No clear consensus has been reached on the alpha-adducin polymorphism (Gly460Trp) and essential hypertension risk. We performed a meta-analysis in an effort to systematically summarize the possible association.
Studies were identified by searching MEDLINE and EMBASE databases complemented with perusal of bibliographies of retrieved articles and correspondence with original authors. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. We selected 22 studies that met the inclusion criteria including a total of 14303 hypertensive patients and 15961 normotensive controls. Overall, the 460Trp allele showed no statistically significant association with hypertension risk compared to Gly460 allele (P = 0.69, OR = 1.02, 95% CI 0.94–1.10, Pheterogeneity<0.0001) in all subjects. Meta-analysis under other genetic contrasts still did not reveal any significant association in all subjects, Caucasians, East Asians and others. The results were similar but heterogeneity did not persist when sensitivity analyses were limited to these studies.
Our meta-analysis failed to provide evidence for the genetic association of α-adducin gene Gly460Trp polymorphism with hypertension. Further studies investigating the effect of genetic networks, environmental factors, individual biological characteristics and their mutual interactions are needed to elucidate the possible mechanism for hypertension in humans.
Citation: Liu K, Liu J, Huang Y, Liu Y, Lou Y, Wang Z, et al. (2010) Alpha-Adducin Gly460Trp Polymorphism and Hypertension Risk: A Meta-Analysis of 22 Studies Including 14303 Cases and 15961 Controls. PLoS ONE 5(9): e13057. https://doi.org/10.1371/journal.pone.0013057
Editor: Amanda Ewart Toland, Ohio State University Medical Center, United States of America
Received: June 13, 2010; Accepted: September 3, 2010; Published: September 28, 2010
Copyright: © 2010 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was financially supported by the National High Technology Research and Development Program (2008AA02Z441) (http://program.most.gov.cn/page/pds/mian1_AA.htm?planId=AA), and the National Eleventh Five-year Plan Program (2008BAI52B03) (http://program.most.gov.cn/page/pds/mian1_BA.htm?planId=BA) from the Ministry of Science and Technology in People's Republic of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Essential hypertension (EH) is a major global public health problem which affects a large proportion of adult population worldwide. The occurrence and development of EH are regarded as a complex multifactorial disorder resulted from genetic and environmental factors, as well as their interactions . Although substantial contribution has been made to unravel the pathophysiological mechanisms of hypertension, the molecular genetics of EH is still an intricate and mysterious field. Approximately, 20% to 60% of the population variability in blood pressure (BP) is genetically determined . As a consequence, it is necessary to explore etiology from many of the genes susceptible to hypertension.
Adducin is a ubiquitously expressed heterodimeric cytoskeleton protein composed of two subunits (α-subunit and either β- or γ-subunit) which are encoded by three genes (ADD1, ADD2 and ADD3, respectively) located on different chromosomes . Previous studies in the Milan hypertensive rat strain model of hypertension and humans proved that an altered adducin function might cause hypertension through an enhanced constitutive tubular sodium reabsorption . At the molecular level, the role of alpha-adducin (ADD1) in hypertension and other cardiovascular diseases has been extensively evaluated, paying particular attention to the rs4961 (Gly460Trp, G460W or G460T) single nucleotide polymorphism (SNP) at exon 10 on chromosome 4p16.3 , in which a guanine-to-thymine transversion at nucleotide 614 leads to a glycine (Gly) to tryptophan (Trp) substitution at amino acid position 460. In clinical studies, some have reproduced the supportive association between Gly460Trp polymorphism and EH or blood pressure (BP) level –, whereas others were unable to replicate these findings –. Although a series of relevant research were carried out on the relationship of this polymorphism to hypertension risk across different nations, the results were still fairly confusing rather than conclusive and showed strong racial and regional variations. Given the accumulation of data, we have conducted a formal meta-analysis from all eligible case-control studies published to date, in order to clarify the role of Gly460Trp polymorphism in hypertension.
Materials and Methods
Identification and eligibility of relevant studies
To identify all studies that examined the association of alpha-adducin Gly460Trp polymorphism with hypertension, we conducted a systematic computerized literature search of PubMed and EMBASE databases (up to May 2010) using the following various combinations of keywords and subject terms: ‘adducin’ OR ‘ADD’, ‘polymorphism’ AND ‘hypertension’. We also retrieved additional studies through the MEDLINE option ‘related articles’. Search results were limited to articles in English and studies on human subjects without country restrictions. Only research articles were included. When studies from the same research group with overlapped population were found, only the one with larger population was included to avoid data duplication. The full text of the retrieved articles was scrutinized to decide whether information on the topic of interest was included. References of the retrieved publications were screened. If an article reported results on different ethnicity subpopulations, each subpopulation was treated as a separate study in our meta-analysis. Studies included in the meta-analysis had to meet all the following criteria: (a) using an unrelated case–control design (a retrospective, cross-sectional, or prospective study design), (b) have available genotype frequency, (c) genotype distribution of control population must be consistent with Hardy–Weinberg equilibrium (HWE). Hypertension was defined as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg and/or treatment with anti-hypertensive medication.
