Alpha-adducin Gene Research Articles

The Association between Gly460Trp-Polymorphism of Alpha-Adducin 1 Gene (ADD1) and Arterial Hypertension Development in Ukrainian Population.

Arterial hypertension (AH) belongs to the diseases with genetic predisposition that determines the necessity of research on the genetic component's influence on this disease development. It is suggested that one of the salt-sensitive arterial hypertension potential markers may be the alpha-adducin gene because its protein product is involved in the ion transport regulation in the renal epithelium. Thus, the aim of the study was to investigate the association between ADD1 Gly460Trp-polymorphism and the AH development risk among patients with different risk factors in the Ukrainian population. The study included 232 Ukrainians: 120 patients with diagnosed arterial hypertension and 112 practically healthy individuals. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used for ADD1 Gly460Trp-polymorphism genotyping. The ADD1 Gly460Trp-polymorphic locus is an important predictor of arterial hypertension development in the Ukrainian population, but other nongenetic factors should be considered in further studies.

Alpha Adducin (ADD1) Gene Polymorphism and New Onset of Diabetes Under the Influence of Selective Antihypertensive Therapy in Essential Hypertension

Background:Different antihypertensive therapies (especially diuretics) are reported to induce the new onset of diabetes in some hypertensive patients. α-adducin-1 (ADD1) gene is salt sensitive gene which has its role in etiology of hypertension via salt sensitivity. Therefore, the G460T polymorphism of ADD1 gene may be associated with new onset of diabetes under the influence of diuretic and other antihypertensive therapies. Aim:To assess the correlation between genetic polymorphism (ADD1 G460T polymorphism) and glycaemic disturbance under influence of diuretic and other antihypertensive drug therapies. Materials and Methods:We recruited study subjects, 270 normotensive as control (150 male and 120 females), 270 hypertensive patients (95 male and 175 females) and 240 hypertensive with new onset of diabetes patients (80 male and 160 females). All study samples were genotyped for ADD1 polymorphic alleles and analyzed the relationship between different genotypes with respect to anthropometric and clinical parameters along with drug therapies. Results: Clinical and anthropometric parameters (such as age, SBP, DBP, FBG, height, weight, WC, HP, W/H ratio, and BMI) of study population were found highly statistically significant (p<0.05) at base value. Further, genotype wise comparison of all the above parameters revealed most of them as non-significant (p>0.05). Whereas, comparison between genotype and different antihypertensive drug therapy of hypertensive patients, specifically, diuretic therapy as mono in male (p=0.0227) and female (p=0.0292) and in combination with BBs in both male (p=0.0023) and female (p=0.0079) revealed a higher FBG level in variant T allele. In case of hypertensive with new onset of diabetes patients, only female population showed a slightly statistically significant (p=0.0413) difference in FBG level with diuretic mono therapy. Other antihypertensive drug therapies were safe and effective either as mono or in combination therapy. Discussion:Anthropometric parameters may be the indicative factors for hypertension and diabetes. Variant T allele of ADD1 gene may be considered as the risk factor for the development of diabetes in hypertensive patients. Diuretics as mono therapy and in combination with BBs may be considered as the risk factor for new onset of diabetes in EH patients carrying variant T allele (either as TG or TT).

