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(Hypertension. 2006;47:532.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Sodium Bicarbonate Cotransporter Polymorphisms Are Associated With Baseline and 10-Year Follow-Up Blood Pressures

Steven C. Hunt; Yuanpei Xin; Lily L. Wu; Richard M. Cawthon; Hilary Coon; Sandra J. Hasstedt; Paul N. Hopkins

From the Cardiovascular Genetics Division and Departments of Human Genetics and Psychiatry, University of Utah School of Medicine, Salt Lake City.

Correspondence to Steven C. Hunt, Cardiovascular Genetics, University of Utah, 410 Chipeta Way, Rm 167, Salt Lake City, Utah 84108. E-mail steve{at}ucvg.med.utah.edu

	Abstract

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The NaHCO₃ cotransporter gene (SLC4A5) on chromosome 2 encodes a protein that transports sodium and bicarbonate across the cell membrane and regulates cellular pH. The National Heart, Lung, and Blood Institute Family Blood Pressure Program found linkage of blood pressure–related traits to the chromosomal region containing SLC4A5 and phenotype associations with single nucleotide polymorphisms (SNPs) in this gene. However, the results were inconsistent over various phenotypes and SNPs. Nevertheless, the evidence was strong enough to propose this gene as a blood pressure–related gene. To extend these findings, SLC4A5 SNPs were genotyped in an independent set of 96 Utah pedigrees of 1040 adult subjects at baseline, 760 of whom were followed longitudinally for 10 years. After adjusting for age, gender, body mass index, and polygenic correlations within pedigrees, SNP hcv1137534 was significantly associated with both systolic blood pressure and diastolic blood pressure (DBP) at baseline (unadjusted P=0.009 and P=0.043; respectively) and at 10-year follow-up (P=0.008 and P=0.007; respectively). In secondary tests of association of baseline-stressed blood pressure, hcv1137534 was borderline or significantly associated with DBP change during an isometric handgrip test (P=0.054), DBP change from supine to standing (P=0.020), and DBP change after a 50° tilt (P=0.034). There was no evidence for compensation of abnormal SLC4A5 sodium transport by genotype-specific differences in sodium–lithium countertransport, lithium–potassium cotransport, altered plasma sodium, chloride, or CO₂ levels. Therefore, in these Utah pedigrees, the SLC4A5 gene was significantly associated with blood pressure and persisted after 10 years of follow-up. These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear.

Key Words: blood pressure • genetics • polymorphism • ion transport

	Introduction

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Linkage analysis of blood pressure traits has shown evidence for multiple chromosomal regions that appear to contain 1 hypertension genes, especially a wide region on chromosome 2.¹ The National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), made up of 4 collaborating, multicenter hypertension networks, also found linkage to this region of chromosome 2.² Candidate genes under this consensus peak were identified, and single nucleotide polymorphisms (SNPs) within those genes were genotyped to identify polymorphisms responsible for the linkage and to define new pathology leading to elevated blood pressure. The strongest signals for association of hypertension-related traits in the Genetic Epidemiology Network of Arteriopathy (GENOA) network to these candidate genes was with the SLC4A5 gene that encodes a NaHCO₃ transporter that helps control cellular pH.² Two other networks within this program confirmed the association with this gene, but the associations were not consistently found for the same SNPs in SLC4A5, nor even with the same blood pressure phenotypes. Nevertheless, 2 of the SNPs in this gene accounted for most of the linkage signal, and the overall association of the SLC4A5 gene with the measured phenotypes in the 3 networks, each with large sample sizes, supported SLC4A5 as a hypertension susceptibility gene.

The study by Barkley et al² was somewhat limited by the subject ascertainment criteria, because many of the subjects were on antihypertensive therapy at the time of their examination. Therefore, pulse pressure was the primary phenotype presented, although medicated systolic blood pressures (SBP) and diastolic blood pressures (DBP) also showed significant results (R.A. Barkley, A. Chakravarti, R.S. Cooper, R.C. Ellison, S.C. Hunt, M.A. Province, S.T. Turner, A.B. Weder, E. Boerwinkle, unpublished data, 2004).

