Alpha Adducin Research Articles

Evaluation of angiotensin converting enzyme insertion/deletion, alpha adducin (ADD1) G460W, and IL-10 gene polymorphisms, and determination of prognostic effects in idiopathic sudden sensorineural hearing loss

ObjectiveThe aim of this study was to examine angiotensin converting enzyme (ACE) insertion/deletion, alpha adducin, and interleukin-10 (IL-10) gene polymorphisms (GPs) in terms of both idiopathic sudden sensorineural hearing loss (ISSNHL) risk and their potential prognostic effects. MethodsThe study group consisted of 70 patients and the control group consisted of 50 patients. Venous blood samples were analyzed for relevant GPs via kompetitive allele-specific polymerase chain reaction. Age, sex, affected side, tinnitus, and vertiginous symptom status, number of days between symptom onset and hospital admission, pure tone audiometry results at admission and after treatment were included in the study. Data were compared statistically. ResultsThe D allele of ACE insertion/deletion GP was significantly more frequent in patients with ISSNHL than in the control group (p = 0.032). II genotype was associated with a reduced risk of ISSNHL (p = 0.036). The amount of hearing loss was significantly higher in patients with the TT genotype (p = 0.027) and T allele of the IL-10 GP (p = 0.035) than in the patients without this allele. Severe hearing loss was a poor prognostic factor (p = 0.008). ConclusionsThe D allele of ACE insertion/deletion GP may be involved in the ISSNHL etiology. Due to the association of this allele with occlusive vascular pathologies, ischemia is believed to be a common pathway in the etiopathogenesis of ISSNHL.

Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development.

The intensive use of anesthetic and sedative agents in the neonatal intensive care unit (NICU) has raised controversial concerns about the potential neurodevelopmental risks. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative on neonates in the NICU. Mounting evidence suggests a single exposure to MDZ during the neonatal period leads to learning disturbances. However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen on postnatal day 3 (P3) pups until day 21. Next, purified synaptosomes from P21 control and MDZ animals were subjected to quantitative mass-spectrometry-based proteomics, to identify potential proteomic signatures. Further analysis by ClueGO identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, which was upregulated in the MDZ group and whose expression was further validated by Western blot. In summary, this study sheds new information on the long-term exposure of MDZ during the early stages of development impacts synaptic function, which could subsequently perturb neurobehavioral outcomes at later stages of life.

Comparative Modeling of Native and Mutated Structures of Alpha adducin Protein

Comparative Modeling of Native and Mutated Structures of Alpha adducin Protein

Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1β (interleukin 1β) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

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.

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

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

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

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

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.

Epitope presentation is an important determinant of the utility of antigens identified from protein arrays in the development of autoantibody diagnostic assays

Autoantibodies represent an attractive biomarker for diagnostic assays principally due to the stability of immunoglobulin in patient serum facilitating measurement with conventional assays. Immune responses to tumorigenesis may facilitate detection of ovarian cancer in the early stages of the disease with identification of a panel of tumour specific autoantibodies. Despite the reporting of many tumour associated autoantibodies using arrays of tumour antigens, this has not led to the advance in diagnostic capability as rapidly as was initially expected. Here we examine the potential diagnostic utility of candidate autoantibody biomarkers identified via screening of serum samples on a high content human protein array from a unique cohort of early stage and late stage ovarian cancer patients. We analyse the performance of autoantibodies to the tumour suppressor protein p53 and the novel autoantigens alpha adducin and endosulfine alpha identified in our array screen. Each antigen has different performance characteristics using conventional ELISA format and Western blot immunoassay. The high attrition rate of promising autoantigens identified by array screening can in part be explained by the presentation of the epitope of the antigen in the subsequent method of validation and this study provides directions on maximising the potential of candidate biomarkers. This article is part of a Special Issue entitled: Translational Proteomics.

