Alpha-adducin Gene Research Articles

Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis.

Polymorphisms in candidate genes related to lipid metabolism, thrombosis, hemostasis, cell-matrix adhesion, and inflammation have been suggested clinically useful in risk assessment of cardiovascular disease. We evaluated a panel of 92 candidate gene polymorphisms, using a multiplex polymerase chain reaction-immobilized probe assay amongst 523 individuals who subsequently developed myocardial infarction (MI), and amongst 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. Of the 92 polymorphisms tested, three that we previously reported on were associated with risk of MI, [pro12ala in the peroxisome proliferator activated-receptor gamma gene (odds ratio, OR = 0.75, P = 0.02); thr164ile in the beta-2 adrenergic receptor gene (OR = 0.14, P = 0.007); and ala23thr polymorphism in the eotaxin gene (OR = 1.87, P = 0.01)]. However, when adjusted for the other 89 polymorphisms evaluated, these findings were no longer statistically significant. Further, in contrast to reports from other investigators, we found little evidence for association of a C677T polymorphism in the 5,10-methylenetetrahydrofolate reductase gene, the angiotensin-I-converting enzyme 1 insertion/deletion polymorphism, a 4G/5G polymorphism in the serine/cysteine proteinase inhibitor-clade E-member 1 gene, the factor V Leiden mutation, the G20210A factor II mutation, a -455G>A polymorphism in the beta-fibrinogen gene, the cys112arg/arg158cys apolipoprotein E gene polymorphism, a gly460trp polymorphism in the alpha-adducin gene, and a -629C>A polymorphism in the cholesteryl ester transfer protein gene with risk of MI. After correction for multiple comparisons, the addition of genetic information observed in the present study had little impact on risk prediction models for MI. The present investigation highlights the importance of replication and validation of findings from genetic association studies.

An alpha-adducin gene polymorphism predicts six-year change in systolic blood pressure: The Gennet family blood pressure program

An alpha-adducin gene polymorphism predicts six-year change in systolic blood pressure: The Gennet family blood pressure program

Role of the adducin family genes in human essential hypertension

In both humans and rats, polymorphisms of the alpha adducin (ADD1) gene are involved in renal sodium handling, essential hypertension and some of its organ complications. Adducin functions within cells as a heterodimer composed of various combinations of three subunits that are coded by three genes (ADD1, 2, 3) each located on a different chromosome. These characteristics provide the biochemical basis for investigating epistatic interactions among these loci. We examined the three adducin gene polymorphisms and their association with ambulatory blood pressure (ABPM) and with plasma levels of renin activity (PRA), endogenous ouabain (EO), in 512 newly discovered and never-treated hypertensive patients. Relative to carriers of the wild type (Gly/Gly) ADD1 gene, patients carrying the mutated Trp ADD1 allele had higher blood pressure (systolic blood pressure (SBP) 143.2 +/- 1.0 versus 140.6 +/- 0.6 mmHg P = 0.027 and diastolic blood pressure (DBP) 94.2 +/- 0.77 versus 92.3 +/- 0.5 mmHg, P = 0.03), lower PRA and EO, consistent with the hypothesis of the renal sodium retaining effect of the Trp allele. Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables. However, the differences in SBP and DBP between the two ADD1 genotypes were greatest in carriers of the ADD3 G allele (around + 8 mmHg). The significance of the interaction between ADD1 and ADD3 ranged between P = 0.020 to P = 0.006 according to the genetic model applied. The interaction of ADD1 and ADD3 gene variants in humans is statistically associated with variation in blood pressure, suggesting the presence of epistatic effects among these loci.

Role of alpha-adducin DNA polymorphisms in the genetic predisposition to diabetic nephropathy.

