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(Hypertension. 1998;31:730-733.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Lack of Association Between the -Adducin Locus and Essential Hypertension in the Japanese Population

Norihiro Kato; Takao Sugiyama; Toru Nabika; Hiroyuki Morita; Hiroki Kurihara; Yoshio Yazaki; ; Yukio Yamori

From the Graduate School of Human and Environmental Studies, Kyoto University (N.K., Y. Yamori); the Institute for Adult Diseases Asahi Life Foundation, Tokyo (T.S.); the Department of Laboratory Medicine, Shimane Medical University (T.N.); and the Third Department of Internal Medicine, Tokyo University (H.M., H.K., Y. Yazaki).

Correspondence to Norihiro Kato, MD, PhD, Graduate School of Human and Environmental Studies, Kyoto University, Yoshida Nihonmatsu-cho Sakyo-ku, Kyoto 606, Japan. E-mail kato{at}helios.jinkan.kyoto-u.ac.jp

	Abstract

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Abstract—Significant linkage and association of -adducin, a cytoskeleton protein involved in transmembrane ion transport, with essential hypertension were recently shown in Caucasian populations, especially in relation to salt sensitivity. The present study investigated the relevance of this candidate gene to hypertension in a well-characterized Japanese population. A total number of 507 individuals were selected from clinic outpatients. Hypertensive subjects were defined on the basis of the individual's blood pressure readings before starting medications; the criteria included systolic blood pressure 160 mm Hg and/or diastolic blood pressure 95 mm Hg. Patients with diabetes mellitus, renal failure, and secondary forms of hypertension had been excluded. Control subjects had blood pressure values <130/85 mm Hg. The allele frequency of a genetic variant at amino acid residue 460 of -adducin (460Trp) was compared between cases and control subjects with ² statistics; in addition, the association was tested with blood pressure as a continuous variable. No significant association was found in either of the statistics tested. The 460Trp variant appeared to be relatively common in the Japanese (54% to 60%) compared with a reported prevalence of 13% to 23% in Caucasians. The present study brought up an important issue concerning the pathophysiological role of -adducin in non-Caucasian populations, given the likely ethnic variation in the nature of genetic susceptibility loci. The 460Trp variant of the -adducin gene is unlikely to have a major effect on susceptibility to hypertension in the Japanese population studied, although the present study does not exclude the involvement of -adducin in the pathogenesis of hypertension.

Key Words: hypertension, essential • case-control studies • sodium, dietary • -adducin • Japanese • genetics

	Introduction

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Essential hypertension is considered to be a multifactorial disease involving genetic and environmental factors. Both factors may interact with each other, leading to the chronic manifestation of elevated BP. If the biochemical and physiological mechanisms that regulate BP are considered, a number of candidate genes present themselves. In addition, human homologues of genes predisposing to hypertension in animal models, particularly inbred hypertensive rats, may also confer susceptibility to hypertension in human beings. Although a number of potential candidate genes have been investigated in hypertension in human beings, few studies seem to have shown conclusive claims about their identification. This may reflect difficulties in the replication of supportive findings under complex circumstances modulating hypertension; for example, the heterogeneous nature of genetic susceptibility and gene-environment interactions. Among the candidate genes tested for EH, the -adducin gene has been implicated as susceptible to hypertension, especially in relation to salt sensitivity, first in rats^{1 2} and then in human beings.^{3 4} Adducin is a membrane skeleton protein consisting of - and ß-subunits. Point mutations in rat adducin subunits were shown to be associated with faster ion transport in genetically hypertensive rats—the Milan hypertensive strain—than in their normotensive control rats—the Milan normotensive strain.^{2 5} Therefore this candidate gene is supposed to explain part of the genetic susceptibility causing BP variation in the two contrasting rat strains. In human beings, a few studies for case-control and/or linkage have demonstrated the potential involvement of -adducin in the pathogenesis of EH.^{3 4} Cusi et al⁴ have recently shown that a genetic variant at amino acid residue 460 of -adducin (460Trp), which resulted in the substitution of Trp for Gly, was associated with EH in a Caucasian population. It is a reasonable question whether or not the association can be replicated in another ethnic group.⁶ We thus conducted an association study in a well-characterized Japanese population. Although association has not been replicated in the present study, the allele frequency of the genetic variant of -adducin proved to be higher in the Japanese (54% to 60%) compared with a reported prevalence of 13% to 23% in Caucasians.⁴