To extend the above findings, SNPs in the SLC4A5 gene were typed in untreated members of large Utah pedigrees that had been followed longitudinally for 10 years. We sought to replicate the associations at both baseline and follow-up exams to demonstrate consistent findings over time. In subjects with abnormal Na⁺-HCO₃^– cotransport, one might expect other types of ion transporters to compensate for these changes by changing their activity and/or number. Therefore, erythrocytic sodium–lithium countertransport (Na-Li CNT), lithium–potassium cotransport (Li-K CoT), and the number of ouabain binding sites (representing the number of Na-K ATPase transport units) were tested for association with SLC4A5. Plasma levels of sodium, chloride, and CO₂ levels were also tested as intermediate phenotypes that might be affected by genetically altered NaHCO₃ transport.

	Methods

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In 1980, 2500 subjects in 98 Utah pedigrees were examined to study the genetic epidemiology of cardiovascular disease. The pedigrees were expanded from 2 probands with early stroke or coronary heart disease death or from probands with hypertension. Details of subject selection and their characteristics have been described previously.³ In 1991, these subjects were again examined to determine predictors of hypertension onset and blood pressure increases.⁴ For the current study, all of the subjects were excluded who were under age 18 at baseline and the adults who were on antihypertensive treatment. After retaining adults with 1 cleaned genotypes (described below), there were 1040 subjects at baseline in 96 pedigrees, 760 of whom had a follow-up examination averaging 10 years from baseline. The average pedigree size was 38 subjects. The University of Utah Institutional Review Board approved this study, subjects signed informed consent forms, and the procedures followed institutional guidelines.

Blood pressure was measured in a sitting position at both exams. It was measured by an automated blood pressure device that traced the blood pressure waveform on a paper disk from which phases 1, 4, and 5 of Korotkoff sounds were read (Infrasonde SR-2, Sphygmetrics, Inc). Appropriate size cuffs were determined by mid-humerus arm circumference, and an average of 4 measurements was obtained. Once the significance of the sitting blood pressures with SLC4A5 was established, secondary tests of association were performed on blood pressure reactivity. These included postural changes in blood pressure, a 50° head-up tilt on a motorized tilt table, and an isometric handgrip task. Two standing blood pressures were obtained after 2 minutes of standing from the supine position. Postural change blood pressure was calculated from the average standing minus the average supine blood pressures. Maximum handgrip strength was determined using an isometric dynamometer. Blood pressures were obtained at 1 and 2 minutes after gripping the device at 50% maximum strength, and the mean sitting blood pressure was subtracted from the average of the 2 grip blood pressure measurements. The average of blood pressures taken 30 seconds and 1 minute from the beginning of the tilt table protocol was compared with the average supine blood pressure for the tilt task. Plasma CO₂, sodium, and chloride were analyzed to test whether there were any effects of SLC4A5 SNPs on these parameters. These were obtained from a clinical chemistry panel through the University of Utah clinical laboratories. The maximum velocity of erythrocyte Na-Li CNT, the number of ouabain binding sites (estimating the number of Na-K ATPase transporters), and the rate constant of the Li-K CoT (estimating Na-K cotransport) were measured at baseline as described previously.^5–7

