The Gly460Trp variant of α-adducin is not associated with hypertension in white anglo-Australians

Wang, William Y.S.; Adams, David J.; Glenn, Cheryl L.; Morris, Brian J.

doi:10.1016/s0895-7061(99)00004-7

Cited by 28 publications

(16 citation statements)

References 30 publications

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“…In 10 populations, a positive association was found (10,13,32,42,80,116,119,124,156), whereas in two populations, a positive association was found only in women (128) or young subjects (132). In 13 populations, no association was present (2,3,38,70,74,79,84,88,100,116,119,124,151). In three studies (116,119,124), both positive and negative associations are observed in different populations.…”

Section: Studies In Humansmentioning

confidence: 89%

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Bianchi

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Bianchi, Giuseppe. Genetic variations of tubular sodium reabsorption leading to "primary" hypertension: from gene polymorphism to clinical symptoms. Am J Physiol Regul Integr Comp Physiol 289: R1536-R1549, 2005. doi:10.1152/ajpregu.00441.2005.-The definition of the most appropriate strategy to demonstrate causation of a given geneticmolecular 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.genes; blood pressure; Na-K pump; Na channel; adducin The difficulty lies, not only in the new ideas, but in escaping the old ones. J. M. Keynes STARLING'S LONG-LASTING concern was to use physiology as a means to bring basic science to the bedside. Indeed, by integrating the capillary fluid exchange with the cardiac pump function, Starling provided a substantial contribution to bridge the gap between the contemporary basic science of circulation and the clinical sympto...

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Section: Studies In Humansmentioning

confidence: 89%

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Bianchi

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The G3 T substitution in exon 10 was genotyped as described previously. 18 Genotyping of a C3 G polymorphism in exon 13 was determined by PCR amplification 19 (forward primer: 5Ј-AAC CCC TTC ACC ACA CTC AC-3Ј and reverse primer: 5Ј-CCA CAA AGA AGC TCC CAG AG-3Ј) followed by digestion with the restriction enzyme BanII.…”

Section: Genotypingmentioning

confidence: 99%

Genome Scan for Blood Pressure in Dutch Dyslipidemic Families Reveals Linkage to a Locus on Chromosome 4p

et al. 2001

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Abstract-Genes contributing to common forms of hypertension are largely unknown. A number of studies in humans and in animal models have revealed associations between insulin resistance, dyslipidemia, and elevated hypertension. To identify genes contributing to blood pressure (BP) variation associated with insulin-resistant dyslipidemia, we conducted a genome-wide scan for BP in a set of 18 Dutch families exhibiting the common lipid disorder familial combined hyperlipidemia. Our results reveal a locus on chromosome 4 that exhibits a significant lod score of 3.9 with systolic BP. In addition, this locus also appears to influence plasma free fatty acid levels (lodϭ2.4). After adjustment for age and gender, the lod score for systolic BP increased to 4.6, whereas the lod score for free fatty acid levels did not change. The chromosome 4 locus contains an attractive candidate gene, ␣-adducin, which has been associated with altered BP in animal studies and in some human populations. However, we found no evidence for an association between 2 intragenic ␣-adducin polymorphisms and systolic BP in this sample. We also observed suggestive evidence for linkage (lodϭ1.8) of diastolic BP to the lipoprotein lipase gene locus on chromosome 8p, supporting a finding previously observed in a separate insulin-resistant population. In addition, we also obtained suggestive evidence for linkage of systolic BP (lodϭ2.4) and plasma apolipoprotein B levels (lodϭ2.0) to a locus on proximal chromosome 19p. In conclusion, our genome scan results support the existence of multiple genetic factors that can influence both BP and plasma lipid parameters. Key Words: genetics Ⅲ hypertension, essential Ⅲ dyslipidemia Ⅲ genome scan Ⅲ linkage analysis S ignificant progress has been made in elucidating the genetic basis for certain mendelian forms of hypertension, but the genetic factors contributing to essential hypertension are largely unknown. 1,2 A number of candidate gene studies and genome scans have been conducted but with varying results. [3][4][5][6] The variation in these latter linkage results could be due the different racial make-up of the study populations and/or the underlying genetic heterogeneity of essential hypertension, which can clearly confound genefinding efforts.One strategy to reduce genetic heterogeneity is to stratify the study population by hypertension that is associated with other pathophysiologic processes, such as insulin-resistant dyslipidemia. A number of studies, those of Williams and colleagues 7 in particular, have revealed associations between hyperlipidemia, insulin resistance, and elevated blood pressure (BP). These studies led to the definition of a condition similar to the metabolic syndrome termed familial dyslipidemic hypertension (FDH), involving a clustering of traits, including central obesity, lipid abnormalities, hypertension, and elevated fasting insulin levels. Several studies have demonstrated a high degree of heritability of this trait, which occurs in Ϸ1% of the general population but in Ϸ12% of pat...

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“…7 Also, a-adducin genotypes are associated with BP levels or the prevalence of hypertension in some but not all populations (Caucasian, African-American, Japanese). [8][9][10][11][12] Blood pressure response to diuretics has been reported to be more pronounced in participants with the Trp allele compared to those homozygous for the Gly allele. 5,7 To determine whether the a-adducin Gly460Trp polymorphism interacts with type of antihypertensive drug to modify risk of coronary heart disease (CHD) and other cardiovascular disease (CVD) outcomes, the Genetics of Hypertension-Associated Treatment (GenHAT) study examined genotype-treatment interaction in participants from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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The Gly460Trp variant of α-adducin is not associated with hypertension in white anglo-Australians

Cited by 28 publications

References 30 publications

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Genome Scan for Blood Pressure in Dutch Dyslipidemic Families Reveals Linkage to a Locus on Chromosome 4p

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

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