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A Review on Adducin from Functional to Pathological Mechanisms: Future Direction in Cancer. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3465929. [PMID: 29862265 PMCID: PMC5976920 DOI: 10.1155/2018/3465929] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 12/14/2022]
Abstract
Adducin (ADD) is a family of membrane skeleton proteins including ADD1, ADD2, and ADD3 that are encoded by distinct genes on different chromosomes. Adducin is primarily responsible for the assembly of spectrin-actin network that provides physical support to the plasma membrane and mediates signal transduction in various cellular physiological processes upon regulation by protein kinase C-dependent and calcium/calmodulin-dependent pathways. Abnormal phosphorylation, genetic variations, and alternative splicing of adducin may contribute to alterations in cellular functions involved in pathogenic processes. These alterations are associated with a wide range of diseases including cancer. This paper begins with a discussion on how adducin partakes in the structural formation of membrane skeleton, its regulation, and related functional characteristics, followed by a review on the pathogenesis of hypertension, biliary atresia, and cancer with respect to increased disease susceptibility mediated by adducin polymorphism and/or dysregulation. Given the functional diversity of adducin in different cellular compartments, we aim to provide a knowledge base whereby its pathophysiological roles can be better understood. More importantly, we aim to provide novel insights that may be of significance in turning the adducin model to clinical application.
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Sadeghi M, Roohafza H, Pourmoghaddas M, Behnamfar O, Pourmoghaddas Z, Heidari E, Mahjoor Z, Mousavi M, Bahonar A, Sarrafzadegan N. How far cardio metabolic and psychological factors affect salt sensitivity in normotensive adult population? World J Cardiol 2017; 9:47-54. [PMID: 28163836 PMCID: PMC5253194 DOI: 10.4330/wjc.v9.i1.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/08/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the prevalence of salt sensitivity and the impact of cardiometabolic and psychological characteristics on salt sensitivity in normotensive population.
METHODS Of all participants, anthropometric measurements and fasting venous blood samples were collected, and study questionnaires were completed. Salt Sensitivity was defined based on the difference in mean arterial pressure with infusion of 2 L of normal saline followed by a low sodium diet and administration of three doses of oral furosemide the day after.
RESULTS Of 131 participants, 56 (42.7%) were diagnosed with salt sensitivity. Crude and age and sex adjusted regression analysis showed that low-density lipoprotein cholesterol and depression were positively associated with salt sensitivity (OR = 1.02, 95%CI: 1.01-1.04 and OR = 1.15, 95%CI: 1.00-1.34, respectively).
CONCLUSION The high prevalence of salt sensitivity and its significant relation with prevalent risk factors necessitates considering its reduction actions at the population level and the need for further research.
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Prevalence of glucose abnormalities and diagnostic value of fasting glucose and fasting insulin in urban Hispanics. Am J Ther 2013; 20:369-75. [PMID: 23528370 DOI: 10.1097/mjt.0b013e318235f2f5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The prevalence of glucose abnormalities (GAs) and the diagnostic value of fasting plasma glucose and insulin in detecting impaired glucose tolerance (IGT) and diabetes mellitus (DM) were determined in urban Latin Americans. An oral glucose tolerance test was conducted in 592 subjects after administration of 75 g of glucose. Employing American Diabetes Association (ADA) and World Health Organization guidelines, GAs were found in 34% of the subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG + IGT (7.8%), and newly diagnosed type-2-DM (6.5%). All newly diagnosed diabetics had 2-hour glucose levels ≥200 mg/dL, but only 46.1% had fasting glucose ≥126 mg/dL. In addition, nearly half of the subjects with IGT (47%) had fasting glucose levels <100 mg/dL. The sensitivity, specificity, positive and negative predictive values of IFG in predicting IGT was 52.9%, 83%, 36.8%, and 90.4 %, respectively. Fasting insulin levels were not sensitive for differentiating glucose tolerant, from IFG and IGT; only the subjects with combined IFG + IGT had increased fasting insulin levels (22% above IFG) (P < 0.01). Two-hour insulin was increased by 30% in IGT and newly diagnosed diabetics, and by 46% in the subjects with combined IFG + IGT. In summary, the very high prevalence of undetected GA encountered in "healthy" subjects living in Caracas, Venezuela, requires immediate sanitary attention. With 50% of diabetic patients being unaware of their condition, half of IGT and DM not detected by ADA guidelines, and the poor sensitivity/specificity of fasting glucose in predicting 2-hour abnormalities, we recommend that 2-hour postload glucose be included when screening for GAs. Measurements of fasting and/or postload insulin are not cost effective for the diagnosis of GA, because they provide little additional clinical information in this context.
