Published online before print January 19, 2004, doi: 10.1161/01.HYP.0000111585.76299.f7
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(Hypertension. 2004;43:477.)
© 2004 American Heart Association, Inc.
Scientific Contribution |
Positional Identification of Hypertension Susceptibility Genes on Chromosome 2
From the Human Genetics Center and Institute of Molecular Medicine (R.A.B., E.B.), University of Texas Health Science Center at Houston; the McKusick-Nathans Institute of Genetic Medicine (A.C.), Johns Hopkins University School of Medicine, Baltimore, Md; the Department of Preventive Medicine and Epidemiology (R.S.C.), Loyola University Medical Center, Maywood, Ill; the Section of Preventive Medicine and Epidemiology (C.E.), Boston University Medical Center, Boston, Mass; the Cardiovascular Genetics Division (S.C.H.), University of Utah, Salt Lake City; the Division of Biostatistics (M.A.P.), Washington University School of Medicine, St. Louis, Mo; the Division of Hypertension and Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minn; and the Division of Hypertension (A.B.W.), University of Michigan, Ann Arbor.
Correspondence to Eric Boerwinkle, PhD, 1200 Herman Pressler, RAS E-453 Houston, Texas 77030. E-mail Eric.Boerwinkle{at}uth.tmc.edu
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Abstract |
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Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.
Key Words: hypertension • genes • blood pressure • association • genetic linkage
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Introduction |
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Complex traits, such as blood pressure level and hypertension status, have many contributing susceptibility genes, each with a relatively small effect.1 Over the last decade, multiple genome-wide linkage analyses have been conducted to localize genes influencing hypertension status and blood pressure levels in a number of population samples and ethnic groups. No single study has yielded definitive evidence, but consistency of results across some of these studies suggests that linkage can guide efforts to localize hypertension susceptibility genes. Multiple linkage analyses have provided statistical evidence that one or more genes on chromosome 2 between 40 and 140 cM from the tip of the p-arm influence blood pressure and hypertension status.2–8 Broad linkage peaks shifted across the chromosome and the fact that every study sample does not reveal a noticeable peak in the same region are consistent with the expectation that multiple genes, each with a small effect, influence blood pressure and contribute to hypertension. The present study reports the results of a study to follow-up evidence of significant linkage on chromosome 2 to identify genes that may influence hypertension status and/or blood pressure level. It is not the goal of this study to "prove" that single genes are involved or to identify causative functional mutations. Such inferences require a convergence of evidence from multiple experimental, clinical, and association studies, for which the data presented here provides a starting point.
When following up a significant linkage result, samples in which the linkage was initially observed will, for practical reasons, comprise the follow-up samples. First, because of the phenotypic and genotypic heterogeneity inherent in complex traits, another sample may not include segregation of the "disease" allele with enough information for it to be detectable. Second, after detecting a promising association with a gene, one would like to know whether polymorphisms in the gene account for the observed linkage result. Finally, the cost of collecting new population samples usually precludes large-scale de novo studies. The multicomponent, multicenter structure of the Family Blood Pressure Program (FBPP) allows for large-scale linkage and association analyses and confirmation of significant results with validation of results in independent samples. The search for hypertension genes reported here focuses on the following analytic steps: (1) define follow-up region based on consistent linkage; (2) select positional candidate genes from databases based on known/inferred information; (3) test polymorphisms within candidate genes; (4) adjust for multiple comparisons; (5) verify significance with permutation test and conditional linkage; and (6) validate results in secondary samples.
