System Gene Polymorphisms Research Articles

Evaluation of the Association of Urokinase Plasminogen Activator System Gene Polymorphisms with Susceptibility and Pathological Development of Hepatocellular Carcinoma

The urokinase plasminogen activator (uPA) system is a serine proteinase system involved in extracellular matrix (ECM) degradation. The levels of uPA system components in tumor tissues are implicated as prognostic biomarkers in a wide range of malignancies. Although the contributions of uPA system components to the formation of many types of cancer are well known, their possible association with the prediction of risk and prognosis of hepatocellular carcinoma (HCC) remains poorly investigated. A total of 102 HCC patients and 344 controls were recruited. Genetic polymorphisms of uPA system genes, including uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1, were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis. When individuals were classified into male and female subgroups to estimate adjusted odds ratios (AORs) with their 95% confidence intervals (CIs) of each uPA system gene, the HCC risks of males and females with PAI-1 5G/5G genotype were 6.06-fold (95% CI = 1.39-26.36) and 0.04-fold (95% CI = 0.003-0.69), respectively, as compared with those with PAI-1 4G/4G genotype. High risk for hepatitis B surface antigen (HBsAg)-positive clinical status and significantly higher serum aspartate aminotransferase (AST) concentration were exhibited in HCC patients with PAI-1 4G/5G and 5G/5G genotypes as compared with 4G/4G homozygotes. The results suggest that PAI-1 genotypes could be an important factor contributing to increased susceptibility and pathological development of HCC in Taiwanese population.

Renin-angiotensin system gene polymorphisms in children with Henoch—Schönlein purpura in West China

It has been suggested that renin-angiotensin system (RAS) gene polymorphism is involved in the pathogenesis of Henoch-Schönlein purpura (HSP) with conflicting reports. We therefore investigate the effect of RAS gene polymorphism on HSP susceptibility and severity in a Chinese cohort. The study included 142 children with HSP and 218 healthy controls that were genotyped for RAS gene polymorphisms. Significantly, differences of T174M-T and ACE-D frequency were found between HSP patients and controls (p(alleo) = .002, OR(alleo) = 2.001; p(alleo) = .007, OR(alleo) = 1.533, respectively). We also found correlations between ACE-I/D and Agt T174M with multiple organ involvements, with significant differences in ACE-D in renal groups (p < 0.05) and Agt T174M in non-renal (p(joint) = .002, p(GI) = .042). Furthermore, decreasing M235T-T and increasing ACE-D were found associated with serious renal complications (p = .019, p = .016). Additionally, ACE-I/D and T174M were significantly associated with high clinical score patients, as opposed to low clinical score patients, when patients were scored depending on the severity of overall complications (p = .045, p = .026). We suggest that RAS gene polymorphisms (ACE-I/D, M235T or T174M) are significantly associated with susceptibility to HSP, organ involvement, and disease severity, which largely account for individual prognosis.

Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?

BackgroundGenotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype.MethodsOur analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates.ResultsGenotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations.ConclusionsWe conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.

Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation

AbstractDespite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen–matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P = .005) and overall survival (P = .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P = .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy.

Renin-angiotensin-aldosterone system gene polymorphisms in coronary artery bypass graft surgery patients

Candidates for coronary artery bypass grafting (CABG) represent a group of patients with well documented, severe coronary artery disease (CAD). Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) components have been associated with CAD. We examined the association of polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT(1) receptor) with severe CAD in CABG patients. One hundred and fifty-four CABG patients and 155 non-CAD controls were included in the study. Established PCR methods were used for genotyping of AGT M235T, AGT T174M, AT(1) receptor A1166C, and ACE I/D polymorphisms. Cumulative effect of analysed polymorphisms was assessed by calculation of each individual's RAAS gene score (addition of 0.5 points for each variant allele and then calculating the sum for all four polymorphisms). No association between AGT M235T, AGT T174M, ACE I/D and AT(1) receptor A1166C polymorphisms and CAD was observed. Within CABG patients, the frequency of homozygous AGT 235TT genotype was higher in hypertensive compared to normotensive CABG patients (21.7% vs. 6.3%, p=0.03). RAAS gene score did not differ between CABG patients and non-CAD controls. There is no association of the analysed RAAS polymorphisms with severe CAD in CABG patients. However, within these patients, an association was found between AGT 235TT genotype and hypertension.

Association of angiotensin converting enzyme and angiotensin type 2 receptor gene polymorphisms with renal damage in posterior urethral valves

To examine the association with renal damage in patients with posterior urethral valves (PUV) of two renin-angiotensin system gene polymorphisms: angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin type 2 receptor (AT2R A1332G), PATIENTS AND METHODS: In 120 patients with PUV, after stabilization, transurethral fulguration or a Blocksom vesicostomy was performed. Records were reviewed for age at diagnosis, biochemical renal function at diagnosis, results of urine cultures, voiding cystourethrograms, radiologic, sonographic and nuclear medicine scan findings, and follow-up data. ACE I/D genotypes were determined by the polymerase chain reaction using allele specific primers. The frequency of the ACE DD genotype was significantly higher in patients with chronic kidney disease (P=0.02) and renal scarring (P=0.05). These genotypes were also associated with a statistically higher incidence of vesicoureteral reflux, diurnal incontinence, proteinuria and hypertension. A significantly higher frequency of the AT2R GG genotype was found in PUV patients as compared to healthy unrelated control subjects (P=0.001), and in PUV patients with scarring (P=0.02). The ACE DD and AT2R GG genotypes are associated with chronic kidney disease and scarring in PUV patients. The GG genotype incidence is higher among PUV patients compared to the control population, and further studies in this area may help understanding of the genetic basis of PUV.

Relationship of Insulin-Like Growth Factors System Gene Polymorphisms with the Susceptibility and Pathological Development of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. The insulin-like growth factors (IGFs) system consists of a group of proteins which may induce cell proliferation and inhibit cell apoptosis through several signal pathways, leading to transformation of normal cells into cancer cells. However, the impact of genetic polymorphisms of the IGFs system on HCC has not been clarified. In this case-control study, a total of 102 HCC patients and 306 age- and gender-matched controls were recruited. The genetic polymorphisms of the IGFs system genes, including IGF-1, IGF-2, IGF-1receptor (IGF-1R), IGF-2R, IGF binding protein (IGFBP-3), and insulin (INS) genes, were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and real-time PCR genotyping analysis. A significant difference (p = 0.02) between case and control group in the distribution frequency of IGF-2 +3580 polymorphism was observed. Multiple regression model analysis showed that the presence of AA or AG at IGF-2R may exhibit a potential protective effect against hepatitis C [odds ratio (OR) = 0.35, 95% confidence interval (CI) = 0.15-0.82]. The combination of IGF-2 +3580 AA genotype and IGF-2R GG genotype may present a significantly lower risk of HCC (OR = 0.20, 95% CI = 0.05-0.87). Additionally, no polymorphisms of any IGFs system genes were associated with liver-related clinicopathological markers in serum. Among IGFs system genes, IGF-2 and IGF-2R gene polymorphisms and combination could be considered as the most important factors contributing to increased susceptibility and pathological development of HCC.

Haplotype-based association of the renin-angiotensin-aldosterone system genes polymorphisms with essential hypertension among Han Chinese: the Fangshan study

Widely evaluated regarding the genetic make-up of essential hypertension are the renin-angiotensin-aldosterone system (RAAS) genes polymorphisms, whereas results are often not reproducible. We thus focused on a large Fangshan population to explore association of thirteen polymorphisms in five genes of RAAS. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing techniques. Data were analyzed using MDR and Haplo.stats programs. All studied polymorphisms satisfied Hardy-Weinberg equilibrium in controls. Three polymorphisms (AGT M235T, ACE I/D and AT1R A1166C) displayed significant differences in the genotype and allele distributions between patients and controls (P < 0.05). Interaction analysis suggested a six-locus model that can be decomposed into three sets of polymorphisms (TaqI and M235T, A-20C and A-6G, I/D and A2350G) each with nonadditive effects. Logistic regression analysis indicated that TaqI [Recessive: crude odds ratio (ORcrude) = 1.47, P = 0.030 and adjusted (ORadjusted) = 1.46, P = 0.050] and I/D (Recessive: ORcrude = 1.40, P = 0.002 and ORadjusted = 1.49, P = 0.002) polymorphisms were significantly and positively associated with the risk of essential hypertension. Under additive and recessive modes of inheritance, similar tendency was observed for M235T polymorphism. Two haplotypes (H6 and H9) were found to significantly reduce essential hypertension risk, whereas after correction only H6 remained significant (OR = 0.25, P = 0.0006). In contrast, haplotype H13 was significantly associated with essential hypertension with a 2.14-2.16-fold increased risk (P < 0.01). Haplotype-phenotype analysis showed significant association of inferred haplotypes with SBP (hap-score = 0.44, simulated P = 0.036). Taken together, we demonstrated three two-locus pairs of polymorphisms with synergistic effect out of three genes in RAAS and found significant haplotype-phenotype interaction. Functional studies to confirm or refute these findings are warranted.

Association between Renin-Angiotensin System Gene Polymorphism and Recurrent Wheezing in Chinese Children: A 4-year Follow-up Study

This study aimed to clarify the association between angiotensin-converting enzyme (ACE) gene polymorphisms and infant wheezing, and to determine whether an association may contribute to early prediction of persistent wheezing and asthma. The study cohort comprised 149 patients with asthma, 169 patients with wheezing but no clinical diagnosis of asthma and 165 healthy control subjects. The insertion/deletion (I/D) polymorphism of the ACE gene was determined by polymerase chain reaction. Total serum immunoglobulin E was determined for the wheezy group and a 4-year follow-up study was carried out to observe wheezing relapse. Significant differences were found between patients and controls in allele frequency and genotype distribution. The DD genotype was more frequent in patients in the wheezing and asthma groups than in the control subjects. Patients with the DD genotype had a higher frequency of relapse than patients expressing the ID or II genotypes. It is concluded that the DD genotype of ACE is a risk factor for recurrent wheezing in early childhood.

Analysis of renin-angiotensin aldosterone system gene polymorphisms in malaysian essential hypertensive and type 2 diabetic subjects

BackgroundThe renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects.MethodsRAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM), 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects.ResultsThere was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, MboI of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05). However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p < 0.001).ConclusionAmong the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.

Association study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients

Tardive dyskinesia (TD) is a side effect of chronic antipsychotic medication exposure. Abnormalities in dopaminergic activity in the nigro-striatal system have been most often suggested to be involved because the agents that cause TD share in common potent antagonism of dopamine D(2) receptors (DRD2). Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of the DRD3 gene and the TaqIA site 3' of the DRD2 gene. The DRD4 gene codes for the third member of the D(2)-like dopamine receptor family, and the variable number tandem-repeat polymorphism in exon 3 of DRD4 has been associated with TD. However, other polymorphisms have not been thoroughly examined. In this study, we investigated five polymorphisms spanning the DRD4 gene and their association with TD in our European Caucasian sample (N=171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag polymorphisms were associated with TD in males. This study suggests that DRD4 may be involved in TD in the Caucasian population, although further replication studies are needed.

A propensity score-based case–control study of renin–angiotensin system gene polymorphisms and diastolic heart failure

Angiotensin II plays an important role in diastolic heart failure (DHF). However, genetic studies of DHF are scarce in the literature. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a propensity score-based case–control study to prove this hypothesis. A total of 666 subjects (285 diagnosed with DHF confirmed by echocardiography and 381 without diastolic dysfunction) were recruited. Genotyped were: the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen (AGT) gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT1R) gene. Propensity scores (PS) were used to find patients with and without DHF with equalized characteristics. We also assembled another set of PS matched groups for all characteristics except left ventricular mass (LVM) to detect the genetic association with DHF through the effect of left ventricular hypertrophy. PS matched 210 patients with DHF to 210 without. In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype (OR = 1.30, 95% CI = 1.13–1.49, permuted P = 0.003) and the AT1R 1166 CC genotype (OR = 2.61, 95% CI = 1.52–4.45, permuted P < 0.001). Significant gene–gene interaction between the two genes was also detected. However, the ACE gene effect was diminished if LVM was not controlled in the propensity scores. We concluded that genetic variants in the RAS genes may determine individual risk to develop DHF through different pathways. Concomitant presence of ACE DD and AT1R 1166 CC genotypes synergistically increased the predisposition to DHF.

Renin–Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs: Results From the GENRES Study

Polymorphisms in genes coding for components of the renin-angiotensin system (RAS) and alpha-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study. The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C. The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively). Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.

Hemodynamic Parameters and Heart Rate Variability during a Tilt Test in Relation to Gene Polymorphism of Renin‐Angiotensin and Serotonin System

The aim of the study was to evaluate the renin-angiotensin system and serotonin transporter gene polymorphisms in relation to hemodynamic parameters and heart rate variability during a head-up tilt test (HUT) in patients with vasovagal syncope. DNA was collected from 191 patients (mean age 44+/-18 years, 61 men, 130 women). The following gene polymorphisms were determined in genomic DNA: angiotensin-converting enzyme insertion/deletion polymorphism (I/D ACE), angiotensinogen gene polymorphism (M 235), angiotensin II receptor type 1 (ATR1) polymorphism (A 11666C), and polymorphism of serotonin transporter gene (5HTTLPR).Heart rate variability during HUT was assessed in 5-minute intervals by low frequency, high frequency, standard deviation of the normal-to-normal (SDNN), and root mean square successive difference parameters. AA genotype of A 1166C polymorphism was associated with lower minimal systolic blood pressure (SBP) and diastolic blood pressure (DBP) during HUT compared with other genotypes (minimal SBP: AA 59.6+/-21,8, AC 79.9+/-22.7, CC 65.4+/-22.7 mmHg, P=0.007), (minimal DBP: AA 36.4+/-22.7, AC 52.3+/-22.9, CC 45.4+/-19.5 mmHg, P=0.007).AA genotype was also associated with higher SDNN compared to other genotypes in the early phase of HUT (SDNN in 5 minutes of tilt: AA 59.7+/-24.6, AC 50.6+/-20.6, CC 46.0+/-13.2, P=0.01) and at syncope occurrence (SDNN: AA 71.0+/-20.9, AC 58.2+/-17.9, CC 58+/-10, P=0.04) AA genotype of A 1166C polymorphism in the ATR1 gene may be associated with hypotension and decline in sympathetic tone during HUT. Its role in genetic predisposition to vasovagal syncope cannot be excluded.

Association between renin–angiotensin system gene polymorphism and essential hypertension: a community-based study

Renin-angiotensin (RAS) genes, a group of promising candidate genes involved in essential hypertension (EH), play a key role in blood pressure regulation. Recently, a series of novel RAS gene polymorphisms were reported, which significantly influence the rate of the gene transcription. This study was designed to explore the association between the RAS gene polymorphisms and EH in a remote countryside population. We examined six polymorphisms in the main component genes of RAS: angiotensin-converting enzyme (ACE) (I/D), angiotensinogen (AGT) (A-6G, A-20C, G-217A and T174 M) and angiotensin type 1 receptor (AT1R) (A1166C). Six polymorphisms were genotyped by gene chip technology. Association studies were performed in 220 EH patients and 235 normotensives. Our results revealed that AGT A-6G, T174 M and ACE-I/D were significantly associated with EH (AGT A-6G: AG+GG vs AA; OR=1.36; 95% CI=1.04-1.77. T174M: CT+TT vs CC; OR=1.45; 95% CI=1.15-1.90. ACE I/D: ID+DD vs II; OR=1.171; 95% CI=1.00-1.37). Moreover the logistic regression analysis suggested that the haplotype of AGT -6A, 174C, -217G and -20A might decrease the risk of EH (OR=0.64; 95% CI=0.49-0.83), after adjusting the confounding factors of gender, age and BMI. In conclusion, the AGT A-6G, T174 M and ACE I/D polymorphisms are associated with EH and the AGT haplotype -6A, 174C, -217G and -20A decrease the risk of EH in the southern Chinese population.

Polymorphisms of renin-angiotensin system genes and endothelial dysfunction in young males with a history of myocardial infarction

We studied relationship between renin-angiotensin system (RAS) gene polymorphisms and parameters of endothelial function in males with history of myocardial infarction in young age. We found endothelial dysfunction in these patients. There were no correlations between certain polymorphic genes and risk of myocardial infarction. At the same time, insertion/deletion polymorphism of the angiotensin-converting enzyme gene was associated with more prominent endothelial dysfunction in males with history of myocardial infarction in young age. These data may confirm influence of RAS gene polymorphism on the endothelial dysfunction.

Significance of angiotensinogen gene haplotypes and genotypes combinations in hypertension

Renin-angiotensin system gene polymorphisms are associated with essential hypertension; angiotensinogen gene variants are considered potential genetic risk factors. The aim of this study was to investigate the contribution of the G-6A, T174M, M235T polymorphisms, genotypic interactions, and haplotypes toward essential hypertension. In a case-control design, 810 consecutive ethnically matched unrelated individuals comprising 450 hypertensive patients and 360 controls were recruited. Genotyping by polymerase chain reaction-restriction fragment length polymorphism, genotypes combinations, and haplotypes analyses were performed. Plasma renin activity and plasma aldosterone concentration were measured. The G-6A and M235T polymorphisms differed significantly (P = 0.007, odds ratio = 1.9, 95% confidence interval = 1.2-2.9; P < 0.0001, odds ratio = 3.7, 95% confidence interval = 2.3-5.7, respectively), wherein the -6A and 235T mutant alleles were over-represented in hypertensive patients (P < 0.0001, each). Genotypes combinations of six wild-type alleles versus the remaining resulted in odds ratio of 2.4 (P < 0.0001), further mutant alleles based combinations linearly correlated with systolic, diastolic, and mean blood pressure. Over-representation of the haplotypes, namely, A/174T, 174T/235T, A/235T, and A/174T/235T in hypertensive patients and G/174T, 174T/235M, G/235M, and G/174T/235M in controls, was identified as risk and protective haplotypes (P < 0.0001, each), respectively. The patients had significantly higher plasma aldosterone concentration and lower plasma renin activity (P < 0.0001), the former correlated with -6A and 235T alleles (P < 0.0001). The interaction among G-6A, M235T and T174M polymorphisms in combinations or haplotypes emerged significant. These findings, conjoint with significant high plasma aldosterone concentration and low plasma renin activity, suggest low-renin hypertension in our study population.

Association of immune system gene polymorphisms with quantitative traits pathogenetically important for chronic virus hepatitis

The IL4 C(−590)T, IL4RA Ile50Val, and TNF G(−308)A polymorphisms were tested for association with quantitative traits important for chronic virus hepatitis, including the levels of IL4, IL10, IL12, TNF-α, fibronectin, collagenase, the proteinase inhibitor, macroglobulin, and free and protein-bound (PBO) oxyproline. Allele A of the TNF G(−308)A polymorphism was associated with a lower TNF-α production by mononuclear cells, a higher production of IL4 and IL12, and a lower PBO level. The genotype CT of the IL4 C(−590)T polymorphism was associated with a high PBO level.

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation: A Regression Approach for the Detection of Gene-Gene Interactions in a Large Hospitalized Population

Objectives: To test the association between renin-angiotensin system gene variants and atrial fibrillation (AF) using a regression approach. Methods: A total of 1,236 consecutive patients (227 with AF and 1,009 with normal sinus rhythm as controls) were recruited. Angiotensin-converting enzyme (ACE) gene I/D polymorphism; T174M, M235T, G–6A, A–20C, G–152A and G–217A polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects and to detect gene-gene interactions by incorporating interaction terms in the model. Results: In single-locus analyses, no locus was associated with AF. After adjustment for AF risk factors, we found significant differences in the global AGT gene haplotype profile (the global score statistic = 30.364, p = 0.001) and individual haplotype frequencies between AF patients and controls. Furthermore, significant 2-way gene-gene interactions between ACE I/D polymorphism and AGT gene haplotypes and between AT1R A1166C polymorphism and AGT gene haplotypes, and 3-way interaction between ACE I/D, AT1R A1166C and AGT gene haplotypes were detected. Conclusions: These results are compatible with the concept of multilocus and multigene effects in determining the risk of complex diseases such as AF, which would be missed with conventional single-locus approaches.

Impact of renin-angiotensin-aldosterone system genes on the treatment response of patients with hypertension and metabolic syndrome

To evaluate the influence of clinical, biochemical and genetic markers on the response to antihypertensive treatment in patients with essential hypertension and the metabolic syndrome (MetS). Measurements of anthropometric indices, blood pressure (BP), and metabolic parameters were obtained from the medical records of 132 (77 women) newly diagnosed, untreated hypertensive patients. Renin-angiotensin-aldosterone system (RAAS) genes polymorphisms (including ACE I/D, angiotensinogen M235T, angiotensin II type 1 receptor [AT1-receptor] A1166C) were determined. Response to treatment was defined as BP less than 140/90 mmHg. Patients with MetS (n=60) had higher systolic BP and pulse pressure and a more atherogenic lipid profile than patients without MetS. The frequencies of the ACE and the AT1-receptor gene polymorphisms were similar between patients with and without MetS. Response to treatment was positively associated with pulse pressure, and the presence of the C allele as well as the AC genotype of the AT1-receptor gene and inversely with age after adjustment for confounding factors. RAAS genes distribution does not differ between hypertensive patients with and without the MetS. Higher baseline pulse pressure levels, the presence of the C allele and/or the AC genotype may be in favour of a better response to structured antihypertensive treatment in patients with MetS. However, these findings need to be evaluated in future studies.