Α-adducin Gene Research Articles

The efficacy of diuretics in complex treatment of patients with hypertension according to the Gly460Trp polymorphism of the α-adducin gene

The aim of the study was to investigate the effect of thiazide diuretics on blood pressure (BP) depending on Gly460Trp ADD1 gene polymorphism in arterial hypertension (AH) patients of the Ukrainian population in order to predict their individual treatment efficacy. Material and methods. The study included 232 persons: 120 patients with verified stage II AH and 112 healthy individuals. Restriction fragment length polymerase chain reaction (PCR-RFLP) was used to detect genotype (the Gly460Trp-polymorphic locus of the ADD1 gene). The patients received standard therapy, which included ACE inhibitor – ramipril 5 mg, calcium channel antagonist – amlodipine 5 mg, statin – atorvastatin 20 mg, acetylsalicylic acid 75 mg. The patients were randomized into two groups: group I (60 persons) additionally taking treatment with 1.5 mg of indapamide retard and group II (60 persons) – with 25 mg of hydrochlorothiazide. The dynamic reduction of blood pressure has been assessed every 4 weeks for 2 months. Results. Among 120 patients with AH, 91 persons (75.8 %) were homozygous for the G allele (GG), 26 persons (21.7 %) – heterozygous (GT) and 3 persons (2.5 %) – homozygous for the T allele (TT), while the G allele frequency in patients with hypertension was 0.87, and the T allele – 0.13. 98 healthy individuals (87.5 %) were homozygous for the G allele, 13 individuals (11.6 %) were heterozygous, and 1 person (0.9 %) was homozygous for the T allele. The carrier frequency of the G and T alleles was 0.93 and 0.07, respectively. Allelic distribution indicated the predominance of the G allele carriers by Gly460Trp polymorphism of the ADD1 gene among the Ukrainian population, regardless of whether AH symptoms were present. It is noteworthy that the number of the T allele carriers was 2 times large among symptomatic patients than that among healthy individuals. In patients with the T allele, the hypotensive efficacy of indapamide was almost 3 times higher than that in patients with the G allele. The antihypertensive effect of hydrochlorothiazide in patients with the GT and TT genotypes was 2 times greater than that in the GG genotype carriers depending on the presence of the T allele G460T polymorphism of ADD1 gene in the genotype. Conclusions. Allelic distribution indicates the predominance of the G allele carriers by Gly460Trp ADD1 gene polymorphism among the Ukrainian population, regardless of whether AH symptoms are present. Among patients with AH, the accumulation of the T allele G460T polymorphic marker of the α-adducin gene is 2 times more than that in healthy individuals. Patients carrying the T allele demonstrate 2 times higher hypotensive efficacy of indapamide compared with hydrochlorothiazide.

α-Adducin nsSNPs affect mRNA secondary structure, protein modification and stability

Adducins help stabilize the spectrin-actin interactions along with other accessory cytoskeletal proteins. Adducins exist as a tetramer composed of either α/β or α/γ heterodimers. Polymorphisms in α-adducin (ADD1) gene have been shown to be associated with hypertension and erythrocyte deformability. Most of the non-synonymous single nucleotide polymorphisms (nsSNPs) of ADD1 are still uncharacterized in terms of their damaging potential. So, in the present study, computational approach has been undertaken to explore and extend the knowledge related to the effect of nsSNPs on α-adducin. In this study, thirty six nsSNPs were subjected to in silico analyses using different computational tools. It is observed that out of thirty six SNP sites of ADD1, position of sixteen residues is highly conserved. It has been found that four nsSNPs have a very low tolerance index (TI) of 0.00 and four nsSNPs show a TI score of 0.01. Fifteen nsSNPs which are predicted as deleterious by the SIFT Server, are also found to be probably damaging by Polyphen Server. Highest pathogenicity score is predicted for Y270N variant of ADD1, followed by R231C, R354C, R396Q, K148I, E376D, L387M, and L387V variants. Several nsSNPs of ADD1 are found to affect post-translational modifications such as methylation, glycosylation, phosphorylation, ubiquitination etc. The stability of the protein ADD1 is also affected by some nsSNPs and it has been found that twenty six variants show decrease in stability. It has also been observed that non-synonymous substitution like R354C, L387M and L387V of ADD1 lead to significant structural changes in ADD1 mRNA. The results obtained from the analyses reveal about prioritization of damaging nsSNPs in ADD1. Furthermore, the predicted disease associated nsSNPs can be analyzed in population based genotyping studies and in futuristic drug development in the area of ADD1 pharmacogenomics.