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Methods |
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Study Participants
All individuals in this study are participants in one of the networks of the FBPP and provided informed consent. Descriptions of original ascertainment, exclusion, and phenotype collection have been previously described.9–12 The FBPP is described at http://www.hypertension.genetics.org and by The FBPP Investigators.9
Large-scale genotyping and initial genetic analyses involved participants in the Genetic Epidemiology Network of Atherosclerosis (GENOA) study of the FBPP. GENOA subjects include 1640 African American subjects (1182 hypertensive, 448 nonhypertensive, 10 undetermined) in 559 sibships from Jackson, Miss; 1339 white individuals (996 hypertensive, 322 nonhypertensive, 21 undetermined) in 487 sibships from Rochester, Minn; and 1616 Mexican Americans (694 hypertensive, 809 nonhypertensive, 113 undetermined) in 412 sibships from Starr County, Tex. The Jackson and Rochester sibships were ascertained on the basis of having two or more siblings defined as hypertensive through either blood pressure measurement (>140/90 mm Hg) or previous diagnosis and prescription for antihypertensive medication. Normotensive siblings were collected when available. Starr County had a slightly different ascertainment scheme because of the high prevalence of type II diabetes and its association with hypertension.9 In Starr County, the sibships were ascertained on the basis of having two or more siblings with type II diabetes, with siblings without diabetes collected when available. Hypertension status was also defined by the same combination of measured blood pressure (>140/90 mm Hg) or previous diagnosis of hypertension and use of antihypertensive medications. The GENOA samples are the primary samples used in analyses reported here; they will hereafter be referred to as the primary African American sibship sample, primary white sibship sample, and primary Mexican American sibship sample.
Subsequent follow-up genotyping and analyses involved participants in both the GenNet and Hypertension Genetic Epidemiology Network (HyperGEN) studies of the FBPP. The GenNet family-based sample includes 778 African American subjects in 528 nuclear families from Maywood, Ill, and 967 white subjects in 301 nuclear families from Tecumseh, Mich. The GenNet sibships were ascertained on the basis of the proband having an elevated blood pressure (>80th percentile for age/sex for African Americans and >75th percentile for age/sex for whites) and one or more siblings available for study regardless of blood pressure level or hypertension status. Parents of the siblings were also collected when available. As part of the secondary validation samples, the GenNet samples will hereafter be referred to as the secondary African American sibship sample and the secondary white sibship sample. For the HyperGEN sample, unrelated cases were selected from sibships with severe hypertension defined as one or more siblings with a blood pressure >160/100 mm Hg or two or more classes of antihypertensive medications. If more than one sibling met this definition of "severe," then the individual with the earliest age at onset of hypertension was selected as the index case for the sibship. The unrelated controls were a random sample of normotensive individuals collected from the same field centers concurrently with the hypertensive sibships. Ethnic groups were analyzed separately, with 230 hypertension cases and 231 controls for African Americans, and 304 hypertension cases and 246 controls for whites from HyperGEN's 5 field centers (Birmingham, AL; Forsyth County, NC; Framingham, Mass; Minneapolis, Minn; and Salt Lake City, UT) represented. The HyperGEN samples are also part of the secondary validation samples; they will hereafter be referred to as the secondary African American case-control sample and the secondary white case-control sample.
Genotyping
Genotyping of 30 microsatellite markers across chromosome 2 (average of 8.9 cM between markers) in the primary sibship samples was performed using standard methods by the Mammalian Genotyping Center of the Marshfield Medical Research Foundation (CHLC/Weber screening set 9.0). Single nucleotide polymorphisms (SNPs) were selected in positional candidate genes in the region using the public NCBI database (http://www.ncbi.nlm.nih.gov) and the private Celera database (http://www.celeradiscoverysystem.com). SNP genotyping on a total of 82 loci in 8 candidate genes was obtained using a combination of two genotyping platforms: mass spectrometer-based detection implemented on a Sequenom MassARRAY system, and the fluorogenic TaqMan assay implemented on a ABI Prism 7900 Sequence Detection System. Primer and probe sequences are available online in Figure I at http://www.hypertensionaha.org.
Statistical Analyses
Multipoint linkage analyses for the primary sibship samples were conducted using Allegro, version 1.1, using allele sharing methods under the linear model.13 Haplotype estimation in the samples of siblings was performed by the same program.
The linkage disequilibrium structure across the region was investigated using GOLD (http://www.sph.umich.edu/csg/abecasis/GOLD), which provides a graphical summary of linkage disequilibrium measures between pairs of loci.14 Using an unrelated sample of one sibling selected at random from each family, the expectation maximization (EM) algorithm was utilized to infer haplotype frequencies.