Genotypes were obtained for the 4 SNPs (Celera database: hcv1137521, hcv1137534, hcv1137538, and hcv8941031; dbSNP database: rs828853, rs10177833, rs6731545, and rs1006502) found to be most consistently related to blood pressure in the study from the GENOA network of the FBPP and which had been selected to be typed in 2 of the other FBPP networks.² A Roche LightTyper instrument, using melting temperature technology, was used to obtain the genotypes. After genotyping, genotypes were tested for incompatibilities by the PEDCHECK program,⁸ and nuclear families identified with incompatibilities had their genotypes set to missing (37 genotypes zeroed out, 0.9%). All of the SNPs were in Hardy–Weinberg equilibrium. Minor allele frequencies were 0.20, 0.48, 0.44, and 0.47, respectively. Linkage disequilibrium among the 4 SNPs was low in the total sample as measured by r²: 0 for hcv8941031 versus the other 3 SNPs; 0.31 and 0.16 for hcv1137521 versus hcv1137534 and hcv1137538, respectively; and 0.42 for hcv1137534 versus 1137538. The SNPs were either intronic or in the 3' untranslated region of the gene.

The QTDT program incorporates both covariate and polygenic background modeling effects while testing for genetic association. Therefore, this program was used to test for association of each SNP while adjusting for age, gender, and body mass index (BMI) and controlling for the relatedness of the pedigree members.⁹ Tests of a large number of SNPs in these pedigrees with the QTDT program have shown no evidence for population stratification. In the absence of population stratification, the total association test within the QTDT program may be used instead of the transmission disequilibrium test test, resulting in greater statistical power because of the larger sample size that can be analyzed. All of the tests were adjusted for gender, age, and BMI.

	Results

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Table 1 shows the blood pressure data at baseline and at 10-year follow-up. BMI increased by 2 units over the 10 years, and blood pressure increased by 7.6/5.8 mm Hg in those who attended both clinic exams. The grip stress test elicited the greatest blood pressure response of the 3 stress tests. Mean plasma electrolyte levels were within the normal range. Three of the SNPs did not show significant associations with any of the phenotypes (P>0.05). SNP hcv1137534 was significantly related to both baseline and follow-up SBPs and DBPs (Table 2). Change in blood pressure over the 10 years was not significantly associated with this SNP. The age-, gender- and BMI-adjusted blood pressures (±SEM) for each genotype of hcv1137534 are also shown in Table 2 and suggest evidence for a mostly recessive effect of the minor C allele on lowering blood pressure. Blood pressure differences among genotypes showing significant results ranged from 2 to 5 mm Hg. Table 3 shows the baseline mean blood pressures for the 3 SNPs not associated with blood pressure. Because of the low linkage disequilibrium among SNPs, haplotype analysis did not increase the significance of our findings.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Utah Pedigree Members at Baseline and at 10-Year Follow-Up

View this table: [in this window] [in a new window]   TABLE 2. Phenotype Means (±SEM) Across Genotypes for SNP hcv1137534 (A/C)

View this table: [in this window] [in a new window]   TABLE 3. Baseline Blood Pressure Means Across Genotypes for the 3 Nonsignificant SNPs

Secondary association tests of stressed DBP showed significance with hcv1137534 (Table 4). In addition, other significant or borderline results were found with the other SNPs in SLC4A5: postural SBP (P=0.040) and DBP (P=0.054) changes with hcv8941031; grip DBP response (P=0.026) and postural DBP change (P=0.037) with hcv1137521; and grip DBP response (P=0.089) and tilt DBP response (P=0.0064) with hcv1137538. Baseline pulse pressure was not significantly related to any SNP, and follow-up pulse pressure showed only borderline results with hcv1137521 (P=0.091).

View this table: [in this window] [in a new window]   TABLE 4. Significance Levels for Stressed Blood Pressures, Plasma Electrolytes, and Ion Transporters vs hcv1137534 (A/C)

Because functional abnormalities in SLC4A5 could have secondary effects on plasma sodium, chloride, or CO₂ levels or induce compensatory activities of the cellular Na-Li CNT, Li-K CoT, or Na-K ATPase transporters, associations with these phenotypes were tested. None of the transporter phenotypes were significantly associated with any of the 4 SNPs (all P>0.29). Likewise, the associations with plasma sodium and chloride were not significant (all P>0.30). Plasma CO₂ had a P value of 0.045 with hcv9841031, but the P value with hcv1137534 was only P=0.11. The homozygous minor allele subjects had slightly higher CO₂ (24.6 mmol/L) than the subjects with the other 2 genotypes (24.4 mmol/L).