α-Adducin gene promoter DNA methylation and the risk of essential hypertension

ABSTRACTThis study was conducted to test the association between promoter DNA methylation of α-Adducin (ADD1) gene and the risk of essential hypertension (EH). A total of 150 EH patients and 100 aged- and gender-matched controls were investigated. DNA methylation levels of five cytosine-phosphate-guanine (CpG) dinucleotides on ADD1 promoter were measured employing bisulfite pyrosequencing technology. Our results showed that females have a higher ADD1 DNA methylation than males and a significantly lower CpG1 methylation level is associated with increased risk of EH among them. As for males, a significant association between lower CpG2-5 methylation levels and increased risk of EH was shown. In addition, CpG2-5 methylation was found to be a highly significant predictor for EH among males. In females, CpG1 methylation was considered a predictor of hypertension. No significant correlations were found with biochemical measures, apart from the concentration of aspartate aminotransferase which was inversely correlated with ADD1 CpG2-5 methylation levels among female controls (r = −0.703). These findings highlight that ADD1 methylation may have a contributing role in the pathogenesis of EH with varying implications for both genders.

Alpha Adducin G460T Variant is a Risk Factor for Hypertension in Tunisian Population.

Adducin is a membrane cytoskeletal protein, consisting of three subunits: α, β, and γ subunits encoded by three different genes (ADD1, ADD2, ADD3). A specific mutation G460T of the α-adducin gene (ADD1) is associated with high renal tubular sodium reabsorption. This mutation is associated with salt sensitivity and may influence the risk of hypertension. In this study, we investigated the relationship between the G460T polymorphism of the ADD1 and essential hypertension (EH) in the Tunisian population. The case-controlled study included 280 patients with hypertension and 257 healthy controls. The G460T polymorphism of ADD1 was determined by polymerase chain reaction-restriction fragment length polymorphism analysis method. In the whole population, the genotypic frequencies of the a-adducin G460T polymorphism in hypertensive and control groups (GG, GT, TT) were 78.6%, 17.5%, 3.9% and 87.5%, 11.29%, 1.16%, respectively (χ2 = 9.13, p < 0.01). The genotype was associated with hypertension, OR = 1.79, 95% CI (1.04 - 3.41), p < 0.03 for GT heterozygous and OR = 1.93, 95% CI (1.39 - 2.22), p < 0.03 for TT homozygous. Moreover, when we stratified the population according to gender, the genotypic frequencies were significantly associated with G460T polymorphism in men (p < 0.01) and in women (p < 0.05). Furthermore, no relationship was found between clinical characteristics and ADD1 G460T genotypes. The present study shows that the a-adducin G460T polymorphism is associated with EH. Our results suggest that this variant can be considered a genetic risk factor for hypertension in the Tunisian population.

Study of Alpha Adducin Gene Polymorphism in Young Essential Hypertensive North Indians

Introduction: Hypertension is a major risk factor for cardiovascular disorders such as stroke, heart failure, vascular disease, and end-stage renal disease, and is one of the leading causes of morbidity and mortality worldwide. The polymorphism of α adducin (ADD1) gene & their expression in the related tissue can reveal the mystery of essential hypertension and this can help in diagnosis, prognosis and management of essential hypertension. This gene analysis would provide a better approach for identifying the genotype-phenotype correlations. Objective: This study was designed to examine the relationship between α-adducin gene polymorphism (Gly460Trp) and essential hypertension in North Indian population. Methods: The subjects were recruited randomly including 101 patients of essential hypertension and 151 healthy controls. Genotyping was performed using polymerase chain reaction (PCR)-restriction fragment length polymerase (RFLP). Results: We found that frequencies of the alpha adducin Trp alleles in hypertensive and control groups were 0.21 and 0.11, respectively. There was approximately double increase in the 460-Trp allele frequency in the North Indian hypertensives compared with the normotensives. Conclusion: The rs4961 polymorphism of the ADD1 gene is associated with essential hypertension. We found a significant association between the Gly460Trp gene polymorphism of the alpha adducin and hypertension in a North Indian population. Furthermore, the study indicated that alpha adducin might be a susceptible gene to essential hypertension in North Indian population. Key words: Cardiovascular, Coronary heart disease, α adducing, Essential hypertension, Stroke.

The interactions between alcohol consumption and DNA methylation of the ADD1 gene promoter modulate essential hypertension susceptibility in a population-based, case-control study.