The family-based association test (FBAT) allows testing for association of genetic loci with both qualitative and quantitative traits in samples of sibships and can be used even if no parental genotype data are available.15 Because there were few unaffected siblings available in the primarily affected sibpair samples, the quantitative traits pulse pressure and pulse rate are also investigated as additional measures of cardiovascular function and aid in increasing the power of the association analyses. SBP and DBP were not studied as antihypertensive treatment, a criterion used to identify many of the probands, alters the values. Pulse pressure is estimated by the difference between SBP and DBP and is less affected by treatment.16
To adjust for multiple comparisons in the case of dependence between the tests (due to partial linkage disequilibrium between loci tested), a resampling-based false discovery rate (FDR) procedure was utilized, with 5000 bootstraps.17 FDR is an estimated ratio of the number of false-positives to the number of results that meet the significance threshold applied. The resampling-based FDR procedure was performed for each trait within each ethnic group in the primary sibship samples.
To evaluate whether individual polymorphisms explain the linkage result, a method of conditional linkage implemented in the STEPC version 1 software by Sun et al was utilized.18 This method compares the expectation of one allele shared identical by descent(IBD) between sibpairs to the conditional distribution of the number of alleles shared IBD by a sibpair at a particular SNP given the sibs’ genotypes at that SNP; the test statistic is applied using a form analogous to the exponential log-likelihood ratio test for linkage, with significance determined by normal approximation to the conditional distribution of each test. The null hypothesis is that "the SNP is the sole causal site in the region of linkage."18
2 and ANOVA analyses were conducted on unrelated individuals using SAS software, version 8.2 for Windows (SAS Institute Inc, Cary, NC).
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Results |
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Eight genes were selected for detailed investigation in the 40- to 140-cM region of consistent linkage on chromosome 2,2–8 including ADD2, ATP6B1, ALMS1, AMSH, SLC4A5, ADRA2B, SLC9A2, and SLC20A1. This selection was limited by functional and expression knowledge reported in databases and literature for each positional candidate gene in the region. These genes were selected as the leading positional candidate genes on the basis of their presumed function, expression in the kidney (the hypertensive effects of most monogenic forms are mediated by effects on renal sodium handling), and previous association with blood pressure regulation.19 In the primary sibship samples, the linkage results for hypertension status in this region and the approximate location of each of these genes is shown in Figure 1. The primary African American sibship sample shows the greatest evidence of linkage with hypertension status at 93 cM with a LOD score of 2.84.
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A total of 82 SNPs within the 8 positional candidate genes were genotyped in the 4595 individuals from the primary African American, white, and Mexican American sibships. The r2 measure of linkage disequilibrium between loci in the primary African American sample shows that, although linkage disequilibrium exists between loci within each gene region, there is not extensive linkage disequilibrium between loci in different genes across this region (Figure 2 and Figure II available at http://www.hypertensionaha.org). The white and Mexican American samples showed similar patterns of linkage disequilibrium as the African Americans. A color-coded presentation of significance results for association tests using FBAT is shown in Figure 3 (for a more detailed table of results, see online Figure III available at http://www.hypertensionaha.org.). Using a permutation-based method that preserves the nonindependence among SNP loci but controls for the number of tests performed, the number of significant FBAT results for the SLC4A5 gene is more than expected by chance (P=0.0042). Resampling-based FDR values, controlling for multiple comparisons conducted within a trait and ethnic group, are presented in the Table for those significant tests with an FDR estimator <10%. The SLC4A5 gene is further implicated as a hypertension-susceptibility gene by virtue of 5 SNP across the African American and white samples having FDR estimates of <10% (for complete FDR results for the primary sample set, see online Figure IV available at http://www.hypertensionaha.org.). Therefore, SLC4A5 was the only tested candidate gene that maintained statistical significance after multiple comparisons adjustment. The most significant results after FDR adjustment were seen for association with pulse pressure in the African American sample and pulse rate in the white sample. ADD2, ALMS1, SLC9A2, and SLC20A1 demonstrated nominal significance in African Americans before adjustments but did not maintain an FDR-adjustment of <10%.