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Association between polymorphisms of alpha-adducin gene and essential hypertension in Chinese population. BIOMED RESEARCH INTERNATIONAL 2013. [PMID: 23509723 DOI: 10.1155/2013/451094.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
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.
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Association between polymorphisms of alpha-adducin gene and essential hypertension in Chinese population. BIOMED RESEARCH INTERNATIONAL 2012; 2013:451094. [PMID: 23509723 PMCID: PMC3591139 DOI: 10.1155/2013/451094] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 10/24/2012] [Accepted: 10/25/2012] [Indexed: 11/21/2022]
Abstract
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.
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Abstract
High blood pressure (BP) is a complex trait determined by genetic and environmental factors, as well as their interactions. Over the past few decades, there has been substantial progress elucidating the genetic determinants underlying BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways subsequently identified in candidate gene studies of salt sensitivity. Despite these advancements, certain candidate gene findings await replication evidence, and some biological pathways warrant further investigation. Furthermore, results from genome-wide association studies (GWASs) and sequencing work have yet to be reported. GWAS will be valuable for uncovering novel mechanisms underlying salt sensitivity, whereas future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.
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Gene-sodium interaction and blood pressure: findings from genomics research of blood pressure salt sensitivity. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 108:237-60. [PMID: 22656380 DOI: 10.1016/b978-0-12-398397-8.00010-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
High blood pressure (BP) is a complex trait determined by both genetic and environmental factors, as well as the interactions between these factors. Over the past few decades, there has been substantial progress in elucidating the genetic determinants underlying the BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways related to salt sensitivity. Candidate gene studies have contributed important information toward understanding the genomic mechanisms underlying the BP response to salt intake, identifying genes in the renin-angiotensin-aldosterone system, renal sodium channels/transporters, and the endothelial system related to this phenotype. Despite these advancements, genome-wide association studies are still needed to uncover novel mechanisms underlying salt sensitivity, while future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP.
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Ramu P, Umamaheswaran G, Shewade DG, Swaminathan RP, Balachander J, Adithan C. Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk. INDIAN JOURNAL OF HUMAN GENETICS 2011; 16:8-15. [PMID: 20838486 PMCID: PMC2927797 DOI: 10.4103/0971-6866.64938] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
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.
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Affiliation(s)
- P Ramu
- Pharmacogenomics Laboratory, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006, India
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Wang R, Zhong B, Liu Y, Wang C. Association between alpha-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis. J Appl Genet 2010; 51:87-94. [PMID: 20145305 DOI: 10.1007/bf03195715] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Linkage and association studies suggested the relationship between alpha-adducin polymorphism (Gly460Trp; rs4961) and genetic susceptibility to salt-sensitivity. However, the currently available results were inconsistent. This study aimed to define quantitatively the association between salt-sensitivity and alpha-adducin Gly460Trp polymorphism in all published case-control studies. Publications from PubMed and other databases were retrieved. The major inclusion criteria were: (1) case-control design; (2) salt-sensitivity confirmed by sodium loading tests, and (3) the distribution of genotypes given in detail. Seven case-control studies fulfilled the inclusion criteria. In total they involved 820 subjects (454 salt-sensitive and 366 non-salt-sensitive). The meta-analysis shows that Gly460Trp polymorphism in general is not significantly associated with salt-sensitivity [OR (95%CI): 1.40 (0.96, 2.04), P = 0.08]. Subgroup analysis showed that the association is statistically significant in Asian people [OR (95%CI):1.33 (1.06, 1.69), P = 0.02] but not in Caucasian people [OR (95%CI):1.98 (0.57, 6.92), P = 0.28]. This indicates that blood pressure response to sodium varies between ethnical groups. More studies based on a larger population are required to evaluate further the role of alpha-adducin Gly460Trp polymorphism in salt-sensitive hypertension.
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Affiliation(s)
- R Wang
- Department of Cardiology, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, Guangxi, China.
