M235T Genotype Research Articles

Angiotensinogen M235T Gene Polymorphism is a Genetic Determinant of Cerebrovascular and Cardiopulmonary Morbidity in Adolescents with Sickle Cell Disease

BackgroundCerebrovascular stroke is a common critical complication of sickle cell disease (SCD). Angiotensinogen (AGT) M235T gene polymorphism is associated with risk of ischemic stroke and cardiovascular disease. AimWe investigated the potential association between angiotensinogen M235T gene polymorphism and susceptibility to cerebrovascular and cardiopulmonary complications in adolescents with SCD. MethodsForty-six patients with SCD in steady state were studied stressing on history of stroke, hydroxyurea/chelation therapy, hematological profile, and echocardiographic findings. Polymerase chain reaction-based restriction fragment length polymorphism analysis was used to detect AGT M235T gene polymorphism. Fifty sex- and age-matched healthy controls were enrolled for assessment of M235T gene polymorphism pattern. ResultsThe distribution of AGT M235T gene polymorphism was similar between SCD patients and healthy controls. The frequency of T allele of AGT M235T gene polymorphism (TT and MT genotypes) was significantly higher among patients with history of manifest stroke (P < .001). Patients with TT and MT genotypes had higher incidence of cardiopulmonary complications (P = .041) as well as higher percentage of HbS (P < .001) and lower hemoglobin level (P = .008) compared with those with MM genotype. Serum ferritin, liver iron concentration, and cardiac T2* were not related to T alleles or genotypes. Logistic regression analysis revealed that M235T genotype was a significant independent factor related to the occurrence of stroke among patients with SCD (Odds Ratio 14.05, 95% confidence interval 3.82-28.91; P = .001). ConclusionAGT M235T gene polymorphism may represent a genetic modifier to vascular morbidities in Egyptian patients with SCD.

27 RELATIONSHIP BETWEEN GENETIC POLYMORPHISM OF ANGIOTENSINOGEN M235T GENE AND ESSENTIAL HYPERTENSION AMONG ETHNICS IN SOUTHEAST SULAWESI

Background: The studies on genetic polymorphism of angiotensinogen M235T gene conducted in several countries showed that the emergence of allele 235T among Asians had increased the risk of hypertension compared to Caucasians. Nevertheless, relations between angiotensinogen gene polymorphism and essential hypertension risk on intra-populations of asian people between ethnics is still less consistent. Objective: This study aimed to examine the relationship in polymorphism of angiotensinogen M235T gene as a risk factor causing essential hypertension among ethnics in Southeast Sulawesi. Method: This research used cross sectional study design. Sixty-one genetic samples (peripheral venous blood from 53 hypertensive and 8 normotensive subjects) were processed through polymerase chain reaction and restriction fragment length polymerase. Results: Tolaki ethnic who had homozygous TT genotype were 27 samples (44.3% of total sample) and homozygous MT genotype were 6 samples (9.8%). Muna ethnic who had homozygous TT genotype were 22 samples (36.1%) and there were no heterozygous MT genotype. Buton ethnic who had homozygous TT genotype were 5 samples (8.2%) dan heterozygous MT genotype was found in 1 sample (1.6%). Overall, the numbers of homozygous TT genotype were 54 samples (88.5%), homozygous MT genotypes were 7 (11.5%) and no subject was homozygous MM genotype. Among the hypertensive group, 46 were TT genotype and 7 were MT genotype. In the normotensive group (all 8 samples), only TT genotype was found (chi-square 1.94, p-value 0.275). Conclusion: This study concluded that there was no relationship between polymorphism of Angiotensinogen M235T gene and essential hypertension among ethnics in Southeast Sulawesi.

The AGT M235T (RS699, 4072T&gt;C) polymorphism is not associated with elite weightlifting performance

It is now well established that genetic background influences an athlete’s ability to excel in different sport disciplines. Previous studies have demonstrated that among power athletes, single nucleotide polymorphism (SNP) in the AGT genotype (Thr-Thr), was significantly more prevalent among weightlifters compared to sprinters and jumpers indicating that despite the common features of these sport subtypes (short and very intense), they vary in their strength and speed abilities, as well as in their genetic make-up. The aim of the present study was to assess whether the AGT SNP can be used also to distinguish elite from national levels weightlifters. The AGT M235T genotype frequencies were assessed in 47 weightlifters (30 elite, 17 national level) and 86 non-athletes control. The Thr-Thr genotype was significantly higher among weightlifters (29.8%) compared to controls (12.8%) (p=0.048). Thr allele frequency was significantly higher among weightlifters (55.3%) compared to controls (37.8%) (p=0.021). However, there was no difference in the prevalence of the polymorphism between national level and elite athletes. In conclusion, the results suggest that the AGT polymorphism cannot predict elite competitive weightlifting performance.