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Five SNP from SLC4A5 selected on the basis of allele frequency and low pairwise-linkage disequilibrium were genotyped in the secondary sibship and case-control samples; these 5 SNP loci included hcv1137521, hcv1137534, hcv1137538, hcv1137542, and hcv8941031. The secondary African American sibship sample displayed a significant association of SLC4A5 at hcv8941031 with hypertension (P=0.0270). The secondary case-control sample achieved statistical significance for pulse pressure for SLC4A5 at hcv1137534 in African Americans (P<0.0001). No statistical significance was observed in either of the secondary white samples for the SLC4A5 loci.
The STEPC program, which tests whether the polymorphism explains the linkage result, was performed on SNP within the SLC4A5 gene in the primary African American sibship sample, with the null hypothesis that the SNP is the sole cause of linkage in the region. Using this method, no single SNP was determined to be the sole cause of the hypertension linkage result. Hcv1137526 and hcv1137542, the two SNPs with the most evidence of explaining the linkage in the region, were combined to produce estimated haplotypes in the primary African American sibship sample, with rare alleles collapsed to create a biallelic system. These estimated haplotypes did account for the observed linkage with hypertension status in this region (P=0.11; recall that the null hypothesis is that the marker is the sole causal site in the region).
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Discussion |
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The region of interest on chromosome 2 (ie, between 40 and 140 cM) was selected on the basis of consistent and convincing linkage evidence for hypertension or blood pressure in the previous studies and the primary African American sample in the present study. Of the FBPP samples available for the present study, the primary African American sibship sample provides the greatest confirmatory evidence of linkage for hypertension in the region, with a peak of 2.84 LOD at 93 cM. Analyses to investigate the role of selected genes in the linked region were performed in the same sibship sample set as that used to perform the original linkage because these sibships are presumed to be segregating for the sought-after susceptibility gene. Association analyses were performed in all 3 populations, African Americans, whites, and Mexican Americans; such methods are generally more powerful than linkage analyses. The samples of African Americans and whites were ascertained through affected siblings, and in these samples, significant association was obtained for pulse pressure and pulse rate, even after adjusting for multiple comparisons. Specifically, significant association remained for the gene SLC4A5 after controlling for multiple comparisons using a FDR method. In independent separate validation samples of cases/controls and siblings, significant association of SLC4A5 continued to be observed in African Americans. The stronger linkage and association evidence in samples of African Americans, as compared with other ethnic groups, may represent differences in allele frequencies, patterns of linkage disequilibrium, genotype-environment interaction, or chance.
The original ascertainment scheme resulted in sibships with multiple hypertensive individuals with nonhypertensive individuals collected when available.9 Lack of nonhypertensive individuals in many sibships made these families uninformative for the association analyses necessary to follow-up a linkage signal. As a result, association analyses with quantitative traits of cardiovascular function were also utilized to achieve greater statistical power. Some of the quantitative traits are potentially confounded by medication use. Because SBP and DBP are most influenced by antihypertensive treatment, these phenotypes were omitted from the analyses presented here. Instead, pulse pressure, more robust to medication status, and pulse rate are included as additional measures of cardiovascular function.
Figure 3 illustrates the significance levels observed for each candidate-gene based SNP for association tests with hypertension status, pulse pressure, and pulse rate (more detailed results online in Figure III). Because of the large number of statistical tests performed, there are concerns regarding type I errors (ie, false-positives). Even after adjusting for the multiple comparisons across the many polymorphic loci investigated, polymorphisms within SLC4A5 remained significant in the primary African American sibship sample, as well as in the primary white sibship sample. Additionally, using a method of conditional linkage in the primary African American sibship sample, although no single SNP displays P>0.05, the hcv1137526/hcv1137542 haplotype recoded as a biallelic system implicated the SLC4A5 gene as explaining the linkage in the region.