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Kelly TN, Rice TK, Gu D, Hixson JE, Chen J, Liu D, Jaquish CE, Bazzano LA, Hu D, Ma J, Gu CC, Huang J, Hamm LL, He J. Novel genetic variants in the alpha-adducin and guanine nucleotide binding protein beta-polypeptide 3 genes and salt sensitivity of blood pressure. Am J Hypertens 2009; 22:985-92. [PMID: 19574959 PMCID: PMC2882159 DOI: 10.1038/ajh.2009.118] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND We examined the association between 12 single-nucleotide polymorphisms (SNPs) in the alpha-adducin (ADD1) and guanine nucleotide binding protein (G protein) beta-polypeptide 3 (GNB3) genes and systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressure responses to salt intake. METHODS A 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) was conducted among 1,906 Han participants from rural North China. Blood pressure (BP) measurements were obtained at baseline and at the end of each intervention period using a random-zero sphygmomanometer. RESULTS We identified a significant association between a rare ADD1 variant rs17833172 and SBP, DBP, and MAP responses to high sodium (P values <0.0001) and DBP response to low sodium (P value = 0.002). Participants homozygous for the variant A allele of this marker had SBP, DBP, and MAP responses (95% confidence interval) to high salt of 1.6 (-1.8, 4.9), -0.8 (-5.6, 4.0), and -0.1 (-4.0, 3.9) mm Hg, respectively, vs. corresponding responses of 4.6 (2.5, 6.6), 1.7 (-0.2, 3.6), and 2.7 (0.9, 4.4) mm Hg, respectively, for those who were heterozygous or homozygous for the G allele. In addition, participants with at least one copy of the A allele of SNP rs1129649 of the GNB3 gene had significantly decreased MAP response to low salt compared to homozygotes for the C allele (P value = 0.004) with responses of -3.4 (-3.8, -3.0) vs. -4.2 (-4.6, -3.8) mm Hg, respectively. CONCLUSIONS These data support a role for the ADD1 and GNB3 genes in BP salt sensitivity. Future studies aimed at replicating these novel findings are warranted.
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Affiliation(s)
- Tanika N Kelly
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
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Interaction between the Gly460Trp α-adducin gene variant and diuretics on the risk of myocardial infarction. J Hypertens 2009; 27:61-8. [DOI: 10.1097/hjh.0b013e328317a74d] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Definition of the phenotype is crucial in designing any genetic study, especially an association study, intended to detect the disease predisposing genes. In this chapter, we review the different types of phenotypes such as discrete or continuous and discuss the issues impacting on the phenotype definition related to study design, specifically, the impact of diagnostic error (misclassification) in case-control studies and measurement error in continuous traits. We show that the power of a study depends heavily on the phenotype measured and that misclassification or measurement error can dramatically reduce the power. We also suggest some possible responses to these challenges.
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Affiliation(s)
- Mary K Wojczynski
- Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Affiliation(s)
- M L G Correia
- Department of Internal Medicine, Carver College of Medicine, General Clinical Research Center, University of Iowa, Iowa City, IA 52242, USA.
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Richart T, Thijs L, Kuznetsova T, Tikhonoff V, Zagato L, Lijnen P, Fagard R, Wang J, Bianchi G, Staessen JA. Intra-erythrocyte cation concentrations in relation to the C1797T beta-adducin polymorphism in a general population. J Hum Hypertens 2007; 21:387-92. [PMID: 17301826 DOI: 10.1038/sj.jhh.1002154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Genetic variability in the ADD1 (Gly460Trp) and ADD2 (C1797T) subunits of the cytoskeleton protein adducin plays a role in the pathogenesis of hypertension, possibly via changes in intracellular cation concentrations. ADD2 1797CC homozygous men have decreased erythrocyte count and hematocrit. We investigated possible association between intra-erythrocyte cations and the adducin polymorphisms. In 259 subjects (mean age 47.7 years), we measured intra-erythrocyte Na(+) [iNa], K(+) [iK] and Mg(2+) [iMg], serum cations and adducin genotypes. Genotype frequencies (ADD1: GlyGly 61.5%, Trp 38.5%; ADD2: CC 80.4%, T 19.6%) complied with Hardy-Weinberg proportions. In men, ADD2 CC homozygotes (n=100) compared to T-carriers (n=23) had slightly lower iK (85.8 versus 87.5 mmol/l cells; P=0.107), higher iMg (1.92 versus 1.80 mmol/l cells; P=0.012), but similar iNa (6.86 versus 6.88 mmol/l cells; P=0.93). In men, iK, iMg and iNa did not differ according to ADD1 genotypes. In men, iK (R(2)=0.128) increased with age and serum Na(+), but decreased with serum total calcium and the daily intake of alcohol. iMg (R(2)=0.087) decreased with age, but increased with serum total calcium. After adjustment for these covariates (P<or=0.04 for all), findings in men for iK (CC versus T: 85.8 versus 87.3 mmol/l; P=0.14) and iMg (1.91 versus 1.82 mmol/l; P=0.03) remained consistent. In 136 women, none of the phenotype-genotype relations reached significance. Changes in intra-erythrocyte cations in ADD2 1797CC homozygous men might lead to osmotic fragility of erythrocytes, but to what extent they reflect systemic changes or are possibly involved in blood pressure regulation remains unknown.
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Affiliation(s)
- T Richart
- Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, Studies Coordinating Centre, University of Leuven, Leuven, Belgium
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Yazdanpanah M, Sayed-Tabatabaei FA, Hofman A, Aulchenko YS, Oostra BA, Stricker BHC, Pols HAP, Lamberts SWJ, Witteman JCM, Janssen JAMJL, van Duijn CM. The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes. Diabetes 2006; 55:2922-7. [PMID: 17003363 DOI: 10.2337/db06-0302] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We examined the association between alpha-adducin 1 (ADD1) gene polymorphism (Gly460Trp) with macrovascular complications and mortality in type 2 diabetes in a Caucasian population aged >or=55 years. The study was part of the Rotterdam Study, a prospective population-based cohort study. ADD1 polymorphism was determined in 6,471 participants, including 599 patients with type 2 diabetes at baseline. The prevalence of hypertension in type 2 diabetic patients was 2.57 times higher in ADD1 TT carriers compared with GG carriers (95% CI 1.05-6.32, P = 0.03). Homozygous T carriers also had a higher mean common carotid intima media thickness (IMT) compared with GG carriers (mean difference 0.05 mm, P for trend = 0.03). In diabetic patients with hypertension, the risk of mortality was 1.83 times higher in homozygous T carriers compared with the GG genotype group (95% CI 1.07-3.16, P = 0.03). The increased risk was only present among TT carriers who did not use antidiabetes medication (hazard ratio 2.18 [95% CI 1.12-4.24], P = 0.02). The results of this population-based cohort study suggest that the ADD1 gene contributes to the risk of hypertension and increases mean common carotid IMT in patients with type 2 diabetes. Furthermore, the study indicates that the ADD1 polymorphism could be useful in identifying hypertensive type 2 diabetic patients with a high risk of mortality.
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Affiliation(s)
- Mojgan Yazdanpanah
- Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
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Castejon AM, Bracero J, Hoffmann IS, Alfieri AB, Cubeddu LX. NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens 2006; 20:772-9. [PMID: 16738684 DOI: 10.1038/sj.jhh.1002057] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Mutations in the NAD(P)H oxidase gene may be associated with abnormal superoxide generation, nitric oxide (NO) availability and cardiovascular diseases. We investigated the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism, and its possible association with blood pressure, NO production, salt sensitivity and cardiovascular risk factors in Hispanics. Genotype frequencies were as follows: CC, 52.9%; CT, 40.3%; and TT, 6.8%. There were no significant differences in systolic blood pressure, diastolic blood pressure, age, weight, fasting and post-load glucose levels, LDL and HDL cholesterol, triglyceride and urinary albumin levels in subjects with CC, CT or the TT genotypes. Presence of the T allele was associated with increased salt sensitivity in women, but not in men. NO metabolite excretion was markedly decreased both in women and men with the TT genotype (CC: 868+/-79 micromol/day; CT: 839+/-75 micromol/day; TT: 534+/-78 micromol/day; P<0.05). In conclusion, the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism in Venezuelans was comparable to that of Caucasians, but different from that of Chinese and Japanese. Although the T allele was not associated with cardiovascular risk factors, hyperinsulinaemia or hypertension, in women, it appeared to be a genetic susceptibility factor for salt sensitivity. Both in women and men, the p22phox gene may play a role in the genetic control of NO levels.
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Affiliation(s)
- A M Castejon
- Department of Pharmaceutical Sciences, Health Professions Division, College of Pharmacy, NOVA Southeastern University (NSU), Fort Lauderdale, FL 33328, USA
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Meckley LM, Veenstra DL. Screening for the alpha-adducin Gly460Trp variant in hypertensive patients: a cost-effectiveness analysis. Pharmacogenet Genomics 2006; 16:139-47. [PMID: 16424826 DOI: 10.1097/01.fpc.0000189801.96220.82] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND 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. METHODS 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. 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. CONCLUSIONS 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.
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Bianchi G. Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms. Am J Physiol Regul Integr Comp Physiol 2005; 289:R1536-49. [PMID: 16278339 DOI: 10.1152/ajpregu.00441.2005] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The definition of the most appropriate strategy to demonstrate causation of a given genetic-molecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the “mutated” gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.