	Methods

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Patients and Control Subjects
This study was approved by an institutional review committee. A total number of 507 individuals selected from outpatients at the Institute for Adult Diseases Asahi Life Foundation were investigated in the present study. Informed consent for participation was obtained from all subjects. Two BP measurements were taken with a sphygmomanometer on separate visits and averaged as the individual's readings. Criteria of hypertension for participants are as follows: (1) SBP 160 mm Hg and/or DBP 95 mm Hg on two consecutive visits for those untreated; (2) absence of a secondary form of hypertension through extensive workup; and (3) subjects with a history of diabetes mellitus and renal failure were excluded. In addition, to minimize nongenetic effects of physiological BP increase related to ageing, we only included hypertensive individuals who were diagnosed before 60 years of age. Here, the age onset of hypertension was defined as the time when BP readings exceeded the above criteria on consecutive visits before starting medication. Therefore the present study did not include those who had started their antihypertensive drugs without definite records of BP readings or had not reached the BP criteria despite chronic treatment. People having SBP <130 mm Hg and DBP <85 mm Hg were categorized into a control group or otherwise regarded as unknown phenotype in the case-control study. Furthermore, to check allele frequencies of the -adducin gene, another panel of 179 healthy students who volunteered at Shimane Medical University also were genotyped.

Genotyping of the -Adducin Polymorphism
To genotype the G-to-T substitution polymorphism, which resulted in the genetic variant of amino acid residue 460 and was located at nucleotide position 614 of exon 10 of the -adducin gene (GenBank accession number L29294),⁷ we adopted the mutagenically separated PCR technique,⁸ as was used elsewhere.⁹ Briefly, two allele-specific primers and their nonselective complementary strand primer were mixed and used for the PCR amplification in a single reaction. Deliberate differences were introduced into the allele-specific primers in addition to the base substitution, and they were able to drastically reduce cross-reactions between two allelic PCRs in a mixed reaction. The following primer sets were used: FP-614G, 5'-GGGGCGAC GAAGCTTCCGAGGTAG-3'; FP-614T, 5'-GCTGAACTCTG GCCCAGGCGACGAAGCTTCCGAGGATT-3'; RP-614, 5'-CCTCCGAAGCCCCAGCTACCCA-3', in which deliberate differences and base substitutions are underlined.

PCR was performed in PTC-100 (MJ Research Inc) in a 15-µL reaction volume containing 2.4 pmol/L of FP-614G, 4.8 pmol/L of FP-614T, and 6 pmol/L of RP-614, 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 25 µmol/L each of dNTPs, 0.4 U Ampli-Taq DNA Polymerase (Perkin Elmer), and 3 mmol/L MgCl₂. The initial denaturation for 3 minutes at 95°C was followed by 35 cycles of denaturation for 20 seconds at 94°C, annealing for 30 seconds at 60°C, and extension for 30 seconds at 72°C. The size of PCR products was 220 bp and 234 bp for the 460Gly and 460Trp alleles, respectively, which were clearly resolved on 4% agarose gel (NuSieve, 3:1 agarose, FMC Bioproducts).

Statistical Analysis
For hypertensive individuals, an initial value for BP at the onset of hypertension was used in the analysis. Statistical analysis was performed in two ways as follows: First, BP was considered as a continuous variable and association of the 460Trp variant with BP was tested with one-way ANOVA, using all the individuals typed. Second, the likelihood ratio ² statistics were calculated between allele frequencies and hypertension status as defined above. Confounding influences of age and BMI were assessed in a multiple logistic regression model.