The results presented here provide consistent evidence that SLC4A5 is a candidate hypertension-susceptibility gene worthy of further investigation. Over both the primary and secondary samples investigated, polymorphisms in SLC4A5 provided evidence that variation in this gene may influence hypertension status, particularly among African American samples. Although no single polymorphism has yet been identified that is significantly associated with hypertension across all samples, the present analyses clearly implicate SLC4A5 as playing a role in hypertension. The lack of global generalization regarding specific SNP across all samples may be because of differing linkage disequilibrium structures or chance sampling not capturing enough hypertensive individuals in which this gene is playing a role (amid the considerable heterogeneity of the trait). Although specific functional loci within SLC4A5 have yet to be demonstrated, the associations that are maintained in the secondary samples provide clues to identifying the functional loci through linkage disequilibrium. Further investigation cataloguing additional variation in the gene and the linkage disequilibrium patterns in different population samples should provide useful in determining the role polymorphisms in this gene might play at the cellular and system-wide levels.
SLC4A5 is a sodium bicarbonate cotransporter, designated solute carrier family 4, member 5. The SLC4A5 locus was formerly named NBC4, as it codes for the fourth sodium bicarbonate cotransporter characterized.20 A total of 6 splicing variants of the gene have been described.20–25 Originally cloned from human heart tissue, previous studies have shown that the highest SLC4A5 expression is in the liver, testes, and spleen with moderate expression levels in the heart and kidney.26 Further characterizations of the physiological functions of the SLC4A5 gene product are necessary to better understand the potential mechanisms by which it may influence blood pressure level and hypertension status. Intermediate phenotypes, such as measuring pH or sodium transport at the cellular level, may aid in understanding if particular polymorphisms are associated with a biologically meaningful phenotype related to blood pressure regulation.
Although not maintaining statistical significance after adjustment for multiple comparisons, ADD2, ALMS1, SLC9A2, and SLC20A1 display nominal significance in the primary African American sibship sample with some duplication of results in the primary white and Mexican-American sibship samples. It is plausible that multiple hypertension genes are located within the region examined. Thus, the present suggestive findings for genes should not be ignored, particularly given other evidence that could support a role for these genes in the regulation of blood pressure. ADD2, encoding the beta subcomponent of adducin, was previously reported to be associated with hypertension in women.27 ALMS1 is a gene recently implicated in Alstrom syndrome, a rare Mendelian disorder with characteristics including obesity, diabetes, and cardiomyopathy.28,29 SLC9A2, an Na+/H+ exchanger, is expressed in many tissues, including the kidney.30 SLC20A1 is a sodium-dependent phosphate symporter with expression across tissues, including the kidney.31
Perspectives
The methodology and results reported here provide a case study of one approach for following-up the results of genetic linkage analyses to identify genes influencing blood pressure levels, hypertension status, and cardiovascular function. At the onset, we assumed that there are multiple genes influencing susceptibility to hypertension, each with a relatively small effect, and that these genes are segregating in the population samples used to identify the linked region. Through collaborative efforts within the Family Blood Pressure Program, internal validation of results has implicated SLC4A5 as a potentially important hypertension susceptibility gene on chromosome 2. Future studies should attempt to replicate these findings in other populations and should seek to identify specific polymorphisms within this gene that are directly associated with blood pressure levels and hypertension status to investigate the impact of such polymorphisms. Understanding how genetic variants influence blood pressure regulation and contribute to hypertension will require analyses at all the hierarchical levels of cardiovascular function from the genome to the organ-level function. Such an understanding will require contributions from the fields of biochemistry, physiology, and anatomy, as well as genetics. Studies of experimental animal models, in which genes can be directly manipulated and phenotypic results quantified, will play an important role in establishing the functional consequences of a gene’s variation. Better understanding of the biologic mechanisms underlying hypertension can help guide better risk assessment and targeting of treatment and preventive efforts.