ALPHA-ADDUCIN POLYMORPHISM'S INFLUENCE ON ISCHEMIC STROKES

Objective: rs4961 Gly460Trp variant of the alpha adducin gene (ADD1) has been associated with renal sodium retention and salt sensitive hypertension. Previous studies indicated that carriers of the 460Trp allele have a higher risk of hypertension and cardiovascular (CV) diseases compared to wild-type homozygotes (Gly460Gly). The aim of this study is to assess whether there is a correlation between this ADD1 variant and the development of ischemic strokes in an Italian population. Design and method: 212 patients with ischemic stroke (IS) were recruited from the Stroke Unit of San Raffaele Hospital in Milan and divided into four categories according to Oxford Classification. These patients were compared to a cohort of elder general population (EGP, 128 patients) and a cohort of hypertensive patients (HYP, 2404 patients), both with no history of strokes. All patients analysed were genotyped for adducin family (ADD1, ADD2, ADD3) and other hypertension-related genes. Scientific data: in IS group mean age at strokes’ diagnosis was 72.34 ± 11.9, 61% men, 39% women. The incidence of CV risk factors was: hypertension 66%, diabetes 22%, hypercholesterolemia 40% and hypertriglyceridemia 13%, previous stroke 14%. Mean creatinine value was 1.07 ± 0.66 mg/dL. Two comparable populations were selected with similar age (71.28 ± 6.9 years for EGP) and with the same incidence of risk factors (for HYP population). Notably, the presence of subjects homozygous for ADD1 mutated allele (rs4961 TrpTrp) is more than double in patients bearing ischemic stroke than in the two other (6.1% IS vs. 2.3% EP, p = 0.049; 6.1% IS vs. 2.2 HYP, p = 0.009; fig. 1). There was no statistically difference among the various types of stroke. No other significant associations were identified with other gene variations. Results: These data suggest a correlation between mutated alpha-Adducin and the increased incidence of all types of ischemic stroke. No correlation was found with the other hypertension-related genes analysed. Conclusions: rs4961 alpha-Adducin polymorphism should be considered as an independent risk factor for ischemic strokes. Furthermore, ischemic stroke does not appear directly linked to hypertension. Finally, alpha-Adducin polymorphism itself might be a candidate gene in the pathogenesis of stroke.

Relationship between ADD1 Gly460Trp gene polymorphism and essential hypertension in Madeira Island.

Essential hypertension (EH) is a complex disease in which physiological, environmental, and genetic factors are involved in its genesis. The genetic variant of the alpha-adducin gene (ADD1) has been described as a risk factor for EH, but with controversial results.The objective of this study was to evaluate the association of ADD1 (Gly460Trp) gene polymorphism with the EH risk in a population from Madeira Island.A case-control study with 1614 individuals of Caucasian origin was performed, including 817 individuals with EH and 797 controls. Cases and controls were matched for sex and age, by frequency-matching method. All participants collected blood for biochemical and genotypic analysis for the Gly460Trp polymorphism. We further investigated which variables were independently associated to EH, and, consequently, analyzed their interactions.In our study, we found a significant association between the ADD1 gene polymorphism and EH (odds ratio 2.484, P = .01). This association remained statistically significant after the multivariate analysis (odds ratio 2.548, P = .02).The ADD1 Gly460Trp gene polymorphism is significantly and independently associated with EH risk in our population. The knowledge of genetic polymorphisms associated with EH is of paramount importance because it leads to a better understanding of the etiology and pathophysiology of this pathology.

Association between alpha-adducin gene rs4963 polymorphism and hypertension risk in Asian population: a meta-analysis

Some studies investigated the association between ADD1 rs4963 polymorphism and hypertension risk. However, the results remained inconclusive. Thus, we performed a meta-analysis. Published reports were searched in PubMed and Google Scholar. The strength of association was assessed by calculating odds ratios (OR) and 95% confidence interval (CI). Twelve studies with 5097 cases and 5937 controls were conducted in this study. Individuals with ADD1 rs4963 polymorphism showed an increased hypertension risk (OR = 1.21; 95%CI, 1.11-1.33; P &lt; 0.0001). Subgroup analyses were performed according to country and age. The results showed that Chinese with ADD1 rs4963 polymorphism showed an increased hypertension risk (OR = 1.28; 95%CI, 1.09-1.51; P = 0.003). However, subjects in Japan and India did not have increased hypertension risk. In the subgroup analysis by age, older subjects, but not younger subjects, with ADD1 rs4963 polymorphism showed an increased hypertension risk (OR = 1.19; 95%CI, 1.07-1.32; P = 0.001). In conclusion, this meta-analysis suggested that ADD1 rs4963 polymorphism might be associated with increased hypertension risk.