	Results

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No significant association was replicated in either of the statistics tested except that a borderline association was found between SBP and a wild-type allele (460Gly) of -adducin (P=.05) (Table 1). Table 2 displays the clinical characteristics of participants according to hypertension status. The lack of observed association was independent of age and BMI. When the case group was further subdivided into severe hypertensive patients (eg, onset of age before 50 years or drug therapy with more than two medications), there was still no significant association (data not shown). Hardy-Weinberg equilibrium (HWE) was tested by a standard goodness-of-fit test,¹⁰ and the population studied was shown to be in HWE, with allele frequencies at the cutoff significance level of 5%. Of note is that allele frequencies were similar between the cases, the control group, and the healthy reference group (Table 3). The 460Trp variant proved to be relatively common in Japanese (54% to 60%) compared with a reported prevalence of 13% to 23% in Caucasians.⁴

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Participants According to Genotypes at Residue 460 of -Adducin

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics of Participants According to Hypertension Status

View this table: [in this window] [in a new window]   Table 3. -Adducin Genotypes in Case-Control and Reference Panels

	Discussion

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The present study, though showing a negative association, is of significance in at least two respects: importance of the replication study for potential susceptibility to EH and possible ethnic variation in its relevance to the pathogenesis of EH.

An association study has been carried out as a valuable tool for detecting susceptibility to various genetic disorders, both monogenic and polygenic diseases. Risch and Merikangas¹¹ recently argued that an association study should be a complementary approach to pedigree-based linkage analysis, especially in the dissection of genes predisposing to polygenic complex diseases; that is, susceptibility genes with "major" effects on the variance of disease phenotype are likely to be identified by linkage analysis, whereas those with "minor" effects can be detected only by the candidate gene/association strategy. In principle, the two approaches are distinct from each other, and hence results replicated in both of them appear to be encouraging, as is the case with -adducin. On the other hand, a number of reports have urged caution in interpreting the results of association studies of complex diseases^{12 13 14} because false-positive results (and false-negative results) may frequently occur, dependent on confounding factors, for example, population stratification, lack of power because of small sample size, and inappropriate adjustment of the significance level to declare positive associations. Thus one or more independent replications are required to confirm the results originally implicated.

Another important issue is to assess the relevance of the -adducin gene to EH in non-Caucasian populations, given the likely ethnic variation in the nature of genetic susceptibility loci. For example, positive linkage and association between the angiotensinogen (AGT) locus and EH were initially found in Caucasians,^{15 16} followed by replications in African Caribbeans¹⁷ and in the Japanese,^{18 19 20} whereas negative associations were also reported in Caucasians^{21 22} and African Americans.²³ The same molecular variant of AGT—the T 235 allele—was shown to bear susceptibility in both Caucasians and Japanese,⁹ although the allele frequency was significantly higher in Japanese and black populations than in Caucasians. In the present study the 460Trp variant of -adducin appeared to be relatively common in the Japanese as well. Differences of these allele frequencies may partly result from genetic drift during the history of individual populations.

Despite a relatively large amount of dietary salt consumed in Japan, it has been reported that the Japanese people may have developed an ethnically unique resistance to salt excess.²⁴ Supposing that the molecular variant of -adducin exerts its genetic effect on BP with relation to salt sensitivity, it is of interest to further characterize the polymorphism with clinical variables for salt sensitivity in the Japanese, although appropriate evaluation of salt sensitivity generally requires invasive procedures such as acute salt loading and depletion protocol.²⁵

To reduce the risk of uncertain ascertainment of hypertensive subjects and control subjects, we set the selection criteria as clearly as possible on the basis of averaged BP readings before the initiation of antihypertensive drugs for the hypertensive subjects. Even so, heterogeneous genetic and environmental backgrounds within the population may make it difficult to detect small statistical differences, if any. Further investigations including the generation of haplotypes^{9 26} and family-based tests for linkage disequilibrium²⁷ are required to clarify whether or not the molecular variants of -adducin predispose to hypertension in the Japanese and in other ethnic populations.

In conclusion, it is unlikely that the 460Trp variant of the -adducin gene has a major effect on susceptibility to EH in the Japanese population studied, although the present study does not exclude the involvement of -adducin in the pathogenesis of hypertension.

	Selected Abbreviations and Acronyms

 

BMI = body mass index BP = blood pressure DBP = diastolic blood pressure EH = essential hypertension PCR = polymerase chain reaction SBP = systolic blood pressure

	Acknowledgments

 
We gratefully acknowledge Chie Fujinami for assisting us in DNA preparation and data arrangement.

Received August 14, 1997; first decision September 11, 1997; accepted November 5, 1997.

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