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Acknowledgments |
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This work was performed as part of the FBPP through the support of the National Heart Lung and Blood Institute. GenNet: HL54512, HL54508, HL54485, HL54466, and HL64777; GENOA: HL54481, HL54504, HL54463, HL54526, HL54457, and HL54464; HyperGEN: HL54471, HL54472, HL54495, HL54497, HL54509, HL54496, and HL54473. Ruth Ann Barkley is a Howard Hughes Medical Institute Predoctoral Fellow. We would also like to thank the participants of the FBPP for their time and effort.
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Footnotes |
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The Family Blood Pressure Program principal investigators also include the following: Donna K. Arnett, Andrew Brown, John H. Eckfeldt, Robert E. Ferrell, Craig L. Hanis, Gerardo Heiss, Howard J. Jacob, Sharon L. R. Kardia, Mark F. Leppert, Albert Oberman, D. C. Rao, and Nicholas J. Schork.
Received September 30, 2003; first decision November 4, 2003; accepted November 26, 2003.
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References |
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1. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001; 69: 124–137.[CrossRef][Medline] [Order article via Infotrieve]
2. Krushkal J, Ferrell R, Mockrin SC, Turner ST, Sing CF, Boerwinkle E. Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation. 1999; 99: 1407–1410.
3. Hsueh WC, Mitchell BD, Schneider JL, Wagner MJ, Bell CJ, Nanthakumar E, Shuldiner AR. QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31–34 in Old Order Amish. Circulation. 2000; 101: 2810–2816.
4. Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, Rao DC. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec Family Study. Circulation. 2000; 102: 1956–1963.
5. Rice T, Rankinen T, Chagnon YC, Province MA, Perusse L, Leon AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC. Genomewide linkage scan of resting blood pressure: HERITAGE Family Study. Health, Risk Factors, Exercise Training, and Genetics. Hypertension. 2002; 39: 1037–1043.
6. Cooper RS, Luke A, Zhu X, Kan D, Adeyemo A, Rotimi C, Bouzekri N, Ward R, Rorimi C. Genome scan among Nigerians linking blood pressure to chromosomes 2, 3, and 19. Hypertension. 2002; 40: 629–633.
7. Atwood LD, Samollow PB, Hixson JE, Stern MP, MacCluer JW. Genome-wide linkage analysis of blood pressure in Mexican Americans. Genet Epidemiol. 2001; 20: 373–382.[CrossRef][Medline] [Order article via Infotrieve]
8. Kristjansson K, Manolescu A, Kristinsson A, Hardarson T, Knudsen H, Ingason S, Thorleifsson G, Frigge ML, Kong A, Gulcher JR, Stefansson K. Linkage of essential hypertension to chromosome 18q. Hypertension. 2002; 39: 1044–1049.
9. The FBPP Investigators. Multi-center genetic study of hypertension: the Family Blood Pressure Program (FBPP). Hypertension. 2002; 39: 3–9.
10. Kardia SL, Rozek LS, Krushkal J, Ferrell RE, Turner ST, Hutchinson R, Brown A, Sing CF, Boerwinkle E. Genome-wide linkage analyses for hypertension genes in two ethnically and geographically diverse populations. Am J Hypertens. 2003; 16: 154–157.[CrossRef][Medline] [Order article via Infotrieve]
11. Thiel BA, Chakravarti A, Cooper RS, Luke A, Lewis S, Lynn A, Tiwari H, Schork NJ, Weder AB. A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans. Am J Hypertens. 2003; 16: 151–153.[CrossRef][Medline] [Order article via Infotrieve]
12. Rao DC, Province MA, Leppert MF, Oberman A, Heiss G, Ellison RC, Arnett DK, Eckfeldt JH, Schwander K, Mockrin SC, Hunt SC. A genome-wide affected sibpair linkage analysis of hypertension: the HyperGEN network(1). Am J Hypertens. 2003; 16: 148–150.[CrossRef][Medline] [Order article via Infotrieve]
13. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A. Allegro, a new computer program for multipoint linkage analysis. Nat Genet. 2000; 25: 12–13.[CrossRef][Medline] [Order article via Infotrieve]
14. Abecasis GR, Cookson WO. GOLD–graphical overview of linkage disequilibrium. Bioinformatics. 2000; 16: 182–183.
15. Laird NM, Horvath S, Xu X. Implementing a unified approach to family-based tests of association. Genet Epidemiol. 2000; 19 Suppl1: S36–S42.[CrossRef]
16. Oparil S, Weber MA. Hypertension: A Companion to Brenner & Rector’s the Kidney. Philadelphia, Pa: W.B. Saunders, 2000.