	Discussion

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This study has replicated in another data set the association of SLC4A5 with blood pressure–related traits originally found in the FBPP.² The previous findings have been extended by showing that the association is robust longitudinally after 10 years of blood pressure follow-up and that stressed blood pressures also show associations with SLC4A5. Most subjects in the FBPP had hypertension, whereas the Utah pedigree members were generally normotensive. In addition, the hypertensive subjects that were in the Utah pedigrees were excluded so that medicated blood pressures would not confound the association analyses of blood pressure. Replication of the association in both studies which were quite different in ascertainment, strongly suggests that the findings are not false positives.

One of the 4 SNPs tested in the Utah pedigrees showed consistent associations with blood pressure. The results found in the study by Barkley et al² did not show consistent associations across the SNPs tested or for the phenotypes tested. The varying associations suggest that the causal variant(s) have not been identified and may have different linkage disequilibrium patterns across the populations tested. However, among the 3 networks involved in that study, there was still overall evidence that the associations of SLC4A5 were real and replicated. Two of the SNPs in the SLC4A5 gene explained the linkage to chromosome 2 in the program. Also, other nearby genes showed little or minimal evidence of being responsible for the linkage signal. Some evidence of association was found in the FBPP for genes more distant from SLC4A5, suggesting that there may be >1 hypertension gene in the linkage region.

The SLC4A5 gene was selected as a candidate gene by the FBPP because it was under a replicated linkage peak. However, in our Utah pedigrees, we did not see evidence for linkage of blood pressure or pulse pressure in this chromosomal region.¹⁰ Logarithm of odds scores were <0.6 for every marker in the region for SBP, DBP, and pulse pressure. This illustrates that lack of linkage does not rule out significant associations of genes in a particular region with phenotypes of interest.

The primary hypotheses tested in this study were that blood pressure at baseline and 10-year follow-up would be associated with SLC4A5. Only after significance was found were the secondary hypotheses concerning stressed blood pressure and ion transport tested. No adjustment for multiple comparisons was made for any of the P values. First, this study was designed as a replication study. Second, the 4 blood pressures tested as part of the primary hypothesis showed high correlations making it more difficult to determine what corrections should be used. The 4 SNPs were not highly correlated, but SNP selection was limited to the SNPs studied in the prior study. Even if adjustment was made for 4 independent tests of these SNPs, the P values for the main blood pressure associations, except for baseline DBP, remain significant (P<0.05). We suggest that the secondary hypothesis testing be viewed as exploratory in trying to understand function and correlates of the inferred abnormal SLC4A5 function.

Despite the consistent associations with blood pressure and less-strong associations with blood pressure reactivity, there were no significant relationships of the 4 SLC4A5 SNPs with ion transport or with serum CO₂, sodium, or chloride levels. Plasma sodium and CO₂ levels were tested for association with the SLC4A5 SNPs because of the possibility that hcv1137534 or a SNP in linkage disequilibrium with this SNP induces functional changes on Na and HCO₃ transport. Chloride was measured because other family members of SLC4A5 are involved with chloride-dependent cotransport, although SLC4A5 acts in a chloride-independent manner.¹¹ If complete counterregulation of a NaHCO₃ transport defect does not occur through other systems, these plasma measurements may be altered. However, extracellular acid-base balance is important to maintain, minimizing the probability that significant alterations would be found in plasma Na or CO₂. It is unclear how to interpret the very borderline CO₂ associations seen with 2 SNPs in this study, neither of which is significant after adjustment for multiple comparisons.