The potential effects of the interactions between DNA methylation (CpG1 and CpG2-5 methylation levels) of the α-adducin (ADD1) gene promoter and ADD1 tagSNPs (tag single-nucleotide polymorphisms) or the environmental factors on essential hypertension (EH) risk have not been clarified. Thus, we performed an age- and gender-matched case-control study to investigate the association between ADD1 tagSNPs and EH. A total of 1020 subjects with EH and 1020 normotensive subjects were genotyped by melting temperature shift technology. Logistic regression was used to assess the associations of ADD1 tagSNPs, environmental factors and EH. The generalized multifactor dimensionality reduction (GMDR) method was applied to explore the potential interactions. Under additive, dominant and recessive models, no significant associations were evidenced between EH and rs3755885, rs2071694, rs4963 or rs3775067 with the complete data set or the gender-stratified analysis after adjusting for triglycerides, body mass index and alcohol consumption. However, we observed a significant association between rs4961 and EH under the dominant model after Bonferroni correction when adjusting for confounding factors in the entire sample (odds ratio (OR)=0.64, 95% confidence interval (CI)=0.50-0.83, P=0.001). In GMDR, the two-factor interaction model of alcohol consumption and DNA methylation (CpG1 methylation) was the best model, with a maximum cross-validation consistency of 9/10 and testing balance accuracy of 0.63 (P=0.01). Our results indicate that the SNP rs4961 has a protective role in the development of EH. In conclusion, the interactions between alcohol consumption and DNA methylation (CpG1 methylation) of the ADD1 gene promoter have a significant role in modifying EH susceptibility.

Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake.

Cardiac left ventricle hypertrophy (LVH) constitutes a major risk factor for heart failure. Although LVH is most commonly caused by chronic elevation in arterial blood pressure, reduction of blood pressure to normal levels does not always result in regression of LVH, suggesting that additional factors contribute to the development of this pathology. We tested whether genetic preconditions associated with the imbalance in sodium homeostasis could trigger the development of LVH without concomitant increases in blood pressure. The results showed that the presence of a hypertensive variant of α-adducin gene in Milan rats (before they become hypertensive) resulted in elevated expression of genes associated with LVH, and of salt-inducible kinase 2 (SIK2) in the left ventricle (LV). Moreover, the mRNA expression levels of SIK2, α-adducin, and several markers of cardiac hypertrophy were positively correlated in tissue biopsies obtained from human hearts. In addition, we found in cardiac myocytes that α-adducin regulates the expression of SIK2, which in turn mediates the effects of adducin on hypertrophy markers gene activation. Furthermore, evidence that SIK2 is critical for the development of LVH in response to chronic high salt diet (HS) was obtained in mice with ablation of the sik2 gene. Increases in the expression of genes associated with LVH, as well as increases in LV wall thickness upon HS, occurred only in sik2+/+ but not in sik2−/− mice. Thus LVH triggered by HS or the presence of a genetic variant of α-adducin requires SIK2 and is independent of elevated blood pressure. Inhibitors of SIK2 may constitute part of a novel therapeutic regimen aimed at prevention/regression of LVH.

Lower ADD1 Gene Promoter DNA Methylation Increases the Risk of Essential Hypertension

The goal of our study is to investigate the contribution of promoter DNA methylation of α-adducin (ADD1) gene to the risk of essential hypertension (EH). Using the bisulphite pyrosequencing technology, DNA methylation levels of five CpG dinucleotides on ADD1 promoter were measured among 33 EH cases and 28 healthy controls. Significantly higher ADD1 DNA methylation levels were observed in the females than in the males (CpG1: P = 0.016; CpG2-5: P = 0.021). A breakdown analysis by gender showed that lower CpG1 methylation was associated with an increased risk of EH in females (adjusted P = 0.042). A much more significant association between lower CpG2-5 methylation levels and the increased risk of EH was found in males (adjusted P = 0.008). CpG1 methylation was inversely correlated with age in females (r = −0.407, P = 0.019) but not in males. ADD1 CpG1 and CpG2-5 methylation levels were significantly lower in post-menopausal (>50 years) women than pre-menopausal (≤50 years) women (CpG1: P = 0.006; CpG2-5: P = 0.034). A significant interaction between CpG1 methylation and age was found in females (CpG1*age: P = 0.029). CpG2-5 methylation was shown as a significant predictor of EH in males [area under curve (AUC) = 0.855, P = 0.001], in contrast that CpG1 methylation was a trend toward indicator in females (AUC = 0.699, P = 0.054). In addition, significant differences were observed between males and females for alanine aminotransferase (ALT, P = 0.001), aspartate aminotransferase (AST, P = 0.005) and uric acid (P<0.001). The concentration of AST was inversely correlated with ADD1 CpG2-5 methylation levels in female controls (r = −0.644, P = 0.024). These observations may bring new hints to elaborate the pathogenesis of EH.