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.

Abstract 12535: Interaction Between Gene Polymorphism of Alpha Adducin (ADD1) and Alcohol Habit on the Risk of Essential Hypertension in A Japanese Population

Objectives: To evaluate the interactions between single nucleotide polymorphism (SNP) of alpha adducin gene(ADD1) and alcohol habits on the risk of hypertension (HT) in Japanese. Methods: We analyzed 19284 Japanese subjects enrolled in the genome banking project at Jichi Medical University, including 8711 HT cases and 10573 non-HT controls.Diagnosis of HT was based on BP≥140/90mmHg or anti-HT medications. We divided the subjects into four groups according to gender and age (≤49 or ≥50) and performed statistical analyses in each group. SNP rs4961(GG/GT/TT, Gly460Trp) of ADD1 was genotyped by TaqMan method. Alcohol habits were categorized to never, sometimes, and daily drinker for frequency of drinking. To assess the contribution of genotypes, alcohol habits, and the combinations of both to HT risk, we compared the frequencies of them between cases and controls by chi-squared test. The strength of the associations was estimated by odds ratios(ORs) and 95% confidence intervals(CI) by using logistic regression analysis. For the interaction, we assessed the joint ORs, which were calculated for each of nine combined categories created by cross-classification. Non-risk reference was never drinker carrying GG. Results: (1)Although genotype distributions did not significantly differ between cases and controls in all groups, the frequencies of alcohol habits and the combinations of both significantly differed in all groups.(2)Compared to GG, the ORs (95%CI) of TT were 1.11(0.83-1.49) in M≤49, 1.00(0.86-1.17) in M≥50, 0.83(0.58-1.17) in F≤49, and 0.99(0.85-1.15) in F≥50. Compared to never drinker, the ORs (95%CI) of daily drinker were 1.77(1.32-2.37, p&lt;0.001) in M≤49, 1.64(1.44-1.87, p&lt;0.001) in M≥50, 1.26(0.88-1.80) in F≤49, and 1.13(0.90-1.43) in F≥50. Compared to never drinker with GG, the ORs (95%CI) of daily drinker with TT were 3.43(1.74-6.73, p&lt;0.001) in M≤49, 1.83(1.41-2.39, p=0.001) in M≥50, 0.77(0.37-1.59) in F≤49, and 1.41(0.92-2.17) in F≥50. Conclusions: The interactions between ADD1 rs4961 and alcohol habits had significant effects on HT risk in Japanese males≤49 years. The interactions between ADD1 genotypes and alcohol habits may contribute to young-onset hypertension in Japanese males.

Association between Polymorphisms of Alpha-Adducin Gene and Essential Hypertension in Chinese Population

The association between polymorphisms of α-adducin (ADD1) gene and essential hypertension is still unclear. Thus, we carried out a case-control study and an interaction analysis to test whether ADD1 is a common candidate gene for hypertension in the Chinese population. Blood samples and information including body mass index (BMI), smoking habit, and alcohol abuse were collected. Meanwhile, total cholesterol, high density lipoprotein, triglyceride were measured by automatic biochemistry analyzer. All 6 tag single nucleotide polymorphisms (tagSNPs) within ADD1 gene were genotyped by SNPstream genotyping system. Multifactor dimensionality reduction (MDR) was used to identify the interactions among the SNPs and the non-genetic factors. Results showed that plasma triglyceride, total cholesterol, and BMI were significantly higher in the hypertensive group than in the control group. Result from genotyping indicated that rs4963 was significantly associated with essential hypertension. After stratification by gender, rs4963 was associated with essential hypertension only in males. MDR analysis indicated that interaction among BMI, rs4963, and rs16843452 were involved in susceptibility of hypertension. The present study indicated that rs4963 within ADD1 gene was associated with essential hypertension in Chinese population, which might be related to altered exonic splicing and disrupted gene regulation.