There is substantial evidence for genetic susceptibility to diabetic nephropathy. In particular, genes that predispose to hypertension in the general population may confer susceptibility to nephropathy in patients with diabetes. A Gly460Trp variant in the alpha-adducin gene has been associated with essential hypertension. Our aim was to screen the alpha-adducin gene for polymorphisms and to determine if any variants predisposed patients with diabetes to nephropathy. A secondary objective was to assess for association between the Gly460Trp variant and hypertension. The exons of the alpha-adducin gene were resequenced in 30 individuals. Selected variants were then genotyped in 155 patients with type 1 diabetes and nephropathy (cases) and 216 persons with type 1 diabetes but no evidence of nephropathy (controls) from Northern Ireland and in 95 cases and 118 controls from the Irish Republic. Eleven polymorphisms were detected, of which six were novel and three caused amino-acid substitutions. The Gly460Trp and a novel Ser617Cys polymorphism were in strong linkage disequilibrium (D' = 0.98). Neither the genotype nor allele frequencies for the Gly460Trp polymorphism (P = 0.89 and 0.93 respectively) or the Ser617Cys polymorphism (P = 0.46 and 0.76) were significantly different between cases and controls when the Northern Ireland and Irish Republic sample groups were combined. Carriage of the 460Trp allele was not significantly associated with systolic or diastolic blood pressure in either the cases (P = 0.48 and 0.06, respectively) or in the controls (P = 0.50 and 0.94, respectively). Variation in the alpha-adducin gene does not play a major role in the development of nephropathy in persons with type 1 diabetes in the Irish population. Furthermore, the Gly460Trp variant was not associated with hypertension in this population.

Low red blood cell potassium is related to higher blood pressure, diabetes mellitus and to the gly allele of the alpha-adducin gene

P-385 Key Words: RBC Potassium, Hypertension, Alfa-Adducin Gene

Alpha-adducin gene G/W460 polymorphism is associated with intracerebral hemorrhage in Chinese

To explore the association between alpha-adducin (ADD1) G/W460 and intracerebral hemorrhage (ICH) in Chinese. Samples of peripheral blood were collected from 456 patients with ICH diagnosed by CT or MRI from 7 clinical centers in China and 454 age, sex, and geographically matched subjects as controls. The ADD1 G/W460 polymorphism was detected by PCR. Information about prior exposure to various potential risk factors was collected by questionnaire survey. The distribution of ADD1gene G460W polymorphisms in the ICH patients and controls were in agreement with the Hardy-Weinberg proportion. The prevalence of 460W allele among ICH cases was 82.2%, higher than that in the controls (76.0%, crude odds ratio, 1.46; 95% CI, 1.05 to 2.05). The ADD1 460W allele was still significantly associated with ICH after adjustment for hypertension and other ICH putative risk factors (adjusted odds ratio, 1.38; 95% CI, 1.01 to 1.88). Alpha-adducin gene G/W 460 polymorphism is significantly associated with the risk of ICH. This association does not appear to be mediated by established ICH risk factors, specifically hypertension status.

Drug-gene interactions between genetic polymorphisms and antihypertensive therapy.

Genetic factors may influence the response to antihypertensive medication. A number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy. In most candidate gene studies, no such drug-gene interactions were found. However, there is observational evidence that hypertensive patients with the 460 W allele of the alpha-adducin gene have a lower risk of myocardial infarction and stroke when treated with diuretics compared with other antihypertensive therapies. With regard to blood pressure response, interactions were found between genetic polymorphisms for endothelial nitric oxide synthase and diuretics, the alpha-adducin gene and diuretics, the alpha-subunit of G protein and beta-adrenoceptor antagonists, and the ACE gene and angiotensin II type 1 (AT(1)) receptor antagonists. Other studies found an interaction between ACE inhibitors and the ACE insertion/deletion (I/D) polymorphism, which resulted in differences in AT(1) receptor mRNA expression, left ventricular hypertrophy and arterial stiffness between different genetic variants. Also, drug-gene interactions between calcium channel antagonists and ACE I/D polymorphism regarding arterial stiffness have been reported. Unfortunately, the quality of these studies is quite variable. Given the methodological problems, the results from the candidate gene studies are still inconclusive and further research is necessary.