Cardiometabolic Diseases and Related Complications: Current Status and Future Perspective

Cardiometabolic Diseases and Related Complications: Current Status and Future Perspective

Strain‐specific hyperkyphosis and megaesophagus in Add1 null mice

The three adducin proteins (α, β, and γ) share extensive sequence, structural, and functional homology. Heterodimers of α- and β-adducin are vital components of the red cell membrane skeleton, which is required to maintain red cell elasticity and structural integrity. In addition to anemia, targeted deletion of the α-adducin gene (Add1) reveals unexpected, strain-dependent non-erythroid phenotypes. On an inbred 129 genetic background, Add1 null mice show abnormal inward curvature of the cervicothoracic spine with complete penetrance. More surprisingly, a subset of 129-Add1 null mice develop severe megaesophagus, while examination of peripheral nerves reveals a reduced number of axons in 129-Add1 null mice at four months of age. These unforeseen phenotypes, described here, reveal new functions for adducin and provide new models of mammalian disease.

Do ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?

This study was undertaken to evaluate the role of ACE and αADDUCIN polymorphisms in patients with recurrent and nonrecurrent hypertensive intracerebral hemorrhage (ICH). A total of 101 nonrecurrent and 33 recurrent hypertensive ICH patients underwent an ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphism study. The risk factors, clinical findings, CT scan abnormalities and functional outcome of recurrent and nonrecurrent ICH were compared. ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphisms were also compared in the two groups and with 198 controls. The patients with recurrent ICH were older compared to those with nonrecurrent ICH and the other stroke risk factors were found in the two groups. Ganglionic-ganglionic pattern of recurrence was the commonest (75.6%) and all had at least one ICH in the location of hypertensive ICH. ACE DD genotype (OR6.18, 95%CI 2.93-13.02) and D allele (OR 2.43, 95%CI 1.70-3.47) were associated with nonrecurrent ICH compared to controls. In patients with recurrent ICH, DD genotype (OR 7.46, 95%CI 2.8-19.4) and D allele (OR 3.16, 95%CI 1.83-5.46) of ACE, and GW (OR 3.49, 95%CI 1.47-8.28), WW (OR 2.9, 95%CI 1.40-4.30) genotypes and W allele (OR 7.46, 95%CI 2.80-19.40) of αADDUCIN were more frequent compared to controls. Recurrent ICH also had higher frequency of WW genotype (OR 9.43, 95%CI 1.49-59.50) and W allele (OR 2.19, 95%CI 1.11-4.03) compared to nonrecurrent ICH. The frequency of DD + WW (P = 0.008) and DD/WW + ID/GW (P = 0.0001) genotypes in the recurrent ICH was higher than in the nonrecurrent ICH and the controls. Variant genotype combinations of ACE and αADDUCIN render the hypertensive patient more vulnerable to recurrent ICH.

Association between α-adducin gene, angiotensin converting enzyme gene polymorphisms and hypertensive kidney lesions in hypertensive patients

ObjectiveTo investigate the association between polymorphisms of α-adducin (ADD) gene Gly460Trp, angiotensin converting enzyme (ACE) gene I/D and kidney lesions in patients with essential hypertension respectively and jointly.MethodsThe case-control study...

Discovery of SNP in exon 14 of the &amp;lt;i&amp;gt;ADD1&amp;lt;/i&amp;gt; gene and its association with fatness traits in four meat-type duck populations (Brief Report)

Abstract. Fatness traits are important economically traits in meat producing animals including duck (WU et al. 2008a, b). In human, the α-Adducin (ADD1) gene polymorphism was associated with blood pressure and other subsequent negative effects related to obesity, cardiovascular and renal failure. In fact, there was some relationship between obesity and hypertension. Thus the ADD1 gene is a candidate gene for fatness traits and the study aims to invest the relationship between the polymorphism of the ADD1 gene and fatness and growth traits.

The influence of α-adducin gene polymorphism on response of blood pressure to exercise in patients with hypertension