In order to extract the information needed, all articles were reviewed and separately collated by two independent investigators (K.L., J.L.) who checked for any discordance and reached a consensus. If they could not come to an agreement, a third one adjudicated the disagreements. The following information was collected on the genotype of Gly460Trp according to different kinds of ethnicities. First author, year of publication, country and racial descent of the subjects included, study design and characteristics were described in Table S1. Diagnostic standard of each study, sample sizes of cases and controls, genotype numbers, allele frequency in both cases and controls, and P values of HWE in controls were summarized in Table S2.
The strength of the association of Gly460Trp with hypertension was measured by odds ratio (OR) corresponding to 95% confidence interval (CI) which was calculated according to the method of Woolf . We examined the association between Trp allele of alpha-adducin Gly460Trp and hypertension risk (Trp vs. Gly), the dominant genetic model (GlyTrp+TrpTrp vs. GlyGly), the recessive genetic model (TrpTrp vs. GlyTrp+GlyGly), and homozygote comparison (TrpTrp vs. GlyGly). In our study, two models of meta-analysis were applied for dichotomous outcomes in Review-Manager 4.2 software: the fixed-effects model and the random-effects model. The fixed-effects model using the Mantel–Haenszel method, assumes that studies are sampled from populations with the same effect size, making an adjustment to the study weights according to the in-study variance. The random-effects model using the DerSimonian and Laird's method, which assumes that studies are taken from populations with varying effect sizes, calculating the study weights both from in-study and between-study variances, considering the extent of variation, or heterogeneity. We performed a chi-square-based Q statistic test to assess the between-study heterogeneity . Heterogeneity was considered significant for p<0.10 because of the low power of the statistic. The inconsistency index I2 was also calculated to evaluate the variation which was caused by heterogeneity rather than by chance, and higher values of the index indicate the existence of heterogeneity . The fixed-effects model (if p>0.10) or the random-effects model (if p<0.10) was used to pool the results . The significance of the pooled OR was determined by the Z test and a P value of <0.05 was considered significant. Studies were also categorized into subgroups based on ethnicity. For each genetic comparison, subgroup analyses were considered for the population of Caucasians, East Asians and others to estimate ethnic-specific OR. The subgroup ‘others’ included the South African Negro population and African-American population. In addition, in order to further uncover the underlying role of the genetic variation in ADD1, subgroup analyses on different diagnostic standards for hypertension were also carried out.
Sensitivity analyses were conducted by sequential deleting a single study each time in an attempt to identify the potential influence of the individual data set to the pooled ORs. In addition, an estimate of potential publication bias was carried out by the funnel plot, in which the standard error of log (OR) of each study was plotted against its OR. An asymmetric plot suggested possible publication bias. Funnel-plot asymmetry was assessed by the method of Egger's linear regression test . Furthermore, we performed a T-test to determine the significance of the intercept, and a P value lower than 0.05 was considered to be statistically significant. HWE was tested by the chi-square test for goodness of fit based on a Web program (http://www.ihg.gsf.de/cgi-bin/hw/hwa1.pl).
Analyses were performed using the software Review-Manager 4.2 (Oxford, England) and Stata version 10.0 (Stata Corporation, College Station, Texas, USA). All P-values were two-sided.
Description of studies identified in meta-analysis
The initial search strategy for hypertension susceptibility related to the alpha-adducin SNP yielded 152 potentially relevant references in PubMed and 158 in EMBASE, most of which were overlapping. In addition, we supplemented the search with a hand search of reference lists from published literature (117 articles). After the subsequent screening, 30 studies were identified for recruitment in the light of the inclusion criteria –, –. All studies were published between 1997 and 2010. Among the 30 eligible articles, the study of He et al.  was replaced by their latter report  which including larger population. Samples selected were all men (both cases and controls) in Psaty et al.  Only one paper by Province et al.  included separate data on subjects of two ethnicities: European-American and African-American, however, the genotyping data in the population of European-American was deviated from HWE (PHWE = 0.000522), as well as in the population of Asian provided in Ramachandran et al.  (PHWE = 0.001644). Thus, those two studies were excluded. Seven papers did not provide relevant data or the data provided were not sufficient, we have contacted corresponding or original authors by e-mail in order to obtain the raw data. Two of them have replied and offered the necessary data , , and the other five have not yet responded –. Furthermore, we also deleted an article by Marcun Varda et al.  that described hypertension in children and young adults, in which the diagnostic standard for EH is different from adults . In conclusion, 22 studies were selected for inclusion in our final analyses (Table S1). All studies used blood sample for genotyping. The flow chart summarizing the process of study selection and reasons for exclusion is presented in Figure 1.
A total of 14303 hypertension patients and 15961 controls were investigated. Population-based and hospital-based studies were all included in our meta-analysis. Twelve studies were population-based , , , , , –, –, and ten were hospital-based studies –, –, , , , . Populations among these studies were as following: ten studies were Caucasians or European descent (7632 cases and 8588 controls), nine studies were East Asians (5957 cases and 6770 controls) and three studies were others (one study recruited South African Negro subjects and the other two studies recruited African-American subjects) involving 714 cases and 603 controls. All genotypes and allele frequencies of cases and controls were shown in Table S2. The pooled overall frequency of the Trp allele were 34.91% and 35.23% in hypertensive cases and in normotensive controls, respectively. Allele Trp had a higher representation in cases and controls of East Asians (56.67% and 55.38%, respectively) than that of Caucasians (20.51% and 21.30%, respectively) and others (7.21% and 7.30%, respectively).