17. Yekutieli D, Benjamini Y. Resampling-based false discovery rate controlling multiple test procedures for correlated test statistics. J Statist Plann Inference. 1999; 82: 171–196.[CrossRef]
18. Sun L, Cox NJ, McPeek MS. A statistical method for identification of polymorphisms that explain a linkage result. Am J Hum Genet. 2002; 70: 399–411.[CrossRef][Medline] [Order article via Infotrieve]
19. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001; 104: 545–556.[CrossRef][Medline] [Order article via Infotrieve]
20. Pushkin A, Abuladze N, Newman D, Lee I, Xu G, Kurtz I. Cloning, characterization and chromosomal assignment of NBC4, a new member of the sodium bicarbonate cotransporter family. Biochim Biophys Acta. 2000; 1493: 215–218.[Medline] [Order article via Infotrieve]
21. Xu J, Wang Z, Barone S, Petrovic M, Amlal H, Conforti L, Petrovic S, Soleimani M. Expression of the Na+-HCO-3 cotransporter NBC4 in rat kidney and characterization of a novel NBC4 variant. Am J Physiol Renal Physiol. 2003; 284: F41–50.
22. Pushkin A, Abuladze N, Newman D, Tatishchev S, Kurtz I. Genomic organization of the DCTN1-SLC4A5 locus encoding both NBC4 and p150(Glued). Cytogenet Cell Genet. 2001; 95: 163–168.[CrossRef][Medline] [Order article via Infotrieve]
23. Pushkin A, Abuladze N, Newman D, Lee I, Xu G, Kurtz I. Two C-terminal variants of NBC4, a new member of the sodium bicarbonate cotransporter family: cloning, characterization, and localization. IUBMB Life. 2000; 50: 13–19.[Medline] [Order article via Infotrieve]
24. Sassani P, Pushkin A, Gross E, Gomer A, Abuladze N, Dukkipati R, Carpenito G, Kurtz I. Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter. Am J Physiol Cell Physiol. 2002; 282: C408–416.
25. Soleimani M, Burnham CE. Na+:HCO(3-) cotransporters (NBC): cloning and characterization. J Membr Biol. 2001; 183: 71–84.[CrossRef][Medline] [Order article via Infotrieve]
26. Soleimani M. Na+:HCO3- cotransporters (NBC): expression and regulation in the kidney. J Nephrol. 2002; 15 Suppl5: S32–S40.[Medline] [Order article via Infotrieve]
27. Wang JG, Staessen JA, Barlassina C, Fagard R, Kuznetsova T, Struijker-Boudier HA, Zagato L, Citterio L, Messaggio E, Bianchi G. Association between hypertension and variation in the alpha- and beta-adducin genes in a white population. Kidney Int. 2002; 62: 2152–2159.[CrossRef][Medline] [Order article via Infotrieve]
28. Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S, White C, Connolly V, Taylor JF, Russell-Eggitt I, Bonneau D, Walker M, Wilson DI. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet. 2002; 31: 79–83.[Medline] [Order article via Infotrieve]
29. Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P, Beck S, Boerkoel CF, Sicolo N, Martin M, Nishina PM, Naggert JK. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet. 2002; 31: 74–78.[CrossRef][Medline] [Order article via Infotrieve]
30. Burckhardt G, Di Sole F, Helmle-Kolb C. The Na+/H+ exchanger gene family. J Nephrol. 2002; 15 Suppl5: S3–S21.[Medline] [Order article via Infotrieve]
31. Kavanaugh MP, Miller DG, Zhang W, Law W, Kozak SL, Kabat D, Miller AD. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters. Proc Natl Acad Sci U S A. 1994; 91: 7071–7075.