The Gly460Trp polymorphism of alpha-adducin gene as a predictor of renal function decline over 4 years of follow-up in an apparently healthy Chinese population

There were conflict data between alpha-adducin Gly460Trp genetic variant and changes of renal function. We conducted a prospective study to investigate the influence of alph-adducin Gly460Trp polymorphism on the quantitative changes of renal function. Of 1500 people screened, 112 non-diabetic normotensive elderly Chinese were recruited and received biochemistry examination at the baseline, at the second and fourth year follow-up. Serum creatinine and calculated renal parameter, using Modification of Diet in Renal Disease (MDRD) Study, were used to evaluate renal function and their progression. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Age was 71.9 ± 3.7 years (range 60-81). Serum creatinine and MDRD glomerular filtration rate (GFR) were significantly worsened at the 2 and 4-year follow-up (all P < 0.001). The magnitude of 4-year decline of MDRD GFR was significantly higher in subjects carrying the a-adducin Gly460Trp G-allele than TT genotype (P = 0.045). The multivariate analyses showed that a-adducin Gly460Trp (P = 0.034), baseline MDRD GFR (P < 0.001), diastolic blood pressure (P = 0.021) and body weight (P = 0.022) could independently predict 4-year change of MDRD GFR. This longitudinal study showed that the aging process was associated with decline of renal function in the healthy elderly. The alpha-adducin Gly460Trp gene polymorphism might modulate these changes in the Chinese. Thisprovides further knowledge essential in the assessment of renal disease and determination of renal function in the older subjects.

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.

Lack of association between α-adducin G460W polymorphism and hypertension: evidence from a case–control study and a meta-analysis

The past two decades have seen an upsurge in detecting the genetic determinants of hypertension. Thereafter, alpha-adducin gene ranks high and one polymorphism, G460W (rs4961), has attracted special attention. We first performed a case-control study to investigate the association of this polymorphism with essential hypertension among Shanghai residents, and then meta-analyzed all available evidence. A total of 950 subjects were recruited for genetic association study. Genotyping for G460W was conducted using PCR and restriction fragment length polymorphism techniques. Meta-analysis search was limited to articles published in English and studies on humans. Data and study quality were assessed in duplicate. Publication bias was evaluated using the fail-safe number. Our case-control study provided no evidence for the association of G460W with essential hypertension, even under assumptions of three genetic modes of inheritance (P>0.05). The subsequent meta-analysis including 15 studies with 4417 cases and 5716 controls also failed to demonstrate overall this association, even upon stratification by race (Caucasians and Asians). For example, the summary odds ratio (OR) under a random effects model indicated that carriers of 460W allele were 1.09 times more likely to develop hypertension (95% confidence interval (CI), 0.96-1.24; P=0.19) among Asians, whereas a protective effect of this allele was observed in Caucasians (OR, 0.93; 95% CI, 0.73-1.18; P=0.54). The fail-safe number at the level of 0.05 was in favour of our findings. Our case-control study and the following meta-analysis failed to provide evidence for the genetic association of alpha-adducin gene G460W polymorphism with hypertension.

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.

Single nucleotide polymorphisms in genes of circulatory homeostasis in surviving pediatric intensive care patients with meningococcal infection*