For each study, we investigated the association between the alpha-adducin Gly460Trp polymorphism and hypertension risk, assuming different inheritance models of the 460Trp allele (Table 1). Overall, when all the eligible studies were pooled into the meta-analysis, no significant associations between ADD1 Gly460Trp polymorphism and hypertension susceptibility were observed in all genetic models. No significant associations were found for allele comparison (Trp vs. Gly: P = 0.69, OR = 1.02, 95% CI 0.94–1.10, Pheterogeneity<0.0001) (Figure 2a), dominant genetic mode (GlyTrp+TrpTrp vs. GlyGly: P = 0.98, OR = 1.00, 95% CI 0.91–1.11, Pheterogeneity = 0.0003) (Figure 2b), recessive genetic model (TrpTrp vs. GlyTrp+GlyGly: P = 0.31, OR = 1.06, 95% CI 0.95–1.18, Pheterogeneity = 0.04) (Figure 2c), and homozygote comparison (TrpTrp vs. GlyGly: P = 0.54, OR = 1.05, 95% CI 0.91–1.21, Pheterogeneity = 0.01) (Figure 2d). Similarly, no significant association was detected in all genetic models in the subgroup analyses by ethnicity and different diagnostic criteria for hypertension (Table 1).
Figure 2a shows the association between Gly460Trp polymorphism and hypertension in allele comparison (Trp vs. Gly). n indicates the total number of Trp allele, N indicates the total number of Trp allele plus Gly allele. Figure 2b shows the association between Gly460Trp polymorphism and hypertension under dominant genetic model (GlyTrp+TrpTrp vs. GlyGly). n indicates the total number of GlyTrp+TrpTrp, N indicates the total number of individuals. Figure 2c shows the association between Gly460Trp polymorphism and hypertension under recessive genetic model (TrpTrp vs. GlyTrp+GlyGly). n indicates the total number of TrpTrp, N indicates the total number of individuals. Figure 2d shows the association between Gly460Trp polymorphism and hypertension in homozygote comparison (TrpTrp vs. GlyGly). n indicates the total number of TrpTrp, N indicates the total number of TrpTrp plus GlyGly.
Sensitivity analyses were conducted to assess whether each individual study affected the final results. The findings revealed that no individual study affected the results in all subjects. In the subgroup analysis, three independent studies (Cusi et al. , Tamaki et al. , and Barlassina et al. ) were considered as the main cause of heterogeneity for Caucasians, East Asians, and others, respectively. The three studies were all hospital-based. After exclusion of these studies, the heterogeneity no longer existed, but still reached a negative association. (data not shown).
The funnel plot was applied for comparison of 460Trp versus Gly460 in the OR analysis of alpha-adducin Gly460Trp, and Egger's test provided no evidence for funnel-plot asymmetry (t = −0.06, P = 0.954) (Figure 3).
To the best of our knowledge, this is one of the largest systematic review of the literature by means of a meta-analysis to date investigating the association between alpha-adducin Gly460Trp polymorphism and EH. Compared with the recent case-control study and meta-analysis by Niu et al. , our meta-analysis conducted here included in total 22 studies with 14303 cases and 15961 controls which were almost three times higher than the study mentioned above. However, we failed to obtain association of Gly460Trp polymorphism with hypertension, even in the stratification analyses based on ethnicity or different diagnostic criteria.
In 1997, Cusi et al. first reported that 460Trp allele of alpha-adducin was associated with hypertension in human subjects, particularly in a salt-sensitive form of EH . Manunta et al. found that the Gly460Trp polymorphism of ADD1 modulates the overall capacity of tubular epithelial cells to transport ions through variations in sodium-potassium ATPase activity and through modifications in the assembly of the actin cytoskeleton . Further findings indicated a reduced renal pressure-natriuresis slope after sodium depletion or sodium load in individuals with Trp allele, which confirmed that humans bearing one Trp allele alpha-adducin variant displayed an increased of renal tubular sodium reabsorption and sodium retention . These findings suggested that 460Trp variant of the α-adducin was probably associated with a sodium-sensitive form of hypertension, which was caused by physiology or pathophysiology mechanisms mentioned above. However, the results of our meta-analysis showed no significant association between Gly460Trp polymorphism and hypertension. It seemed that 460Trp variant was associated with renal Na+ handling (sodium transport and reabsorption) rather than the salt-sensitive form of EH. Among white hypertensive patients in Italy, five salt sensitivity studies conducted by BP response to acute salt loading test (saline infusion) and chronic diuretic treatment effect were performed by the same research group, which showed evidence to support the role of 460Trp in salt-related hypertension , –. Grant et al. replicated the above result, using a high and low sodium diet , while another study failed to detect this effect in Polish hypertensives . Turner et al. reported a negative study involved two ethnicities (African American and non-Hispanic white), revealing that no relationship existed between α-adducin genotypes and the BP response to the diuretics . A recent study by Suonsyrjä et al. showed no influence of Trp allele on the magnitude of BP fall with diuretics among Finnish hypertensive men . Taken together with previous results, the impact of 460Trp on diuretics treatment varied among different ethnic and geographic populations. Results from a newly published meta-analysis investigating the association between α-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity suggested that Gly460Trp polymorphism in general is not significantly associated with salt-sensitivity (P = 0.08, OR = 1.40, 95% CI 0.96–2.04) . This was consistent with our results. However, considering the potential confounders of studies included in the meta-analysis, our results should be interpreted with caution.