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 C. A. Gurnett, R. Veile, J. Zempel, L. Blackburn, M. Lovett, and A. Bowcock Disruption of Sodium Bicarbonate Transporter SLC4A10 in a Patient With Complex Partial Epilepsy and Mental Retardation Arch Neurol, April 1, 2008; 65(4): 550 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kato, T. Miyata, Y. Tabara, T. Katsuya, K. Yanai, H. Hanada, K. Kamide, J. Nakura, K. Kohara, F. Takeuchi, et al. High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project Hum. Mol. Genet., February 14, 2008; 17(4): 617 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Hunt Tyrosine Hydroxylase: Another Piece of the Genetics of Hypertension Puzzle Circulation, August 28, 2007; 116(9): 970 - 972. [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Arnett and for the Writing Group Summary of the American Heart Association's Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1682 - 1686. [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Morrison, L. A. Bare, L. E. Chambless, S. G. Ellis, M. Malloy, J. P. Kane, J. S. Pankow, J. J. Devlin, J. T. Willerson, and E. Boerwinkle Prediction of Coronary Heart Disease Risk using a Genetic Risk Score: The Atherosclerosis Risk in Communities Study Am. J. Epidemiol., July 1, 2007; 166(1): 28 - 35. [Abstract] [Full Text] [PDF]
|
|
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|
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|
D. K. Arnett, A. E. Baird, R. A. Barkley, C. T. Basson, E. Boerwinkle, S. K. Ganesh, D. M. Herrington, Y. Hong, C. Jaquish, D. A. McDermott, et al. Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group Circulation, June 5, 2007; 115(22): 2878 - 2901. [Abstract] [Full Text] [PDF]
|
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|
 B. Kalmyrzaev, A. Aldashev, M. Khalmatov, A. Polupanov, A. Jumagulova, L. Mamanova, M. R. Wilkins, and M. Town Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family Hypertension, November 1, 2006; 48(5): 908 - 913. [Abstract] [Full Text] [PDF]
|
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|
 A. Pushkin and I. Kurtz SLC4 base (HCO3-, CO32-) transporters: classification, function, structure, genetic diseases, and knockout models Am J Physiol Renal Physiol, March 1, 2006; 290(3): F580 - F599. [Abstract] [Full Text] [PDF]
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S. C. Hunt, Y. Xin, L. L. Wu, R. M. Cawthon, H. Coon, S. J. Hasstedt, and P. N. Hopkins Sodium Bicarbonate Cotransporter Polymorphisms Are Associated With Baseline and 10-Year Follow-Up Blood Pressures Hypertension, March 1, 2006; 47(3): 532 - 536. [Abstract] [Full Text] [PDF]
|
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S. Padmanabhan, C. Wallace, P. B. Munroe, R. Dobson, M. Brown, N. Samani, D. Clayton, M. Farrall, J. Webster, M. Lathrop, et al. Chromosome 2p Shows Significant Linkage to Antihypertensive Response in the British Genetics of Hypertension Study Hypertension, March 1, 2006; 47(3): 603 - 608. [Abstract] [Full Text] [PDF]
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W. Chen, S. Li, S. R Srinivasan, E. Boerwinkle, and G. S. Berenson Autosomal Genome Scan for Loci Linked to Blood Pressure Levels and Trends Since Childhood: The Bogalusa Heart Study Hypertension, May 1, 2005; 45(5): 954 - 959. [Abstract] [Full Text] [PDF]
|
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 P. Meneton, X. Jeunemaitre, H. E. de Wardener, and G. A. Macgregor Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases Physiol Rev, April 1, 2005; 85(2): 679 - 715. [Abstract] [Full Text] [PDF]
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A. F. Dominiczak, D. Graham, M. W. McBride, N. J.R. Brain, W. K. Lee, F. J. Charchar, M. Tomaszewski, C. Delles, and C. A. Hamilton Cardiovascular Genomics and Oxidative Stress Hypertension, April 1, 2005; 45(4): 636 - 642. [Abstract] [Full Text] [PDF]
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