Clinical studies have indicated that an excessive response of blood pressure (BP) to exercise predicts risk of cardiovascular mortality. Although the mechanism responsible for the excessive BP response to exercise has not been revealed, there are some plausible mechanisms linking with underlying structural abnormalities in the cardiovascular system. Carriers of the Trp460 allele of the α-adducin Gly460Trp polymorphism have an increased risk of hypertension. The aim of the present study was to examine the influence of α-adducin gene polymorphism on response of BP to exercise in patients with hypertension. The cross-sectional observational study consisted of 49 hypertensive patients (29 women and 20 men; mean age, 53.1±8.8 years). All participants underwent a multistage exercise treadmill test according to the Bruce protocol. Arterial BPs were compared at rest, peak exercise and end of the recovery phase. Patients were classified according to their α-adducin gene polymorphisms; Gly460Gly homozygotes - Group 1 (n=28) and Trp460Trp homozygotes and Gly460Trp heterozygotes - Group 2 (n=21). Statistical analysis was performed using Chi-square, unpaired t, Mann-Whitney U and ANCOVA tests. Mean exercise duration and mean exercise capacity in metabolic equivalents were not different between Group 1 and 2. The major finding of the study was that systolic BP responses at peak exercise and recovery period (3. min) were significantly higher (p=0.036) in hypertensive patients carrying at least one Trp460 allele of the α-adducin gene. Our results suggest that genetic variants that alter renal function and/or vasoreactivity are logical candidates to explain some of the individual variability in the BP response to exercise.

Alpha-Adducin Gly460Trp Polymorphism and Hypertension Risk: A Meta-Analysis of 22 Studies Including 14303 Cases and 15961 Controls

BackgroundNo 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.Methodology/Principal FindingsStudies 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.Conclusions/SignificanceOur 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.

Association of the polymorphisms of sodium transport related genes with essential hypertension

To investigate the association of the polymorphisms of rs4961 in alpha-adducin (ADD1) and rs28933400 in Na+/K+ -ATPase a2 (ATP1A2) genes, the products of which are important for sodium transport, with essential hypertension. Mutagenically separated PCR (MS-PCR) was used to detect the genotypes of the two loci. The subjects were recruited randomly including 196 patients of essential hypertension and 192 healthy controls. The frequencies of genotypes and alleles of in the ADD1 gene were significantly different between the patients and controls respectively (P=0.03, P=0.04). There was significant relationship between the genotypes of rs4961 and systolic blood pressure and blood sodium concentration. However, there was no significant relationship between the rs4961 genotypes and diastolic blood pressure, body mass index, blood kalium and chlorine concentrations. There was no polymorphism at the rs28933400 locus in the subjects analyzed. The rs4961 polymorphism of the ADD1 gene is associated with essential hypertension, but the rs28933400 locus in the ATP1A2 gene may have no association with essential hypertension in the studied population.

Interaction between the Gly460Trp α-adducin gene variant and diuretics on the risk of myocardial infarction

The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. The aim of the study was to determine whether the alpha-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the alpha-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). This study suggests that the alpha-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.

Renin–Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs: Results From the GENRES Study

Polymorphisms in genes coding for components of the renin-angiotensin system (RAS) and alpha-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study. The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C. The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively). Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.

α-Adducin Gly 460 Trp Variant Increases the Risk of Stroke in Hypertensive Dutch Women

The Gly460Trp variant of the alpha-adducin gene has been associated with renal sodium retention and salt-sensitive hypertension. Independent of blood pressure, salt sensitivity has been related to cerebrovascular events. We studied the risk of stroke, coronary heart disease (CHD), and myocardial infarction (MI) associated with the alpha-adducin variant and examined the extent to which this risk is modified by the presence of hypertension. We performed a case-cohort study in a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model with an estimation procedure adapted for case-cohort designs to study the relation of the polymorphism and CHD (n=210), MI (n=71), any stroke (n=74), and ischemic stroke (n=49). Subjects with the Gly460Trp variant had a 2.8 times higher risk of stroke (95% confidence intervals [CI] 1.3 to 5.8) under the dominant genetic model, which did not attenuate after adjustment. The same pattern was found under per-allele comparison. Risk of ischemic stroke in the variant allele carriers was 3.9 times higher than in subjects with the common genotype (95% CI 1.7 to 8.6) using dominant inheritance model. The same patterns were found under per-allele comparison. CHD and MI were not related to the variant. The risk of ischemic stroke was more pronounced among women with systolic hypertension (10.9; 95% CI 3.6 to 31.5). The findings in this prospective study in a population based cohort of Dutch women strongly suggest that presence of the alpha-adducin Gly460Trp polymorphism increases the risk of stroke. This risk is particularly elevated in the presence of systolic hypertension.

Are there interactions between the Gly460Trp α-adducin gene variant and the use of diuretics?

Treatment with a thiazide diuretic is associated with large interindividual differences in blood-pressure reduction. Both environmental and genetic factors might play a role. Several individual polymorphisms have already been studied for association with blood-pressure response in patients treated with diuretics. α-adducin is one of the more extensively studied polymorphisms. Unfortunately, conflicting results have been found in different populations. More research is needed to unravel the possible interactions between diuretics and the α-adducin polymorphism.