Mutation in the beta adducin subunit causes tissue-specific damage to myogenic tone

Damage to renal artery myogenic tone is universally associated with progressive kidney damage. Recently, we have observed that mutations in the beta adducin subunit are associated with proteinuria in the Milan rat. Because of the role of adducin as a component of the cytoskeleton we hypothesized that this mutation may be associated with changes in myogenic tone. Congenic rats were generated with beta adducin subunit mutation (NB rats) and compared with a previously studied rat model with alpha adducin subunit mutation (NAs rats). Blood pressure and urinary protein excretion were studied at two time points: 6 weeks and 4 months of age, and at these time points, small renal, middle cerebral and skeletal (cremaster) arteries were isolated and studied using pressure myography. Agonist-induced vasoconstriction was not different between the two groups at any age. However, myogenic tone in renal arteries was significantly damaged in the NB rat compared to its NAs counterpart and this was associated with a decrease in vascular distensibility. There was a smaller reduction in myogenic tone in the middle cerebral arteries from the NB rat, whereas in the skeletal arteries there was no difference between the two strains. In the NB rat, this tissue-specific damage to myogenic tone was associated with progressive proteinuria despite lower blood pressure than the NAs rat. Mutations in the beta subunit of the adducin protein result in damage to renal artery myogenic tone and this is associated with renal damage as manifest by proteinuria.

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.

High sodium intake interacts with ADD1 Gly460Trp polymorphism in increasing hypertension odds among Filipino women

Hypertension (HTN) is a multifactorial disease influenced by environmental and genetic factors. We examined the association between high sodium (Na) intake and HTN among 1747 unrelated Filipino women (ages 35‐69 yr) and assessed whether the association is modified by a gene polymorphism (Gly460Trp of alpha adducin (ADD1)) shown to increase Na re‐absorption in the kidney. We used data gathered by the Cebu Longitudinal Health and Nutrition Survey in 2005 and defined high Na intake as: at least 4600 mg/day (200% of recommended upper limit). Mean Na consumption was 2900 mg/day, 15% were categorized as high intake, and 29% were hypertensive. Adjusting for age, BMI, overweight duration and other confounders, logistic regression analyses showed that high Na intake increased HTN odds, especially among women homozygous for the 460Trp allele (19%). Women with lower Na intake carrying one or more copies of the 460Gly allele (reference) had the lowest odds of HTN: odds ratio (OR, 95% CI) for women with high Na intake carrying the 460Gly allele was 1.2 (0.8, 1.6) while that for women with high Na intake and homozygous for 460Trp was 2.9 (1.4, 6.0). The association among Na intake, ADD1 Gly460Trp, and hypertension was further modified by overweight duration. With relatively high frequency of the 460Trp allele compared to Caucasians, efforts to reduce Na intake should be strengthened.1R03TW008133‐01, 1 R01 HL085144‐01, R01 DK078150

Commentary on Viewpoint: Perspective on the future use of genomics in exercise prescription

VIEWPOINTCommentary on Viewpoint: Perspective on the future use of genomics in exercise prescriptionLinda S. PescatelloLinda S. PescatelloPublished Online:01 Apr 2008https://doi.org/10.1152/japplphysiol.01312.2007MoreSectionsPDF (28 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat to the editor: There is considerable intra- and interphenotype variability in the health-related response to exercise (1). This heterogeneity is attributed to genetic and environmental factors that are poorly understood (3). These observations provide the foundation for the promise and challenge of the use of kinesiogenomics in personalized medicine. The promise of this approach is the eventual use of genetic and clinical information to individualize exercise prescription for targeted or at-risk phenotypes. However, work in kinesiogenomics presents significant challenges (6). Reasons include: the biologic complexity of the phenotypes and pathways examined, a focus on individual genetic variants, inadequate statistical power, publication bias, and population stratification (2). Recent work from our laboratory has revealed that Caucasian, middle-aged, overweight men with pre- to stage 1 hypertension who are genetically predisposed to cardiovascular disease lower blood pressure after lower intensity, aerobic exercise (40% of peak oxygen consumption, V̇o2 peak); whereas men less genetically predisposed to cardiovascular disease lower blood pressure after moderate intensity, aerobic exercise (60% V̇o2 peak; Refs. 4, 5).These findings illustrate the limitations of a “one-size fits all” approach to exercise prescription. For a person who has a positive response to one dose of exercise may have a non- or even an adverse response to a different dose exercise for the same targeted or at-risk phenotype. Exercise will continue to be recommended to nearly all people for its numerous health benefits. However, kinesiogenomics will eventually enable exercise science professionals and clinicians to tailor exercise prescriptions for subgroups of people to maximize the effectiveness of exercise as therapeutic option.REFERENCES1 Bouchard C, Rankinen T. Individual differences in response to regular physical activity. Med Sci Sports Exerc 33: S446–S451, 2001.Crossref | PubMed | ISI | Google Scholar2 Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 361: 598–604, 2003.Crossref | ISI | Google Scholar3 Materson BJ. Variability in response to antihypertensive drugs. Am J Med 120: S10–S20, 2007.Crossref | PubMed | ISI | Google Scholar4 Pescatello LS, Blanchard BE, Tsongalis GJ, Maresh CM, Thompson PD. Alpha adducin Gly460Trp polymorphism interacts with exercise intensity to alter the blood pressure response following endurance exercise. Clin Sci (Colch) 113: 251–258, 2007. First published May 2, 2007 doi:10.1042/Clin Sci.0345.2006.Crossref | Google Scholar5 Pescatello LS, Turner D, Rodriguez N, Blanchard BE, Tsongalis GJ, Maresh CM, Duffy V, Thompson PD. Dietary calcium intake and renin angiotensin system polymorphisms alter the blood pressure response to aerobic exercise: a randomized control design. Nutr Metab: January 4, 2007; 10.1186/nutrmetabol.1743-7075-4-1.2007.Google Scholar6 Roth SM. Viewpoint: Perspective on the future use of genomics in exercise prescription. J Appl Physiol; doi:10.1152/japplphysiol.01000.2007.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: L. S. Pescatello, Univ. of Connecticut, Dept. of Kinesiology, Human Performance Laboratory, Neag School of Education, 2095 Hillside Road, U-1110, Storrs, CT 06269-1110 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByDose–Response Matters! – A Perspective on the Exercise Prescription in Exercise–Cognition Research1 November 2019 | Frontiers in Psychology, Vol. 10Commentary: Physical Exercise as Personalized Medicine for Dementia Prevention?31 October 2019 | Frontiers in Physiology, Vol. 10Genetics and sport performance: current challenges and directions to the futureRevista Brasileira de Educação Física e Esporte, Vol. 28, No. 1 More from this issue > Volume 104Issue 4April 2008Pages 1247-1247 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01312.2007PubMed18385302History Published online 1 April 2008 Published in print 1 April 2008 Metrics

