood pressure in hypertensive persons, but correlations within a population between sodium intake and blood pressure have been less consistent (3, 33). In the present study, we confirmed our results showing a strong relation between urinary excretion of sodium from causal samples and markers of sodium intake in a larger previous study in the EPIC-Norfolk cohort (4). Other work with biomarkers of dietary intake in spot urine supports the utility of these samples in assessing gene-nutrient interactions, at least in this large population (34). Although this trial was cross-sectional rather than interventional, it is plausible that the relation between blood pressure and dietary sodium in this free-living population reflects a causal relation; however, the magnitude of the effect is likely to be attenuated by the random measurement error from the use of spot urine samples. The positive association of sodium intake with blood pressure appeared to be stronger with SBP than with DBP. Urinary sodium excretion has been shown in some studies (20, 35, 36) to relate significantly to SBP but not to DBP. In a clinical trial in normotensive and hypertensive elderly subjects, there was a linear relation with SBP and DBP, but the increase was greater for SBP (37).

Blood pressure, responses to high salt intake, and the degree of salt sensitivity vary between persons and racial groups (38). Differences have also been shown between whites and African Americans in the distribution of the AGT G-6A and M235T genotypes (12). In this exclusively white population, we showed only very small effects of the M235T genotype on blood pressure and a significant effect only in women.

In contrast, the relation of sodium to blood pressure was observed in all persons, but the regression coefficient was of greater magnitude in persons carrying the T allele (corresponding to the A allele of AGT G-6A) than in persons not carrying the T allele, with significant interactions between the genotypes for both SBP and DBP. These results showing strong associations between blood pressure and salt intake with respect to the T allele are in line with the TOPH study Phase II, in which blood pressure levels were significantly lower after salt restriction in patients carrying the AA genotype of AGT G-6A (corresponding to the T variant measured here), and there was no effect in the patients with the MM genotype after 36 mo of reduced sodium intake (13). In the DASH study, blood pressure responses were also greatest in subjects with the AGT G-6A AA genotype and least in those with the GG genotype (P = 0.009) (12). However, not all trials are consistent, possibly because of different exposures, different racial compositions, and small sample size (10, 38, 39).

The power of this very large cross-sectional study has allowed interactions to be shown, particularly at higher exposures of sodium intake. Nevertheless, all genotypes showed highly significant associations between salt and blood pressure, a finding that supports current public health recommendations for an overall reduction in the salt content of food in populations as a whole.