In the course of a meningococcal infection, invasive and severe disease occurs in a restricted number of individuals. The predominant mechanism of death in case of meningococcal septic shock is circulatory failure. Inotropic requirements between patients vary widely. We investigated whether polymorphisms in genes regulating the hemodynamic response influence the amount of inotropics required or the susceptibility to severe meningococcal disease. Retrospective case control study. Single-center pediatric intensive care unit (PICU). Fifty-six cases (all consecutive patients admitted to the PICU between 1993 and 2001 with a proven meningococcal infection) and 136 controls. Patients were divided into two groups according to their inotropic requirements. DNA analysis was performed to determine the polymorphisms of the beta-adrenergic receptor gene-1, beta-adrenergic receptor gene-2, alpha-adducin, angiotensin converting enzyme, and angiotensin II type-1 receptor-1 genes. For the alpha-adducin gene a significant difference of the genotype distribution was found between the cases and controls. The odds ratio for admission to the PICU with meningococcal sepsis with or without meningitis, for carriers of the variant allele (Gly460Trp or Trp460Trp) was 2.1 (95% confidence interval 1.11-4.04; p < 0.02). Cases, homozygote for the wild-type allele of the beta-1 adrenergic receptor at locus 389, were more likely to have a low pediatric risk of mortality score on admission (odds ratio 3.6, 95% confidence interval 1.11-11.76). No difference was found in the distribution of the beta-adrenergic receptor gene-1, beta-adrenergic receptor gene-2, angiotensin converting enzyme, and angiotensin II type-1 receptor-1 polymorphisms between the two groups of patients or between cases and controls. Among patients admitted to the PICU with a meningococcal infection, the variant allele of the alpha-adducin gene was more prevalent compared with controls. Patients with the variant allele of the beta-adrenergic receptor gene-1 at locus 389 were more likely to have a high pediatric risk of mortality score on admission. The mechanism and clinical relevance of these findings is unclear.

Endogenous cardiotonic steroids: clinical perspectives

Several endogenous digitalis-like cardiotonic steroids (CTS) have been identified in humans, including endogenous ouabain, a cardenolide, and marinobufagenin which belongs to a class of bufadienolides. The main function of CTS is maintenance of sodium homeostasis and regulation of natriuretic function. Endogenous cardiotonic steroids bind to the Na/K-ATPase and exhibit two kinds of effects, inhibition of transmembrane transport of monovalent cations, and induction of a complex cascade of cell signaling. In Dahl salt-sensitive rats with NaCl-induced hypertension, endogenous ouabain, acting as a neurohormone stimulates adrenocortical marinobufagenin, which raises blood pressure via inhibition of vascular Na/K-ATPase. In a subgroup of hypertensive subjects, which possess a polymorphism of alpha-adducin gene, elevated levels of endogenous ouabain activate renotubular Na/K-ATPase and induce renal sodium retention. Elevated levels of CTS also contribute to pathogenesis of congestive heart failure, preeclampsia, and diabetes mellitus. The approaches to pharmacological antagonism of the effects of CTS include blockade of CTS receptor site on the Na/K-ATPase, immunoneutralization, and interactions at the levels of Na/K-ATPase phosphorylation/dephosphorylation by protein kinases С and G.

Association of alpha-adducin gene and G-protein beta3-subunit gene with essential hypertension in Chinese

To investigate the relationship between the alpha-adducin (ADD1) gene G460W and the G-protein beta 3-subunit (GNB3) gene C825T polymorphisms and essential hypertension (EH) in a northern Chinese Han population. Peripheral blood samples were collected from 256 hypertensive patients and 495 normotensive controls. Polymerase chain reaction combined with restriction enzyme digestion was used to detect the polymorphisms of ADD1 and GNB3 genes. Their body mass index, blood lipids, blood glucose and blood uric acid levels were also determined. The allele frequencies of the ADD1 gene G460W and the GNB3 gene C825T polymorphisms were in Hardy-Weinberg equilibrium. The WW frequency in the EH group was 35.2%, significantly higher than that in the normal group (27.4%, chi(2) = 4.768, P = 0.029, OR = 1.43). Adjusted for the conventional risk factors of hypertension, alpha-adducin polymorphism still played an independent role on systolic blood pressure. The genotypes CC, CT, and TT of the GNB3 gene in the EH group were 20%, 52%, and 28% respectively, not significantly different from those in the control group (21%, 53%, and 26% respectively, P = 0.755). The frequencies of the alleles C and T of the GNB3 gene C825T were 46% and 54% respectively, not significantly different from those of the normotensive controls (47% and 53% respectively, P = 0.561). Body mass index, blood lipids, and glucose level did not differ significantly among the three genotype groups in both EH and normotensive control groups. The alpha-adducin gene may be a susceptible gene to EH in northern Chinese Han population, however, the GNB3 gene C825T polymorphism may not play a significant role in EH in the same population.