Furthermore, it is important to highlight that, EH is a complex polygenic disease responsive to environmental factors. A single polymorphism or gene likely has weak effects on the individual's phenotype, because multiple genes and genetic interactions have been implicated in the regulation of BP. A family study from van Rijn et al.  showed that the Gly460Trp polymorphism of ADD1 was able to explain only a very small proportion of the heritability of BP traits (approximately 0.2% of the SBP variance, P = 0.16; 0.1% of DBP variance, P = 0.78; 0.3% of the variance of pulse pressure, P = 0.07). Therefore, it is necessary to explore the combined effect of Gly460Trp with other related polymorphisms in the same gene or different genes such as ADD2, ADD3, and angiotensin-converting enzyme gene (ACE). Lanzani et al. provided evidence for an epistatic interaction of ADD1 and ADD3 gene variants was associated with variation in BP among the hypertensive patients . Another similar study by Staessen et al. reported that epistatic interaction between the ACE and ADD1 contributed to the prevalence and incidence of hypertension in Caucasians . Epistasis is the potentiation or suppression of a gene by other non-allelic genes , which is probably ignored in the majority of case-control and population studies. Consequently, the negative findings of studies on the genetic determinants of EH focused on single-gene effect are not surprising in these settings. More studies based on larger population and well-designed, especially studies investigating the combined effect of Gly460Trp and other polymorphisms are required to further evaluate the role of these polymorphisms in hypertension.
Moreover, environmental factors and individual biological characteristics ought not to be neglected. The former include, most importantly, salt intake, smoking, alcohol consumption, etc. For instance, Yamagishi et al. pointed out that the α-adducin TrpTrp genotype was associated with higher systolic BP among men with a higher sodium intake . The latter include race, age, gender, body mass index (BMI), health condition, and general physiological/neurological functioning, etc. Perhaps most important among above factors is age, which is a determinant of the penetrance of genetic variants . Older age increases Na+ sensitivity, makes the relationship between BP and exchangeable body Na+ stronger, reduces renal perfusion, and compromises the buffering effects of the large arteries on both systolic and diastolic pressure . On these grounds, comprehensive consideration of interrelations and interactions with the context of genetic backgrounds, environmental factors, and individual biological characteristics is indispensable when exploring the association between a single gene variant and hypertension risk. Just as Bianchi et al. mentioned that ‘when context is taken into account, the impact of adducin in hypertension and its related disorders is clear’ , .
In the sensitivity analysis, three hospital-based studies (Cusi et al. , Tamaki et al. , and Barlassina et al. ) were considered as the main cause of heterogeneity. In order to uncover the potential influence of the sample sources (population or hospital-based), further research was conducted on the different sources of subjects. The results indicated that no heterogeneity was observed in population-based stuides (Pheterogeneity = 0.34, I2 = 10.4%, allele comparison) (Figure 4a), while considerable heterogeneity existed in hospital-based stuides (Pheterogeneity<0.00001, I2 = 80.5%, allele comparison) (Figure 4b). There were still no significant association in the two analyses above. The controls of the hospital-based studies might be ill-related population. They might not be a representative of the general population. Thus, such studies usually have some selection biases, which might affect the quality and reliability of individual studies.
Figure 4a shows the forest plot of ADD1 Gly460Trp polymorphism and hypertension risk among population-based studies in allele comparison. Figure 4b shows the forest plot of ADD1 Gly460Trp polymorphism and hypertension risk among hospital-based studies in allele comparison.
The results of the present meta-analysis should be interpreted within the context of its limitations. First, this meta-analysis only focused on papers published in the English language, so some local literature biases were inevitable. Second, not all the control subjects were age- and sex- matched to cases in the studies included in our meta-analysis, which was likely one of the causes for heterogeneity. In addition, another potential confounding effect is that some of the young normotensive controls might develop hypertension later in their life. Perhaps using stricter criteria for the selection of normal controls, such as normotensive subjects aged 55–60 years or older, could exclude the false-negative controls , . Third, the strong heterogeneity observed in the relationship between the Gly460Trp polymorphism and hypertension precluded a consistent estimate of the effect of this variant, even when analyzed by ethnicity. Furthermore, in our study, we did not perform an evaluation of potential interactions such as gene-gene, gene-environment, which might influence the results.
In conclusion, our meta-analysis suggested that the Gly460Trp polymorphism in ADD1 was not associated with susceptibility to hypertension even upon stratification by ethnicity or diagnostic criteria. Based on our discussion and the results from the meta-analysis, we may conclude that the Gly460Trp polymorphism is probably not a genetic indicator for increased risk of hypertension. To better understand the potential mechanism for hypertension in humans, future research should be carried out to explore the effect of genetic networks, environmental factors, individual biological characteristics and their mutual interactions.
Detailed characteristics of eligible studies considered in the meta-analysis
(0.10 MB DOC)
Diagnostic standard of each study, the distribution of Gly460Trp genotypes and alleles among hypertension of cases and controls, and P-values of HWE in controls
(0.09 MB DOC)
We are very grateful and thank Dr Ken Sugimoto and Dr Cristiano Fava for providing additional information and data on their studies. We also thank all the participants in this study.
Conceived and designed the experiments: KL JL ZL SW. Performed the experiments: KL JL YH. Analyzed the data: KL JL YH YL. Contributed reagents/materials/analysis tools: YH YL YL ZW HZ SY. Wrote the paper: KL JL ZL SW.
- 1. O'Shaughnessy KM (2001) The genetics of essential hypertension. Br J Clin Pharmacol 51: 5–11.KM O'Shaughnessy2001The genetics of essential hypertension.Br J Clin Pharmacol51511
- 2. Kurtz TW, Spence MA (1993) Genetics of essential hypertension. Am J Med 94: 77–84.TW KurtzMA Spence1993Genetics of essential hypertension.Am J Med947784
- 3. Matsuoka Y, Li X, Bennett V (2000) Adducin: structure, function and regulation. Cell Mol Life Sci 57: 884–895.Y. MatsuokaX. LiV. Bennett2000Adducin: structure, function and regulation.Cell Mol Life Sci57884895
- 4. Tripodi G, Valtorta F, Torielli L, Chieregatti E, Salardi S, et al. (1996) Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 97: 2815–2822.G. TripodiF. ValtortaL. TorielliE. ChieregattiS. Salardi1996Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport.J Clin Invest9728152822
- 5. Lin B, Nasir J, McDonald H, Graham R, Rommens JM, et al. (1995) Genomic organization of the human alpha-adducin gene and its alternately spliced isoforms. Genomics 25: 93–99.B. LinJ. NasirH. McDonaldR. GrahamJM Rommens1995Genomic organization of the human alpha-adducin gene and its alternately spliced isoforms.Genomics259399
- 6. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, et al. (1997) Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 349: 1353–1357.D. CusiC. BarlassinaT. AzzaniG. CasariL. Citterio1997Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension.Lancet34913531357
- 7. Tamaki S, Iwai N, Tsujita Y, Nakamura Y, Kinoshita M (1998) Polymorphism of alpha-adducin in Japanese patients with essential hypertension. Hypertens Res 21: 29–32.S. TamakiN. IwaiY. TsujitaY. NakamuraM. Kinoshita1998Polymorphism of alpha-adducin in Japanese patients with essential hypertension.Hypertens Res212932
- 8. Barlassina C, Norton GR, Samani NJ, Woodwiss AJ, Candy GC, et al. (2000) Alpha-adducin polymorphism in hypertensives of South African ancestry. Am J Hypertens 13: 719–723.C. BarlassinaGR NortonNJ SamaniAJ WoodwissGC Candy2000Alpha-adducin polymorphism in hypertensives of South African ancestry.Am J Hypertens13719723
- 9. Ju Z, Zhang H, Sun K, Song Y, Lu H, et al. (2003) Alpha-adducin gene polymorphism is associated with essential hypertension in Chinese: a case-control and family-based study. J Hypertens 21: 1861–1868.Z. JuH. ZhangK. SunY. SongH. Lu2003Alpha-adducin gene polymorphism is associated with essential hypertension in Chinese: a case-control and family-based study.J Hypertens2118611868
- 10. Kato N, Sugiyama T, Nabika T, Morita H, Kurihara H, et al. (1998) Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population. Hypertension 31: 730–733.N. KatoT. SugiyamaT. NabikaH. MoritaH. Kurihara1998Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population.Hypertension31730733
- 11. Ishikawa K, Katsuya T, Sato N, Nakata Y, Takami S, et al. (1998) No association between alpha-adducin 460 polymorphism and essential hypertension in a Japanese population. Am J Hypertens 11: 502–506.K. IshikawaT. KatsuyaN. SatoY. NakataS. Takami1998No association between alpha-adducin 460 polymorphism and essential hypertension in a Japanese population.Am J Hypertens11502506
- 12. Alam S, Liyou N, Davis D, Tresillian M, Johnson AG (2000) The 460Trp polymorphism of the human alpha-adducin gene is not associated with isolated systolic hypertension in elderly Australian Caucasians. J Hum Hypertens 14: 199–203.S. AlamN. LiyouD. DavisM. TresillianAG Johnson2000The 460Trp polymorphism of the human alpha-adducin gene is not associated with isolated systolic hypertension in elderly Australian Caucasians.J Hum Hypertens14199203
- 13. Larson N, Hutchinson R, Boerwinkle E (2000) Lack of association of 3 functional gene variants with hypertension in African Americans. Hypertension 35: 1297–1300.N. LarsonR. HutchinsonE. Boerwinkle2000Lack of association of 3 functional gene variants with hypertension in African Americans.Hypertension3512971300
- 14. He X, Zhu DL, Chu SL, Jin L, Xiong MM, et al. (2001) alpha-Adducin gene and essential hypertension in China. Clin Exp Hypertens 23: 579–589.X. HeDL ZhuSL ChuL. JinMM Xiong2001alpha-Adducin gene and essential hypertension in China.Clin Exp Hypertens23579589
- 15. Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19: 251–253.B. Woolf1955On estimating the relation between blood group and disease.Ann Hum Genet19251253
- 16. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127: 820–826.J. LauJP IoannidisCH Schmid1997Quantitative synthesis in systematic reviews.Ann Intern Med127820826
- 17. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560.JP HigginsSG ThompsonJJ DeeksDG Altman2003Measuring inconsistency in meta-analyses.BMJ327557560
- 18. Petitti DB (1994) Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis. NewYork: Oxford University Press. pp. 15–20.DB Petitti1994Meta-analysis, Decision Analysis, and Cost-effectiveness Analysis.NewYorkOxford University Press1520
- 19. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.M. EggerG. Davey SmithM. SchneiderC. Minder1997Bias in meta-analysis detected by a simple, graphical test.BMJ315629634
- 20. Wang WY, Adams DJ, Glenn CL, Morris BJ (1999) The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians. Am J Hypertens 12: 632–636.WY WangDJ AdamsCL GlennBJ Morris1999The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians.Am J Hypertens12632636
- 21. Melander O, Bengtsson K, Orho-Melander M, Lindblad U, Forsblom C, et al. (2000) Role of the Gly460Trp polymorphism of the alpha-adducin gene in primary hypertension in Scandinavians. J Hum Hypertens 14: 43–46.O. MelanderK. BengtssonM. Orho-MelanderU. LindbladC. Forsblom2000Role of the Gly460Trp polymorphism of the alpha-adducin gene in primary hypertension in Scandinavians.J Hum Hypertens144346
- 22. Psaty BM, Doggen C, Vos HL, Vandenbroucke JP, Rosendaal FR (2000) Association of the alpha-adducin polymorphism with blood pressure and risk of myocardial infarction. J Hum Hypertens 14: 95–97.BM PsatyC. DoggenHL VosJP VandenbrouckeFR Rosendaal2000Association of the alpha-adducin polymorphism with blood pressure and risk of myocardial infarction.J Hum Hypertens149597
- 23. Province MA, Arnett DK, Hunt SC, Leiendecker-Foster C, Eckfeldt JH, et al. (2000) Association between the alpha-adducin gene and hypertension in the HyperGEN Study. Am J Hypertens 13: 710–718.MA ProvinceDK ArnettSC HuntC. Leiendecker-FosterJH Eckfeldt2000Association between the alpha-adducin gene and hypertension in the HyperGEN Study.Am J Hypertens13710718
- 24. Clark CJ, Davies E, Anderson NH, Farmer R, Friel EC, et al. (2000) alpha-adducin and angiotensin I-converting enzyme polymorphisms in essential hypertension. Hypertension 36: 990–994.CJ ClarkE. DaviesNH AndersonR. FarmerEC Friel2000alpha-adducin and angiotensin I-converting enzyme polymorphisms in essential hypertension.Hypertension36990994
- 25. Sugimoto K, Hozawa A, Katsuya T, Matsubara M, Ohkubo T, et al. (2002) alpha-Adducin Gly460Trp polymorphism is associated with low renin hypertension in younger subjects in the Ohasama study. J Hypertens 20: 1779–1784.K. SugimotoA. HozawaT. KatsuyaM. MatsubaraT. Ohkubo2002alpha-Adducin Gly460Trp polymorphism is associated with low renin hypertension in younger subjects in the Ohasama study.J Hypertens2017791784
- 26. Sunder-Plassmann G, Kittler H, Eberle C, Hirschl MM, Woisetschläger C, et al. (2002) Angiotensin converting enzyme DD genotype is associated with hypertensive crisis. Crit Care Med 30: 2236–2241.G. Sunder-PlassmannH. KittlerC. EberleMM HirschlC. Woisetschläger2002Angiotensin converting enzyme DD genotype is associated with hypertensive crisis.Crit Care Med3022362241
- 27. Yamagishi K, Iso H, Tanigawa T, Cui R, Kudo M, et al. (2004) Alpha-adducin G460W polymorphism, urinary sodium excretion, and blood pressure in community-based samples. Am J Hypertens 17: 385–390.K. YamagishiH. IsoT. TanigawaR. CuiM. Kudo2004Alpha-adducin G460W polymorphism, urinary sodium excretion, and blood pressure in community-based samples.Am J Hypertens17385390
- 28. Shin MH, Chung EK, Kim HN, Park KS, Nam HS, et al. (2004) Alpha-adducin Gly460Trp polymorphism and essential hypertension in Korea. J Korean Med Sci 19: 812–814.MH ShinEK ChungHN KimKS ParkHS Nam2004Alpha-adducin Gly460Trp polymorphism and essential hypertension in Korea.J Korean Med Sci19812814
- 29. Mead PA, Harvey JN, Rutherford PA, Leitch H, Thomas TH (2005) Sodium-lithium countertransport and the Gly460—>Trp alpha-adducin polymorphism in essential hypertension. Clin Sci (Lond) 108: 231–236.PA MeadJN HarveyPA RutherfordH. LeitchTH Thomas2005Sodium-lithium countertransport and the Gly460—>Trp alpha-adducin polymorphism in essential hypertension.Clin Sci (Lond)108231236
- 30. Yazdanpanah M, Sayed-Tabatabaei FA, Hofman A, Aulchenko YS, Oostra BA, et al. (2006) The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes. Diabetes 55: 2922–2927.M. YazdanpanahFA Sayed-TabatabaeiA. HofmanYS AulchenkoBA Oostra2006The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes.Diabetes5529222927
- 31. Nakamura Y, Tabara Y, Miki T, Tamaki S, Kita Y, et al. (2007) Both angiotensinogen M235T and alpha-adducin G460W polymorphisms are associated with hypertension in the Japanese population. J Hum Hypertens 21: 253–255.Y. NakamuraY. TabaraT. MikiS. TamakiY. Kita2007Both angiotensinogen M235T and alpha-adducin G460W polymorphisms are associated with hypertension in the Japanese population.J Hum Hypertens21253255
- 32. Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, et al. (2007) Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender. Am J Hypertens 20: 981–989.C. FavaM. MontagnanaP. AlmgrenL. RosbergGC Guidi2007Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender.Am J Hypertens20981989
- 33. Niu WQ, Zhang Y, Ji KD, Gao PJ, Zhu DL (2010) Lack of association between alpha-adducin G460W polymorphism and hypertension: evidence from a case-control study and a meta-analysis. J Hum Hypertens 24: 467–474.WQ NiuY. ZhangKD JiPJ GaoDL Zhu2010Lack of association between alpha-adducin G460W polymorphism and hypertension: evidence from a case-control study and a meta-analysis.J Hum Hypertens24467474
- 34. Ramachandran V, Ismail P, Stanslas J, Shamsudin N (2009) Analysis of renin-angiotensin aldosterone system gene polymorphisms in Malaysian essential hypertensive and type 2 diabetic subjects. Cardiovasc Diabetol 8: 11.V. RamachandranP. IsmailJ. StanslasN. Shamsudin2009Analysis of renin-angiotensin aldosterone system gene polymorphisms in Malaysian essential hypertensive and type 2 diabetic subjects.Cardiovasc Diabetol811
- 35. Iwai N, Tamaki S, Nakamura Y, Kinoshita M (1997) Polymorphism of alpha-adducin and hypertension. Lancet 350: 369.N. IwaiS. TamakiY. NakamuraM. Kinoshita1997Polymorphism of alpha-adducin and hypertension.Lancet350369
- 36. Glorioso N, Manunta P, Filigheddu F, Troffa C, Stella P, et al. (1999) The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 34: 649–654.N. GloriosoP. ManuntaF. FilighedduC. TroffaP. Stella1999The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study.Hypertension34649654
- 37. Shioji K, Kokubo Y, Mannami T, Inamoto N, Morisaki H, et al. (2004) Association between hypertension and the alpha-adducin, beta1-adrenoreceptor, and G-protein beta3 subunit genes in the Japanese population; the Suita study. Hypertens Res 27: 31–37.K. ShiojiY. KokuboT. MannamiN. InamotoH. Morisaki2004Association between hypertension and the alpha-adducin, beta1-adrenoreceptor, and G-protein beta3 subunit genes in the Japanese population; the Suita study.Hypertens Res273137
- 38. van Rijn MJ, Bos MJ, Yazdanpanah M, Isaacs A, Arias-Vásquez A, et al. (2006) Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk. Stroke 37: 2930–2934.MJ van RijnMJ BosM. YazdanpanahA. IsaacsA. Arias-Vásquez2006Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk.Stroke3729302934
- 39. Zafarmand MH, van der Schouw YT, Grobbee DE, de Leeuw PW, Bots ML (2008) Alpha-adducin Gly460Trp variant increases the risk of stroke in hypertensive Dutch women. Hypertension 51: 1665–1670.MH ZafarmandYT van der SchouwDE GrobbeePW de LeeuwML Bots2008Alpha-adducin Gly460Trp variant increases the risk of stroke in hypertensive Dutch women.Hypertension5116651670
- 40. Marcun Varda N, Zagradisnik B, Herodez SS, Kokalj Vokac N, Gregoric A (2006) Polymorphisms in four candidate genes in young patients with essential hypertension. Acta Paediatr 95: 353–358.N. Marcun VardaB. ZagradisnikSS HerodezN. Kokalj VokacA. Gregoric2006Polymorphisms in four candidate genes in young patients with essential hypertension.Acta Paediatr95353358
- 41. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. (1996) Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics 98: 649–658.National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents.1996Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program.Pediatrics98649658
- 42. Manunta P, Barlassina C, Bianchi G (1998) Adducin in essential hypertension. FEBS Lett 430: 41–44.P. ManuntaC. BarlassinaG. Bianchi1998Adducin in essential hypertension.FEBS Lett4304144
- 43. Manunta P, Cusi D, Barlassina C, Righetti M, Lanzani C, et al. (1998) Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients. Kidney Int 53: 1471–1478.P. ManuntaD. CusiC. BarlassinaM. RighettiC. Lanzani1998Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients.Kidney Int5314711478
- 44. Glorioso N, Manunta P, Filigheddu F, Troffa C, Stella P, et al. (1999) The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 34: 649–654.N. GloriosoP. ManuntaF. FilighedduC. TroffaP. Stella1999The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study.Hypertension34649654
- 45. Barlassina C, Schork NJ, Manunta P, Citterio L, Sciarrone M, et al. (2000) Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion. Kidney Int 57: 1083–1090.C. BarlassinaNJ SchorkP. ManuntaL. CitterioM. Sciarrone2000Synergistic effect of alpha-adducin and ACE genes causes blood pressure changes with body sodium and volume expansion.Kidney Int5710831090
- 46. Sciarrone MT, Stella P, Barlassina C, Manunta P, Lanzani C, et al. (2003) ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. Hypertension 41: 398–403.MT SciarroneP. StellaC. BarlassinaP. ManuntaC. Lanzani2003ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy.Hypertension41398403
- 47. Grant FD, Romero JR, Jeunemaitre X, Hunt SC, Hopkins PN, et al. (2002) Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism. Hypertension 39: 191–196.FD GrantJR RomeroX. JeunemaitreSC HuntPN Hopkins2002Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism.Hypertension39191196
- 48. Ciechanowicz A, Widecka K, Drozd R, Adler G, Cyrylowski L, et al. (2001) Lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives. Kidney Blood Press Res 24: 201–206.A. CiechanowiczK. WideckaR. DrozdG. AdlerL. Cyrylowski2001Lack of association between Gly460Trp polymorphism of alpha-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.Kidney Blood Press Res24201206
- 49. Turner ST, Chapman AB, Schwartz GL, Boerwinkle E (2003) Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. Am J Hypertens 16: 834–839.ST TurnerAB ChapmanGL SchwartzE. Boerwinkle2003Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide.Am J Hypertens16834839
- 50. Suonsyrjä T, Hannila-Handelberg T, Fodstad H, Donner K, Kontula K, et al. (2009) Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study. Am J Hypertens 22: 169–175.T. SuonsyrjäT. Hannila-HandelbergH. FodstadK. DonnerK. Kontula2009Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study.Am J Hypertens22169175
- 51. Wang R, Zhong B, Liu Y, Wang C (2010) Association between α-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis. J Appl Genet 51: 87–94.R. WangB. ZhongY. LiuC. Wang2010Association between α-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis.J Appl Genet518794
- 52. van Rijn MJ, Schut AF, Aulchenko YS, Deinum J, Sayed-Tabatabaei FA, et al. (2007) Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes. J Hypertens 25: 565–570.MJ van RijnAF SchutYS AulchenkoJ. DeinumFA Sayed-Tabatabaei2007Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.J Hypertens25565570
- 53. Lanzani C, Citterio L, Jankaricova M, Sciarrone MT, Barlassina C, et al. (2005) Role of the adducin family genes in human essential hypertension. J Hypertens 23: 543–549.C. LanzaniL. CitterioM. JankaricovaMT SciarroneC. Barlassina2005Role of the adducin family genes in human essential hypertension.J Hypertens23543549
- 54. Staessen JA, Wang JG, Brand E, Barlassina C, Birkenhäger WH, et al. (2001) Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens 19: 1349–1358.JA StaessenJG WangE. BrandC. BarlassinaWH Birkenhäger2001Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population.J Hypertens1913491358
- 55. Frankel WN, Schork NJ (1996) Who's afraid of epistasis? Nat Genet 14: 371–373.WN FrankelNJ Schork1996Who's afraid of epistasis?Nat Genet14371373
- 56. Staessen JA, Wang J, Bianchi G, Birkenhäger WH (2003) Essential hypertension. Lancet 361: 1629–1641.JA StaessenJ. WangG. BianchiWH Birkenhäger2003Essential hypertension.Lancet36116291641
- 57. Bianchi G, Ferrari P, Staessen JA (2005) Adducin polymorphism: detection and impact on hypertension and related disorders. Hypertension 45: 331–34.G. BianchiP. FerrariJA Staessen2005Adducin polymorphism: detection and impact on hypertension and related disorders.Hypertension4533134
- 58. Citterio L, Lanzani C, Manunta P, Bianchi G (2010) Genetics of primary hypertension: The clinical impact of adducin polymorphisms. Biochim Biophys Acta. In press. L. CitterioC. LanzaniP. ManuntaG. Bianchi2010Genetics of primary hypertension: The clinical impact of adducin polymorphisms.Biochim Biophys Acta. In press
- 59. Casari G, Barlassina C, Cusi D, Zagato L, Muirhead R, et al. (1995) Association of the alpha-adducin locus with essential hypertension. Hypertension 25: 320–326.G. CasariC. BarlassinaD. CusiL. ZagatoR. Muirhead1995Association of the alpha-adducin locus with essential hypertension.Hypertension25320326
- 60. Bianchi G, Tripodi MG, Casari G, Torielli L, Cusi D, et al. (1995) alpha-adducin may control blood pressure both in rats and humans. Clin Exp Pharmacol Physiol Suppl 22S7–9.G. BianchiMG TripodiG. CasariL. TorielliD. Cusi1995alpha-adducin may control blood pressure both in rats and humans.Clin Exp Pharmacol PhysiolSuppl 22S79