Alpha-Adducin Gly460Trp Polymorphism and Essential Hypertension in Korea

Previous studies have suggested that the Gly460Trp polymorphism of the alpha-adducin gene (ADD-1) is associated with salt sensitivity and primary hypertension. The results of linkage or association studies of ADD-1 of different populations are controversial. This study investigated the relationship between the Gly460Trp polymorphism of ADD-1 and essential hypertension in a Korean population. The subjects (n=903) were participants in a population-based study in Jangseong County, Korea. The Gly460Trp polymorphism of ADD-1 was determined using a polymerase chain reaction method. The frequency of the 460Trp allele was 59.4% in normotensives and 61.1% in hypertensives (p=0.523). The frequencies of the genotypes did not differ significantly between the hypertensive and normotensive groups (16.3% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in normotensives; 16.2% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in hypertensives; p=0.928). After adjusting for other risk factors, Gly/Trp and Trp/Trp were not associated with hypertension (OR 1.00, 95% CI 0.65-1.53, Gly/Trp vs. Gly/Gly; OR 1.22, 95% CI 0.79-1.90, Trp/Trp vs. Gly/Gly). These findings suggest that the Gly460Trp polymorphism of ADD-1 is not associated with hypertension.

Genetic factors associated with volume-sensitive hypertension

Defining the genetic basis of essential hypertension is most informative when the blood pressure regulation is correlated with physiologic mechanisms, e.g., responses of the renin–angiotensin aldosterone system (RAAS) in hypertensive subjects. The aldosterone response to angiotensin II (Ang II) on a low salt diet is influenced by gender, plasma renin activity, and most significantly, familial resemblance, but only in males and in post-menopausal females. There is familial aggregation of low-renin hypertension, no association with candidate genes of the RAAS, but, a highly significant association with polymorphisms in the alpha-adducin gene. Finally, angiotensinogen (AGT) genotype effects renal and adrenal responses to Ang II in patients with hypertension. These results strongly suggest that in contrast to population-based studies that use hypertension as the phenotype, classifying patients by the variability in physiologic, mechanistic traits enhances the probability of identifying the genetic factors influencing a rise in blood pressure.

Alpha-adducin gene polymorphism is associated with essential hypertension in Chinese: a case-control and family-based study.

A polymorphism at position 460(G <-- W) of the alpha-adducin gene was found to be associated with essential hypertension in some but not all studies. The aim of the present study was to further investigate the association of the alpha-adducin 460W allele with essential hypertension in Chinese population. Individuals from a population-based sample (n = 748) and 95 nuclear families and 47 discordant sibships were studied by questionnaire as well as by physical examination and biochemical analyses. The alpha-adducin gene G460W polymorphism was determined by polymerase chain reaction and restriction enzyme digestion. Chi-square test, one-way analysis of variance, logistic regression, linear regression, haplotype-based haplotype relative risk and transmission/disequilibrium test analyses were used to determine the association between the alpha-adducin G460W polymorphism and essential hypertension. In the case-control study, the prevalence of hypertension was higher in individuals with the WW genotype (40.0%) as compared with those with the GW and GG genotype (31.7%) (chi2 = 4.768, P = 0.029, odds ratio = 1.43). Adjusted for the conventional risk factors of hypertension, alpha-adducin polymorphism still plays an independent role on systolic blood pressure. We confirmed the results of our case-control study by observing a significant preferential transmission of the 460W allele of the alpha-adducin to the affected subjects in another northern Chinese population (for haplotype-based haplotype relative risk, chi2 = 6.24, P = 0.01; and for the transmission/disequilibrium test, chi2 = 4.69, P = 0.03). The present findings show a positive association between the alpha-adducin G460W polymorphism and essential hypertension in a northern Chinese population. This evidence indicates that the alpha-adducin gene may be a susceptible gene to essential hypertension.

Salt, endogenous ouabain and blood pressure interactions in the general population.

Experimental data show that ouabain is a modulator of the sodium-potassium pump, which plays an important role in sodium homeostasis and blood pressure regulation. We investigated the distribution of plasma ouabain in the general population in relation to blood pressure and other determinants of sodium homeostasis. In 379 subjects enrolled in a Belgian population study, we measured plasma ouabain, clinical characteristics including blood pressure, serum and urinary electrolytes, urinary aldosterone excretion, various lifestyle factors, and the Gly460Trp polymorphism of the alpha-adducin gene. Our statistical methods included analysis of covariance and multiple linear regression. Plasma ouabain (median, 140 pmol/l) correlated independently and positively with male gender (n = 182, P = 0.002), smoking (n = 116, P = 0.05), urinary potassium excretion (mean 69 mmol/day, P < 0.0001), and mutation of the alpha-adducin gene (n = 161, P < 0.0001). Both before and after adjustment for covariables, continuous as well as categorical analyses revealed a significant interaction (P < or = 0.02) between plasma ouabain and urinary sodium excretion (mean 194 mmol/day) in relation to blood pressure (mean systolic blood pressure/diastolic blood pressure, 123/76 mmHg). In individuals with plasma ouabain values below the median, blood pressure increased by 2.2 mmHg systolic and 1.4 mmHg diastolic for each 50 mmol/day increment in urinary sodium excretion (P < or = 0.01). No association between blood pressure and urinary sodium excretion was found when plasma ouabain exceeded the median. Plasma ouabain behaves as a blood pressure modulating factor, possibly released in response to potassium, either inhibiting the pressor effect of an excessive salt intake or counteracting the depressor action of sodium depletion.

Salt sensitivity of Japanese from the viewpoint of gene polymorphism.

Excess salt intake is an important environmental risk for the predisposition to essential hypertension. Previous physiological studies have shown that salt sensitivity is associated with insulin resistance, enhancement of sympathetic nerve activity and decrease of blood pressure decline at night. We have been examining the genetic importance of candidate gene polymorphisms of salt-sensitive hypertension using several populations. The angiotensinogen gene (AGT) is a thrifty gene which increases the risk for common disease with growth of civilization via sodium and body fluid retention. The CC genotype of the AGT/T+31C polymorphism, which is in complete linkage disequilibrium with the TT genotype of the M235T polymorphism, was associated with a decrease of blood pressure decline at night in the Ohasama Study. On the other hand, the Gly460Trp genotype of the alpha-adducin gene (ADD1) is associated with erythrocyte sodium transport and increases tubular sodium reabsorption and risk for hypertension. We also revealed in the Ohasama Study that the Trp460 allele of ADD1 is associated with hypertension in young subjects with low renin activity. In addition to these polymorphisms, the T(-344)C polymorphism in the promoter of the aldosterone synthase gene (CYP11B2) and the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) are considered candidates for the genetic risk of salt-sensitive hypertension. We compared the allele frequency of five candidate genes between Japanese and Caucasians; the results showed that the frequencies of all alleles were significantly higher in Japanese than in Caucasians. This interesting finding might suggest a feasible explanation for the huge interracial differences in the frequency of salt-sensitive hypertension.

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

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

Role of the α-adducin genotype on renal disease progression

A genetic susceptibility to hypertension may predispose to the development of end-stage renal disease (ESRD) and promote a more rapid loss of renal function in patients with renal diseases. The alpha-adducin (ADD) gene, alone or in combination with the angiotensinogen (AGT) and the angiotensin-converting enzyme (ACE), is a candidate for abnormal blood pressure regulation and thus for increased susceptibility or faster progression to ESRD. Genotyping for the G460W-ADD, M235T-AGT and the insertion/deletion (I/D)-ACE gene polymorphisms was performed in 260 control subjects and 260 ESRD patients using polymerase chain reaction, gel analysis and appropriate restriction digest. The frequencies of the ADD, AGT and ACE genotypes in ESRD patients did not differ from observed frequencies in control subjects. The average (+/-SE) time from diagnosis to the onset of ESRD tended to be shorter in the presence of the ADD-460WW (5.1 +/- 1.1 years, N = 10) than with the GW (9.9 +/- 0.7 years, N = 81) and GG (11.3 +/- 1.0 years, N = 164) genotypes (F-ratio=2.71, P = 0.068; WW vs. GW P < 0.06 and vs. GG <0.03). In the 167 patients homozygous for the ADD-G allele, a more rapid progression with the ACE-DD genotype as compared to ACE-DI and II was found (P < 0.02). The ADD genotype is predictive of the course of renal function loss in an unselected renal population and influences the effect of the ACE genotype to modulate the rate of progression to ESRD. Thus, the ADD genotype may play a role for the understanding of interindividual differences in the course of renal diseases.

Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism.

Defining the genetic basis of common forms of human essential hypertension is most informative when correlated with physiological mechanisms that underlie blood pressure regulation. A polymorphism of the alpha-adducin gene as been associated with elevated blood pressure in the rat, but previous studies of the 460Trp polymorphism of the human alpha-adducin gene have not clearly identified an association with hypertension. In this study, the frequency of the 460Trp allele was 19% and 9 of 279 subjects (3.2%) were homozygous for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium was significantly greater in subjects homozygous for the 460Trp allele (25 +/- 4 mm Hg) compared with subjects heterozygous for 460Trp (12 +/- 2 mm Hg) or homozygous for the 460Gly allele (14 +/- 1 mm Hg). Intracellular erythrocyte sodium content, sodium-lithium countertransport, and renal fractional excretion of sodium were significantly decreased in subjects homozygous for the 460Trp polymorphism (P<0.05). There was a significant association between homozygosity for the 460Trp allele and low-renin hypertension. Subjects heterozygous for the 460Trp allele did not have increased salt-sensitivity or an increased frequency of low-renin hypertension. Therefore, this study demonstrates a common genetic basis for altered cellular sodium homeostasis, impaired renal sodium handling, and salt-sensitivity of systolic blood pressure in individuals homozygous for the 460Trp polymorphism of the alpha-adducin gene. Homozygosity for this alpha-adducin allele may be an important determinant for approximately 10% of individuals with low-renin hypertension.

Lack of Association between Gly460Trp Polymorphism of Alpha-Adducin Gene and Salt Sensitivity of Blood Pressure in Polish Hypertensives

Background: Previous studies have suggested that α-adducin (α-ADD) polymorphism may identify patients with a salt-sensitive form of hypertension. Aim: To investigate the association between Gly460Trp polymorphism of α-ADD and the pattern of blood pressure response to subacute (1 week) salt loading and depletion in young adult thin Polish hypertensives. Methods: The study group consisted of 44 subjects with salt-sensitive hypertension (SS) and 24 subjects with non-salt-sensitive hypertension (SR). Genomic DNA isolated from peripheral blood leukocytes was amplified by PCR method with primers flanking the polymorphic region. The mismatch near to 3′-end of the upstream primer was introduced to create a Nla III restriction site in Trp 460 allele. In addition, excreted fraction of filtered sodium (FENa), plasma renin activity (PRA) and plasma concentrations of aldosterone (ALDO) were determined on normal, low and high salt diets. Results: FENa on normal or high salt diets were significantly lower in the SS hypertensives as compared with the SR patients. PRA in SS group was also significantly lower as compared with results in SR group, but only on high salt diet. No significant difference was detected in frequencies of genotypes and alleles of α-ADD gene between SS and SR subjects. An additional analysis with regard to genotype (Gly/Gly vs. Gly/Trp+Trp/Trp) showed no significant difference in changes of blood pressure as well as in results of laboratory investigations. Conclusion: Our results suggest lack of association between Gly460Trp polymorphism of α-adducin gene and salt sensitivity of blood pressure in Polish hypertensives.

Genetic mapping of blood pressure quantitative trait loci in Milan hypertensive rats.

In a previous study, by using a candidate gene approach, we detected in both Milan hypertensive rats and humans a polymorphism in the alpha-adducin gene (ADD1) that was associated with blood pressure and renal sodium handling. In the present study, a genomewide search with 264 informative markers was undertaken in 251 (Milan hypertensive strain x Milan normotensive strain) F2 rats to further investigate the contribution of the adducin gene family (Add1, Add2, and Add3) and to identify novel quantitative trait loci (QTLs) that affect blood pressure. The influence of 2 different methods of blood pressure measurement, the intracarotid catheter and the tail-cuff method, was also evaluated. We found evidence that QTLs affected systolic blood pressure (SBP) measured at the carotid (direct SBP) on rat chromosome 1 with a logarithm of the odds (LOD) score peak of 3.3 on D1Rat121 and on rat chromosome 14 on Add1 locus (LOD=3.2). A QTL for SBP measured at the tail (indirect SBP) was found on rat chromosome 10 around D10Rat33 (LOD=5.0). All of these QTLs identified chromosomal regions not detected in other rat studies and harbor genes (Na(+)/H(+) exchanger A3; alpha-adducin; alpha(1B)-adrenergic receptor) that may be involved in blood pressure regulation. Therefore, these findings may be relevant to human hypertension, also in consideration of the biochemical and pathophysiological similarities between MHS and a subgroup of patients of primary hypertension, which led to the identification of alpha-adducin as a candidate gene in both species.

Homozygosity for an Alpha-Adducin Polymorphism (460TRP) Is Associated with Salt-Sensitivity and Low-Renin Hypertension in Humans

P133 Single nucleotide polymorphisms of the adducin genes have been associated with the development of elevated blood pressure in the rat. However, previous studies of the 460Trp polymorphism of human alpha-adducin have not clearly identified an association with the development of human hypertension. In this study, 281 hypertensive subjects were subgrouped by the intermediate phenotypes of plasma renin status and sensitivity of systolic blood pressure to dietary sodium. The frequency of the 460Trp allele was 19% and 9 of 281 subjects (3.2%) were homozygous (TT) for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium (&gt;150 meq/d vs. ≤30 meq/d) was significantly (p &lt; 0.05) greater in TT subjects (25 ± 2 mmHg) compared to those heterozygous (GT) for the 460Trp allele (12 ± 2 mmHg) or homozygous (GG) for the 460Gly allele (14 ± 1 mmHg). There was a significant (p &lt; 0.005) association between homozygosity for the 460Trp allele and low-renin hypertension. Six of 67 (9%) low-renin subjects, but only 3 of 214 (1.4%) normal- renin subjects had the TT genotype. Heterozygous (GT) subjects did not have increased salt-sensitivity of systolic blood pressure and did not have an increased frequency of low-renin hypertension. Erythrocyte sodium content was significantly (p &lt; 0.01) less in subjects with the TT genotype (24.5 ± 1.0 mmol/kgHgb) compared to all subjects (33.2 ± 0.4 mmol/kgHgb). Subjects with the TT genotype had a significantly (p &lt; 0.05) lower sodium-lithium countertransport (SLC) (0.16 ± 0.04 mmol/l/h) than other subjects (0.28 ± 0.01 mmol/l/h). However, the mean SLC of all low-renin hypertensive subjects (0.25 ± 0.02 mmol/l/h) was not significantly different than the mean SLC of normal-renin hypertensive subjects (0.26 ± 0.01 mmol/l/h). Thus, a decreased SLC is associated with the TT genotype and is not a characteristic of all individuals with low-renin hypertension. These findings suggest that homozygous expression of the 460Trp polymorphism of the alpha-adducin gene alters sodium handling in humans and may be an important contributor to the development of low-renin hypertension in some individuals.