Overview of the Pharmacoeconomics of Pharmacogenetics

Pharmacoeconomics and pharmacogenetics are two fields converging together as it is increasingly recognized that genetic markers predicting efficacy and toxicity to drugs can cost-effectively improve patient care. While pharmacogenetics aims at identifying genetic markers underlying the response to drugs, pharmacoeconomics aims at delivering healthcare cost-effectively. Several studies have investigated the potential cost-effectiveness of pharmacogenetic-based approaches. Recent evidences include screening for thiopurine methyltransferase gene polymorphisms to prevent azathioprine-induced myelosuppression, or screening for human leukocyte antigen (HLA)B5701 to prevent hypersensitivity reactions to abacavir therapy. Furthermore, examples suggesting a cost-effectiveness of markers predicting drug efficacy include screening the angiotensin-converting enzyme gene polymorphisms for statins therapy, the alpha-adducin gene variant for diuretic therapy and the assessment of human epidermal growth factor receptor (HER2) expression for trastuzumab therapy. However, thus far, all these pharmacoeconomic analyses are exploratory and validations in prospective randomized clinical trials are warranted.

Antihypertensive therapy, the α-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study

In a double-blind, outcome trial conducted in hypertensive patients randomized to chlorthalidone (C), amlodipine (A), lisinopril (L), or doxazosin (D), the alpha-adducin Gly460Trp polymorphism was typed (n=36 913). Mean follow-up was 4.9 years. Relative risks (RRs) of chlorthalidone versus other treatments were compared between genotypes (Gly/Gly+Gly/Trp versus Trp/Trp). Primary outcome was coronary heart disease (CHD). Coronary heart disease incidence did not differ among treatments or genotypes nor was there any interaction between treatment and genotype (P=0.660). Subgroup analyses indicated that Trp allele carriers had greater CHD risk with C versus A+L in women (RR=1.31) but not men (RR=0.91) with no RR gender differences for non-carriers (gender-gene-treatment interaction, P=0.002). The alpha-adducin gene is not an important modifier of antihypertensive treatment on cardiovascular risk, but women Trp allele carriers may have increased CHD risk if treated with C versus A or L. This must be confirmed to have implications for hypertension treatment.

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.

Screening for the alpha-adducin Gly460Trp variant in hypertensive patients: a cost-effectiveness analysis

Studies have shown that approximately 80% of hypertensive patients do not take diuretics despite their recommendation as a first-line therapy. A recent study reported that hypertensive patients with the Gly460Trp variant in the alpha-adducin gene are more likely to benefit from diuretic therapy. The objective of this study was to evaluate the potential cost effectiveness of screening for the alpha-adducin Gly460Trp variant among hypertensive patients. A decision analytic Markov model was developed to estimate the clinical and economic outcomes comparing screening for the Gly460Trp variant to identify patients for addition of a diuretic compared to no screening and no addition of diuretic (usual care) in a hypothetical cohort of treated hypertensive patients not receiving diuretic therapy. We used a lifetime horizon and payer perspective. Cost, utility and epidemiological data were obtained from the literature. One-way, probabilistic, and scenario sensitivity analyses were conducted to evaluate the uncertainty in the results. The screening strategy increased quality adjusted life years (QALYs) by 0.14 (95% confidence range [CR]: 0.05, 0.36) and saved dollar 1834 (dollar 505, dollar 5174) compared to usual care. The most influential input was the strength of the interaction between the alpha-adducin gene variant and diuretic effect. Our results suggest that screening for the alpha-adducin gene variant may be a useful mechanism to identify patients most likely to benefit from diuretic therapy and improve compliance with current treatment guidelines.