Genetic Polymorphisms and Spontaneous Preterm Birth

To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and alpha adducin (ADD1, P=.047). We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and alpha adducin may be contributors to risk of spontaneous preterm birth. II.

Adducin and microalbuminuria: a complex association

Adducin and microalbuminuria: a complex association

RFX-1, a putative alpha Adducin interacting protein in a human kidney library

Adducin regulates tubular absorption of sodium by modulating the expression levels of the sodium–potassium-ATPase in renal tubular cells. Adducin is a candidate gene in the pathogenesis of hypertension. Yeast two hybrid screen showed a specific interaction between human alpha Adducin and the regulatory factor for X box (RFX-1), a nuclear protein that down regulates the expression of several proteins in non neuronal cells. The interaction was confirmed in cells through coimmunoprecipitation and colocalization experiments. The binding of alpha Adducin to RFX-I and their nuclear co-localization suggests that Adducin can have a role in modulating the transcriptional regulating activity of RFX-I.

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.

Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes

Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore gene-only and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.

Pharmacogenetics of loop diuretics

Objective Genetic variability in pharmacokinetics and pharmacodynamics of diuretics is incompletely studied. We compared the extent of variability in different loop diuretics and determined to what extent this is influenced by polymorphisms in candidate genes. Methods Single oral doses of bumetanide 2 mg, furosemide 80 mg and torasemide 10 mg were given in two week intervals to 84 healthy male volunteers. Results Mean data (standard deviation) of volume, Na+ and K+ excretion are given in the Table. Variances were not significantly different between the three loop diuretics (equal variance test p> 0.05). Repeated measures ANOVA revealed interindividual variation amounting to 70, 43 and 53% of total variation for volume, Na+ and K+, respectively. In contrast, the within-subject variation between the 3 study days amounted to only 1, 17 and 10% of total variation despite the use of three different loop diuretics. Polymorphisms in the G-protein subunit 3 (GNB3) and alpha adducin (ADD1) were not correlated with the 24 h excretion of volume, Na+ or K+. Conclusions A high interindividual variation combined with low intraindividual variation may be explained by genetic polymorphisms in several of the transport and signaling proteins implicated in the action of diuretics. Clinical Pharmacology & Therapeutics (2004) 75, P63–P63; doi: 10.1016/j.clpt.2003.11.239 Urine volume (L/24 h) Na+ (mmol/24 h) K+ (mmol/24 h) Bumetanide 3.77 (0.90) 316 (49) 42 (10) Furosemide 3.75 (0.96) 302 (72) 45 (12) Torasemide 3.21 (0.96) 225 (52) 33 (9)