The 460Trp polymorphism of the human alpha-adducin gene is not associated with isolated systolic hypertension in elderly Australian Caucasians.

The study was undertaken to determine whether polymorphic variants of the alpha-adducin gene are associated with isolated systolic hypertension (ISH) in elderly Australian Caucasians. Participants were classified with ISH (n = 87, systolic blood pressure (SBP) > or =160 mm Hg and diastolic blood pressure (DBP) < or =90 mm Hg) or normotension (n = 124, SBP <140 mm Hg and DBP <90 mm Hg with no family history of hypertension). To collect demographic data, a structured questionnaire was used. DNA was extracted using standard techniques from 211 subjects (age range 61-89, mean age 73 +/- 6.6 years, male: female ratio 1.1:1). Genotypes (gly/gly, trp/gly and trp/trp) were assigned in triplicate by polymerase chain reaction (PCR) followed by electrophoresis, using a laser scanning electrophoresis unit. The validity of the method was confirmed by sequencing. Frequencies of allele distribution in ISH or control groups were determined by Chi-square tests and a stepwise logistic regression model, which controlled for potential confounders, was used to examine any independent association between alpha-adducin genotypes or alleles with ISH and normotensive controls. Mean BP (+/- s.d.) was: 170/79.8 +/- 14.9/8.3 mm Hg and 122.1/ 73.4 +/- 8. 8/7.6 mm Hg in the ISH and normotension groups respectively. The unadjusted allele and genotypes frequencies were not significantly different in the ISH patients groups compared with normotensive controls (chi2 = 1.59, P = 0.45 and chi2 = 1.23, P = 0.28 respectively). In this elderly cohort, after adjustment for potential confounders, no statistically significant association was found between alpha-adducin genotype and SBP (P = 0.65 for homozygotes, P = 0.59, for heterozygotes), DBP (P = 0.49 homozygotes, for heterozygotes P = 0.45) pulse pressure (P = 0.87 homozygotes, for heterozygotes P = 0.95) diagnosis of ISH (P = 0.72 for homozygotes, P = 0.68 for heterozygotes). However age and renal disease predicted the diagnosis of ISH (P = 0.001, P = 0.459, respectively), a large pulse pressure (P < 0.0001, P = 0.033, respectively) and a higher SBP (P < 0.0001, P = 0.025, respectively) in this large cohort of elderly Australian Caucasian volunteers. Journal of Human Hypertension (2000) 14, 199-203.

Linkage but lack of association for blood pressure and the alpha-adducin locus in normotensive twins.

alpha-adducin is a cytoskeletal protein involved with sodium-pump activity in the renal tubule. The alpha-adducin gene locus has been linked to hypertension and a polymorphism identified which is associated with hypertension; however, the role of the alpha-adducin gene locus in normal blood pressure regulation is not defined. We performed a combined linkage and association study in normotensive monozygotic (MZ) and dizygotic (DZ) twins and their parents to address this issue. We studied 126 MZ and 70 DZ twin pairs and parents of DZ twins. Blood pressure values and responses to a cold pressor test were obtained. Cardiac dimensions were measured echocardiographically. Three microsatellites adjacent to the alpha-adducin gene were studied as well as the 460 Trp mutation in the alpha-adducin gene. We obtained strong evidence for linkage (P< 0.001) between the alpha-adducin gene locus and systolic blood pressure. However, we were not able to associate the 460 Trp mutation with higher blood pressures, cold pressor responses or cardiac dimensions. The alpha-adducin gene locus is relevant to blood pressure regulation in normal subjects. Failure to find an association between higher blood pressures and the 460 Trp mutation suggests that this mutation may become important only when hypertension is triggered, or that other variations in alpha-adducin are present which have not yet been discovered.