   ACKNOWLEDGMENTS
 
The authors’ responsibilities were as follows—TN: statistical analysis and writing the first draft of the manuscript; RB: the genotyping; RL: the formation and collection of the databases; AW: collection of nutritional data; KTK, NW, and SB (Principal Investigators of the EPIC Norfolk study): assisted with statistical analyses and reviewed and critiqued the manuscript; and SB: initiated the work and wrote the manuscript together with TN. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988;297:319–28.[Medline]
  2. Chobanian AV, Hill M. National Heart, Lung, and Blood Institute Workshop on Sodium and Blood Pressure: a critical review of current scientific evidence. Hypertension 2000;35:858–63.[Free Full Text]
  3. Frost CD, Law MR, Wald NJ. By how much does dietary salt reduction lower blood pressure? II—Analysis of observational data within populations. BMJ 1991;302:815–8.[Medline]
  4. Khaw KT, Bingham S, Welch A, et al. Blood pressure and urinary sodium in men and women: the Norfolk Cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). Am J Clin Nutr 2004;80:1397–403.[Abstract/Free Full Text]
  5. Midgley JP, Matthew AG, Greenwood CM, Logan AG. Effect of reduced dietary sodium on blood pressure: a meta-analysis of randomized controlled trials. JAMA 1996;275:1590–7.[Abstract]
  6. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001;344:3–10.[Abstract/Free Full Text]
  7. Bloem LJ, Foroud TM, Ambrosius WT, Hanna MP, Tewksbury DA, Pratt JH. Association of the angiotensinogen gene to serum angiotensinogen in blacks and whites. Hypertension 1997;29:1078–82.[Abstract/Free Full Text]
  8. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169–80.[Medline]
  9. Rotimi C, Cooper R, Ogunbiyi O, et al. Hypertension, serum angiotensinogen, and molecular variants of the angiotensinogen gene among Nigerians. Circulation 1997;95:2348–50.[Medline]
  10. Schorr U, Blaschke K, Beige J, Distler A, Sharma AM. Angiotensinogen M235T variant and salt sensitivity in young normotensive Caucasians. J Hypertens 1999;17:475–9.[Medline]
  11. Morgan T, Craven C, Nelson L, Lalouel JM, Ward K. Angiotensinogen T235 expression is elevated in decidual spiral arteries. J Clin Invest 1997;100:1406–15.[Medline]
  12. Svetkey LP, Moore TJ, Simons-Morton DG, et al. Angiotensinogen genotype and blood pressure response in the Dietary Approaches to Stop Hypertension (DASH) study. J Hypertens 2001;19:1949–56.[Medline]
  13. Hunt SC, Cook NR, Oberman A, et al. Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II. Hypertension 1998;32:393–401.[Abstract/Free Full Text]
  14. Inoue I, Nakajima T, Williams CS, et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 1997;99:1786–97.[Medline]
  15. Brand E, Chatelain N, Paillard F, et al. Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis. Eur J Hum Genet 2002;10:715–23.[Medline]
  16. Brand-Herrmann SM, Kopke K, Reichenberger F, et al. Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives. J Hypertens 2004;22:1289–97.[Medline]
  17. Jeunemaitre X, Inoue I, Williams C, et al. Haplotypes of angiotensinogen in essential hypertension. Am J Hum Genet 1997;60:1448–60.[Medline]
  18. Sun B, Dronma T, Qin WJ, et al. Polymorphisms of renin-angiotensin system in essential hypertension in Chinese Tibetans. Biomed Environ Sci 2004;17:209–16.[Medline]
  19. Tian HG, Guo ZY, Hu G, et al. Changes in sodium intake and blood pressure in a community-based intervention project in China. J Hum Hypertens 1995;9:959–68.[Medline]
  20. The INTERSALT study. An international co-operative study of electrolyte excretion and blood pressure: further results. J Hum Hypertens 1989;3:279–407.[Medline]
  21. Elliott P, Stamler J, Nichols R, et al. Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group. BMJ 1996;312:1249–53.[Abstract/Free Full Text]
  22. Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction lower blood pressure? I—Analysis of observational data among populations. BMJ 1991;302:811–5.[Medline]
  23. Day N, Oakes S, Luben R, et al. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br J Cancer 1999;80(suppl):95–103.[Medline]
  24. Bingham SA, Gill C, Welch A, et al. Validation of dietary assessment methods in the UK arm of EPIC using weighed records, and 24-hour urinary nitrogen and potassium and serum vitamin C and carotenoids as biomarkers. Int J Epidemiol 1997;26(suppl):S137–51.[Abstract/Free Full Text]
  25. McKeown NM, Day NE, Welch AA, et al. Use of biological markers to validate self-reported dietary intake in a random sample of the European Prospective Investigation into Cancer United Kingdom Norfolk cohort. Am J Clin Nutr 2001;74:188–96.[Abstract/Free Full Text]
  26. Welch AA, McTaggart A, Mulligan AA, et al. DINER (Data Into Nutrients for Epidemiological Research)—a new data-entry program for nutritional analysis in the EPIC-Norfolk cohort and the 7-day diary method. Public Health Nutr 2001;4:1253–65.[Medline]
  27. Ahmadian A, Gharizadeh B, Gustafsson AC, et al. Single-nucleotide polymorphism analysis by pyrosequencing. Anal Biochem 2000;280:103–10.[Medline]
  28. Alderborn A, Kristofferson A, Hammerling U. Determination of single-nucleotide polymorphisms by real-time pyrophosphate DNA sequencing. Genome Res 2000;10:1249–58.[Abstract/Free Full Text]
  29. Nyren P, Karamohamed S, Ronaghi M. Detection of single-base changes using a bioluminometric primer extension assay. Anal Biochem 1997;244:367–73.[Medline]
  30. Ronaghi M, Karamohamed S, Pettersson B, Uhlen M, Nyren P. Real-time DNA sequencing using detection of pyrophosphate release. Anal Biochem 1996;242:84–9.[Medline]
  31. Russ AP, Maerz W, Ruzicka V, Stein U, Gross W. Rapid detection of the hypertension-associated Met235->Thr allele of the human angiotensinogen gene. Hum Mol Genet 1993;2:609–10.[Free Full Text]
  32. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Smith GD, Altman D, eds. Systematic reviews in health care. Meta-analysis in context. 2nd ed. London, United Kingdom: BMJ Books, 2001:285–312.
  33. Watt GC, Foy CJ. Dietary sodium and arterial pressure: problems of studies within a single population. J Epidemiol Community Health 1982;36:197–201.[Abstract/Free Full Text]
  34. Low YL, Dunning AM, Dowsett M, et al. Implications of gene-environment interaction in studies of gene variants in breast cancer: an example of dietary isoflavones and the D356N polymorphism in the sex hormone-binding globulin gene. Cancer Res 2006;66:8980–3.[Abstract/Free Full Text]
  35. Joossens JV, Kesteloot H. Trends in systolic blood pressure, 24-hour sodium excretion, and stroke mortality in the elderly in Belgium. Am J Med 1991;90:5S–11S.[Medline]
  36. Sciarrone SE, Beilin LJ, Rouse IL, Rogers PB. A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects. J Hypertens 1992;10:287–98.[Medline]
  37. Johnson AG, Nguyen TV, Davis D. Blood pressure is linked to salt intake and modulated by the angiotensinogen gene in normotensive and hypertensive elderly subjects. J Hypertens 2001;19:1053–60.[Medline]
  38. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database Syst Rev 2004;CD004937.
  39. Poch E, Gonzalez D, Giner V, Bragulat E, Coca A, de La Sierra A. Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. Hypertension 2001;38:1204–9.[Abstract/Free Full Text]
Received for publication August 16, 2007. Accepted for publication February 13, 2008.


Related articles in AJCN:

Genes and environment in blood pressure control—salt intake again shows its importance
Paul R Conlin
AJCN 2008 88: 255-256. [Full Text]  



This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
P. R Conlin
Genes and environment in blood pressure control--salt intake again shows its importance
Am. J. Clinical Nutrition, August 1, 2008; 88(2): 255 - 256.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Related articles in AJCN
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.
Agricola
Right arrow Articles by Norat, T.
Right arrow Articles by Bingham, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS