ADD1 Polymorphisms Research Articles

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Effects of ACE and ADD1 gene polymorphisms on blood pressure response to hydrochlorothiazide: a meta-analysis

Hydrochlorothiazide (HCTZ) is used to treat uncomplicated hypertension. However, many studies have reported the variance of inter-individual response to HCTZ. A meta-analysis of published data was conducted to evaluate the pharmacogenetic associations of ACE I/D and ADD1 Gly460Trp polymorphisms with blood pressure changes during HCTZ therapy. To analyze the influence of ACE I/D polymorphism, 4 studies including 1,439 patients were assessed and the 3 genotypes were compared (II vs. ID, II vs. DD, and ID vs. DD) with respect to blood pressure changes. A significant association between ACE and blood pressure change was observed for the comparison of the II and DD (standard differences in means = 0.256; 95% CI, 0.109 - 0.403). For ADD1 Gly460Trp polymorphism, 4 studies including 1,001 patients were assessed, and GlyGly vs. GlyTrp, GlyGly vs. TrpTrp and GlyTrp vs. TrpTrp genotype comparisons were analyzed. A significant association between ADD1 and blood pressure change was observed for the comparisons of GlyGly vs. GlyTrp (standard differences in means= 2.78; 95% CI, 0.563 - 4.99) and GlyGly vs. TrpTrp (standard differences in means = 1.80; 95% CI, 1.38 - 2.22). This study is the first meta-analysis to evaluate the influences of ACE and ADD1 polymorphisms on blood pressure responses to HCTZ to combine the inconsistent results of previous studies.

A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke

Background Stroke is a common cerebrovascular accident. ACE and ADD1 gene are known to be associated with vascular complications leading to stroke susceptibility. The present study was carried out to evaluate the relative frequency of ACE and ADD1 common polymorphisms in ischemic stroke and intracerebral hemorrhage (ICH). Methods A total of 386 CT or MRI proven stroke patients were included; 193 each had ischemic stroke and ICH. The locations and type of stroke were noted. ACE- I/D (rs4646994) and ADD1 (rs4961) gene polymorphisms were analyzed by polymerase chain reaction (PCR). The genotype and allele frequencies of ACE and ADD1 polymorphisms were compared between patients and controls as well as between ischemic stroke and ICH. Results ACE (DD) genotype was significantly higher in ischemic stroke (37.8%) and ICH (33.7%) compared to controls (11.7%). D allele was also more frequent in ischemic stroke (57.3%) and ICH (56.7%) compared to controls (38.3%). ADD1 (WW) genotype and W allele frequencies were not significantly different in ischemic stroke, ICH and controls. In contrast, we found a synergistic role of ACE (DD)* ADD1(GW) interaction showing a positive association in both ischemic and hemorrhagic strokes. Conclusion Our study suggests that ACE (DD) genotype and D allele significantly increase the susceptibility to ischemic and hemorrhagic strokes.

Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk

BACKGROUND:Essential hypertension is a complex genetic trait. Genetic variant of alpha adducin (ADD1) gene have been implicated as a risk factor for hypertension. Given its clinical significance, we investigated the association between ADD1 Gly460Trp gene polymorphism and essential hypertension in an Indian population. Further, a meta-analysis was carried out to estimate the risk of hypertension.METHODS:In the current study, 432 hypertensive cases and 461 healthy controls were genotyped for the Gly460Trp ADD1 gene polymorphism. Genotyping was determined by real time PCR using Taqman assay. Multiple logistic regression analysis was used to detect the association between Gly460Trp polymorphism and hypertension.RESULTS:No significant association was found in the genotype and allele distribution of Gly460Trp polymorphism with hypertension in our study. A total of 15 case-control studies were included in the meta-analysis. There was no evidence of the association of Gly460Trp polymorphism with hypertension in general or in any of the sub group.CONCLUSIONS:We found that the Gly460Trp polymorphism is not a risk factor for essential hypertension in a south Indian Tamilian population. However, the role of ADD1 polymorphism may not be excluded by a negative association study. Further, large and rigorous case-control studies that investigate gene–gene–environment interactions may generate more conclusive claims about the molecular genetics of hypertension.

α-Adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: Results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES)

The alpha-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes

To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed. Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.

α-Adducin and angiotensin-converting enzyme polymorphisms in hypertension: evidence for a joint influence on albuminuria

A single-nucleotide polymorphism (Gly460Trp) within the alpha-adducin gene (ADD1) may influence several renal phenotypes, including salt sensitivity, susceptibility to renal failure, the renal haemodynamics and confer a worse cardiovascular risks profile. However, its relationship with microalbuminuria, a marker of early renal and cardiovascular damage and an independent predictor of morbid events in hypertension, is unknown. For this reason, we related the ADD1 genetic polymorphism to urine albumin levels and other clinical variables in essential hypertensive men. The angiotensin-converting enzyme (ACE) insertion/deletion (ID) polymorphism was also evaluated because of its interactive potential with the ADD1 genotype. Albuminuria (three overnight collections), echocardiographic left ventricular mass index, blood pressure, body mass index, renal function, glucose and lipids were measured in 238 genetically unrelated, never treated, uncomplicated Caucasian essential hypertensive men. Polymerase chain reaction or a 5' nuclease assay were used to characterize the ACE ID and ADD1 Gly460Trp variants, respectively. Microalbuminuria (albuminuria >or= 15 microg/min) was more frequent in patients with the ACE DD variant, but only in those with a ADD1 Gly460Gly background. In contrast, urine albumin did not differ by ACE ID genotype in the presence of mutated ADD1 Trp alleles. ADD1 polymorphisms per se were not associated with albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed among different genetic backgrounds. ACE DD and ADD1 Gly460Gly polymorphisms may jointly influence albuminuria in hypertensive men, 460Gly homozygosis facilitating or, possibly, the 460Trp allele mitigating the noxious renal impact of the ACE DD genotype. The data highlight further the complex pathophysiological implications of microalbuminuria in hypertension.

The 460Trp allele of α-adducin increases carotid intima–media thickness in young adult males

The 460Trp allele of the alpha-adducin gene (ADD1), which is involved in a form of salt-sensitive hypertension, has been associated with patterns of target organ damage. As carotid artery intima-media thickness (IMT) largely depends upon unknown genetic factors, besides being associated to conventional risk factors, we tested the association of the 460Trp allele of ADD1 with IMT in a well-characterized sample of young healthy normotensive subjects, to assess the role of ADD1 polymorphism without overlapping effects of age or already elevated blood pressure. Anthropometric measurements, blood pressure (BP), and carotid artery wall IMT (high-resolution sonography and digitalized morphometry) were obtained in 420 healthy normotensive Caucasian university students. Genotypes for ADD1 were detected by automated genomic polymerase chain reaction (PCR). ADD1 genotypes were evenly distributed between genders. IMT was significantly larger in carriers of the 460Trp allele of ADD1, while a significant gender x ADD1 interaction (P = 0.02) demonstrated that IMT was increased only in males carrying the 460Trp allele (P < 0.001). No significant association was found in females. The 460Trp allele of ADD1 contributes substantially to increase carotid IMT, in a male hormonal milieu only, at least in the young age range.

Adducin Polymorphism

Adducin is a heterodymeric cytoskeleton protein, the 3 subunits of which are encoded by genes (ADD1, ADD2, ADD3) mapping to 3 different chromosomes. A long series of parallel studies in the Milan hypertensive rat strain model of hypertension and humans indicated that an altered adducin function may cause hypertension through an enhanced constitutive tubular sodium reabsorption. Six human linkage studies showed positive results when a DNA marker mapping to 30 kb from the ADD1 locus or single-nucleotide polymorphisms (SNPs) of 1 of the 3 adducin genes were considered either alone or in combination with each other or angiotensin-converting enzyme (ACE) D allele or salt intake. When DNA markers mapping at much larger distance from the ADD1 locus were used, negative results were found by 4 studies. Positive results were also obtained in 18 of 20 association studies that, in addition to blood pressure, investigated variables reflecting body sodium or the renin-angiotensin system. Mixed results regarded case-control studies or studies in predominantly normotensive populations that did not consider the above-mentioned variables. Four of 5 studies showed a selective beneficial effect of diuretics in carriers of the mutated ADD1. Twelve of 16 studies found that ADD1 polymorphism alone or in combination with that of ACE positively associates with stroke or coronary heart disease or renal or vascular dysfunctions. In conclusion, when context is taken into account, the impact of adducin in hypertension and its related disorders is clear.

Combined Analysis of Polymorphisms in Angiotensinogen and Adducin Genes and Their Effects on Hypertension in a Japanese Sample: The Shigaraki Study

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Thr or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06-1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13-1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16-1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18-2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03-1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.

Alpha-Adducin Gly460Trp polymorphism is associated with low renin hypertension in younger subjects in the Ohasama study.

The Gly460Trp polymorphism of the alpha-adducin gene (ADD-1 ) has been examined as a candidate gene for essential hypertension with salt sensitivity in the Caucasian population. However, we failed to detect a positive association between the Gly460Trp polymorphism of ADD-1 and hypertension in a small series of Japanese subjects. To examine the precise association between the Gly460Trp polymorphism of ADD-1 and blood pressure (BP), we carried out an association study using a Japanese population: the Ohasama Study. Subjects (n = 1490) were recruited from participants in the Ohasama Study, which is a cohort in a rural community of northern Japan. DNA was extracted from the buffy coat of the participants who gave informed consent for genetic analysis, and the Gly460Trp polymorphism of ADD-1 was determined by the TaqMan polymerase chain reaction method. Various BP values (casual BP, ambulatory BP and home BP) were measured in the Ohasama study. We used the mean values of these BP measurements for analysis. The frequencies of genotypes in the Ohasama population were 23% Gly/Gly, 49% Gly/Trp, and 28% Trp/Trp. In the baseline characteristics, age, sex, body mass index, frequency of diabetes and hyperlipidemia were significantly different between hypertensive or normotensive subjects. In total subjects, all BP values were not different among genotypes. In the younger subjects ( 60 years old) with low plasma renin activity (< 1.0 ng/ml per h), however, ambulatory BP and home BP were significantly higher in the subjects with the Gly/Trp or Trp/Trp genotypes of ADD-1 polymorphism than in those with the Gly/Gly genotype. In the same population, the frequency of the Gly/Trp or Trp/Trp genotypes of was significantly higher in hypertensives than in normotensives (83 versus 72%, chi1(2) = 4.04, P<0.05; odds ratio, 2.12; 95% confidence interval, 1.02-4.68). These findings suggest the possibility that the Gly460Trp polymorphism of ADD-1 is associated with low renin hypertension.