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Affiliation(s)
- Giuseppe Bianchi
- School of Nephrology, Univ. Vita Salute San Raffaele, Division of Nephrology, Dialysis and Hypertension, San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy.
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Abstract
UNLABELLED PURPOSE IDENTIFICATION: Inter-individual variability in blood pressure response to treatment is well documented, but a clinically useful means to distinguish responders from non-responders has been elusive. With the advent of new technologies and genomic knowledge, more investigators are seeking to identify genetic determinants of blood pressure response to therapy. STUDY SELECTION We identified studies of candidate polymorphisms from an initial PubMed search using the MESH terms 'Hypertension: Drug Therapy' and 'Genetics' or 'Pharmacogenetics', limiting results to English-language publications on studies in human adults. We further identified specific polymorphisms of interest noted in earlier reviews and performed additional PubMed searches based on these candidate genes. Pertinent studies were further extracted from the references of studies already identified. We focused on clinical trials that measured blood pressure response to a medication or class of medications over a minimum of 4 weeks. DATA EXTRACTION We evaluated studies looking at blood pressure response to commonly used classes of antihypertensive medications by major genetic variants. RESULTS OF ANALYSIS: Although many studies show that blood pressure response to a given class of antihypertensive medications varies by genotype for different polymorphisms, none of the genotypes identified consistently predicted blood pressure response. CONCLUSIONS Common variants may influence response to diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, but studies of polymorphisms have generally yielded conflicting results. The inclusion of pharmacogenomic studies in large clinical trials and other more innovative investigative methods may provide greater clarity of the potential role for genotyping in the treatment of patients with hypertension.
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Affiliation(s)
- Philip B Mellen
- Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA
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Hoffmann IS, Tavares-Mordwinkin R, Castejon AM, Alfieri AB, Cubeddu LX. Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens 2005; 19:233-40. [PMID: 15565175 DOI: 10.1038/sj.jhh.1001801] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.
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Affiliation(s)
- I S Hoffmann
- Center for the Detection and Treatment of Silent Risk Factors for Cardiovascular and Metabolic Disease, Division of Clinical Pharmacology Unit, School of Pharmacy, Central University of Venezuela
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Cwynar M, Staessen JA, Tichá M, Nawrot T, Citterio L, Kuznetsova T, Wojciechowska W, Stolarz K, Filipovský J, Kawecka-Jaszcz K, Grodzicki T, Struijker-Boudier HA, Thijs L, Van Bortel LM, Bianchi G. Epistatic interaction between α- and γ-adducin influences peripheral and central pulse pressures in white Europeans. J Hypertens 2005; 23:961-9. [PMID: 15834281 DOI: 10.1097/01.hjh.0000166836.70935.e7] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Adducin is a membrane skeleton protein consisting of alpha- and beta- or alpha- and gamma-subunits. Mutations in alpha- and beta-adducin are associated with hypertension. In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding alpha-adducin (Gly460Trp), beta-adducin (C1797T) and gamma-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness. METHODS We measured peripheral and central PP by conventional sphygmomanometry and applanation tonometry, respectively. We randomly recruited 642 subjects (162 nuclear families and 70 unrelated individuals) from three European populations. In multivariate analyses, we used generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS Peripheral and central PP averaged 46.1 and 32.6 mmHg, respectively. Among carriers of the alpha-adducin Trp allele, peripheral and central PP were 5.8 and 4.7 mmHg higher in gamma-adducin GG homozygotes than in their AA counterparts, due to an increase in systolic pressure. gamma-Adducin GG homozygosity was associated with lower urinary Na/K ratio among alpha-adducin Trp allele carriers and with higher urinary aldosterone excretion among alpha-adducin GlyGly homozygotes. Sensitivity analyses in founders and offspring separately, and tests based on the transmission of the gamma-adducin G allele across families, confirmed the interaction between the alpha- and gamma-adducin genes. CONCLUSIONS In alpha-adducin Trp allele carriers, peripheral and central PP increased with the gamma-adducin G allele. This epistatic interaction is physiologically consistent with the heterodimeric structure of the protein and its influence on transmembranous sodium transport.
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Affiliation(s)
- Marcin Cwynar
- Department of Internal Medicine and Gerontology, Medical College, Jagiellonian University, Cracow, Poland
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Abstract
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.
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Affiliation(s)
- Giuseppe Bianchi
- School of Nephrology, Dialysis and Hypertension, University Vita Salute San Raffaele, Milan, Italy.
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