Although decreased CO₂ occurs in metabolic acidosis and can result from renal insufficiency, it seems more likely that the effects of an abnormal transporter would be intracellular. In this case, intracellular pH could be affected. Na-Li CNT is activated as cellular pH decreases¹² and could show compensatory activity. Although Na-Li CNT essentially is a Na-Na transporter in vivo, it has been thought by some to function as a Na-H antiporter in the presence of increased intracellular acidity, particularly in the proximal tubules of the kidney.¹³ If this transporter were to be stimulated/inhibited by the result of an abnormal NaHCO₃ transporter, altered sodium transport could result, with changes in the amounts of Na delivered to the loop of Henle or distal tubule/collecting duct. Changes in Na-K cotransport might then be expected to occur in the loop of Henle. However, we found no evidence that either of these 2 transporters were affected by hcv1137534 in the SLC4A5 gene. In addition, the number of Na-K-ATPase transporter units, as measured by the number of ouabain binding sites on the erythrocytic membrane, was not significantly changed, indicating that the main sodium transport system did not sense the need to increase the transporter number. Changes in transporter number can happen fairly rapidly after physiological sodium changes (eg, from diet changes)^7,14 and is an important method of controlling sodium homeostasis. Increased dietary sodium and administration of angiotensin II in animal models have been shown to increase bicarbonate reabsorption and hydrogen secretion.^15,16

If 1 of these mechanisms really are involved in the blood pressure elevation, several possibilities could be suggested for the lack of significance in this study, including: (1) the SLC4A5 effects in the subjects studied were too small to be detected with the assays used; (2) the wrong measurements of the Na-Li CNT were obtained (eg, maximum velocity instead of the rate constant); (3) the NaHCO₃ transporter abnormality acts to alter blood pressure through other pathways (eg, epithelial sodium channel or some nonsodium-related mechanism); or (4) these transporters may have downstream effects on other systems that, when altered and stabilized, allow these upstream measured systems to return to normal. It appears that any serum abnormalities that might be caused by functional polymorphisms in this gene are fully compensated for by other regulatory mechanisms. These compensatory mechanisms do not seem to include the specific parameters of the 3 sodium transporters investigated in this study. Finally, the above discussion assumes that the associations of SLC4A5 and hcv1137534 represent functionally abnormal transport of sodium and HCO₃. Actual measurements of the activity and kinetics of this transporter by genotype are required to prove this assumption. Such measurements, although difficult to perform, may additionally help define other intermediate phenotypes to identify how blood pressure might be altered.

Perspectives
Worldwide epidemiological studies have shown that dietary sodium intake has important influences on hypertension prevalence.¹⁷ In addition, the rare, monogenic hypertension syndromes involve genetic defects that act in the kidney to control sodium homeostasis. More recent evidence has shown that not only can blood pressure be reduced with dietary salt reduction^18–21 but that this reduction may be modulated by underlying genotypes of key blood pressure–regulating genes.^22–25 Two of the genes with common alleles that have had the greatest amount of evidence suggesting involvement with hypertension are the angiotensinogen and -adducin genes.^1,26,27 Both of these genes are involved in sodium control in the kidney. Therefore, it is not surprising that another gene that controls sodium levels in the kidney has now been implicated in multiple studies as a hypertension-related gene. In this case, the sodium transport involves NaHCO₃ transport. Although the mechanisms of action of this gene and of how blood pressure might be increased are not clear, the association study in this article and that of the FBPP suggest that this gene should be additionally molecularly and biochemically characterized. If the present pattern holds that most hypertension-associated genes relate to sodium metabolism, this additionally strengthens the concept that hypertension may be caused by small effects from many genes, most of which respond to sodium intake. Once substantiated, this would argue for additional demands for decreased sodium content in processed foods and increased education of the population on how to reduce dietary sodium. Only small population–wide decreases in sodium intake could have important beneficial effects on disease end points associated with hypertension.²⁸

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL21088, HL24855, HL44738, and AG18734.

Received September 27, 2005; first decision October 13, 2005; accepted November 7, 2005.

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