Human AGT -p.Met268Thr and coronary heart disease risk: a case-control study and meta-analysis

Summary Background. Polymorphisms in genes, which is involved in the renin–angiotensin system, play an important role in the pathogenesis of coronary heart disease (CHD). Polymorphism of c.803T>C in the human angiotensinogen gene results in methionine (M) to threonine (T) substitution at codon 268 (p.Met268Thr), which traditionally has been known as M235T. This polymorphism may contribute to cardiovascular diseases. Objectives. The aim of this study was to investigate the association between p.Met268Thr polymorphism in the angiotensinogen gene and coronary heart disease (CHD) through a case-control study, which is followed by a meta-analysis. Material and methods. In the case-control study, c.803T>C genotyping of 217 subjects (102 CHD cases vs 115 controls) was investigated by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In the meta-analysis, 31 studies were included, reflecting 12,028 people with CHD and 16,362 healthy controls. Results. The data from the case-control study revealed that MT (OR, 1.875; 95%CI, 1.060–3.316; p = 0.031) and TT (OR, 3.389; 95%CI, 1.251–9.179; p = 0.016) genotypes are significantly associated with CHD. The meta-analysis revealed a significant association in the recessive model (OR, 1.156; 95%CI, 1.011–1.321; p = 0.034). Conclusions. Although the pooled OR of the meta-analysis showed that there is an increased risk of CHD conferred by p.Met268Thr of the AGT gene, this association was weak, which could be attributed to a bias in publications. © Copyright by Wydawnictwo Continuo.

Angiotensin II receptor type 1 A1166C modifies the association between angiotensinogen M235T and chronic kidney disease.

Single nucleotide polymorphisms (SNPs) in renin-angiotensin system (RAS) genes are associated with RAS imbalance and chronic kidney disease (CKD). We performed a case-control study and meta-analysis to investigate the association between angiotensinogen (AGT) M235T polymorphism and CKD. A total of 634 patients with end-stage renal disease and 739 healthy controls were studied. We also searched PubMed and the Cochrane Library to identify prospective observational studies published before December 2015. We found that the TT and MT genotypes were associated with a higher risk of CKD than the MM genotype (odds ratio [OR]: 3.56; 95% confidence interval [CI]: 1.14–11.16 and OR: 2.93; 95% CI: 0.91–9.46, respectively). Thirty-eight study populations were included in the meta-analysis. The T allele was associated with a higher risk of CKD than the M allele in all populations (OR: 1.19; 95% CI: 1.08–1.32). The OR was 1.33 in Asians (95% CI: 1.06–1.67) and 1.10 in Caucasians (95% CI: 1.02–1.18). Evaluation of gene-gene and gene-environment interactions using epistasis analysis revealed an interaction between AGT M235T and angiotensin II receptor type 1 A1166C in CKD (OR: 0.767; 95% CI: 0.609–0.965). Genetic testing for CKD in high-risk individuals may be an effective strategy for CKD prevention.

Association between ACE and AGT polymorphism and cardiovascular risk in acromegalic patients.

Whether the renin-angiotensin-aldosterone system plays a role or not in the development of cardiovascular morbidity in acromegaly patients is unknown. The aim of the study was to investigate the association between ACE (I/D) and AGT (M235T) gene polymorphisms and cardiovascular and metabolic disorders in the acromegaly. The study included one hundred and seventeen acromegalic patients (62F/55M, age: 50.2 ± 12.3 years) and 106 healthy controls (92F/14M, age: 41.4 ± 11.3 years). PCR method was used to evaluate the prevalence of ACE and AGT genotype. The genotypes of ACE polymorphism in acromegalic patients were distributed as follows; 41.0% (n: 48) for DD, 44.4% (n: 52) for ID and 14.5% (n: 17) for II genotype. The control group had significantly different distribution of the ACE polymorphism [48.1% (n: 51) for DD, 25.5% (n: 27) for ID and 26.4% (n: 28) for II genotype]compared to acromegalic group. Regarding AGT polymorphism, AGT-MT genotype was seen in 88.9% of the acromegalic patients while MM and TT genotype (9.4% and 1.7%, respectively) were present in the rest. The controls had similar distribution of the AGT genotype with the acromegaly group (80.2% MT genotype, 15.1% MM genotype and 4.7% TT genotype). Due to the small number of patients with TT allele (n: 2), T carriers for AGT genotype (AGT-MT+TT) were subgrouped and compared to those with AGT-MM group. ACE-DD, ID and II groups had similar anthropometric measures, blood pressure values and baseline GH and IGF-1 levels. Significantly higher baseline GH levels were found in AGT-MM group compared to T allele carriers [40 (16-60) vs. 12 (5-36)µg/L, p < 0.05]. The compared groups in both polymorphisms had similar fasting plasma glucose levels. Patients with ACE-II genotype had significantly higher HDL-C levels compared to those with ACE-DD and ACE-ID polymorphisms (p < 0.05) whereas there was no significant difference in lipid profile between AGT-MM group and AGT-T allele carriers. Moreover, the compared groups in both polymorphisms had similar distribution of hyperlipidemia, hypertension, impaired glucose metabolism (prediabetes or type 2 diabetes mellitus) and coronary artery disease. In terms of echocardiographic parameters, systolic and diastolic function was similar among the groups in ACE and AGT genotypes. Interestingly, AGT-MM group had higher mitral inflow Apeak values than T allele carriers (0.94 ± 0.46 vs. 0.73 ± 0.20; p = 0.051). No significant difference was observed in LV mass index values in acromegalic patients among the groups in both polymorphisms. Both ACE (I/D) and AGT (M235T) gene polymorphisms do not seem to have a significant effect on the development of clinical properties or cardiovascular comordities of acromegalic patients.

The Association of Angiotensinogen (AGT M235T) Gene Polymorphism and Essential Hypertension in Thai Post-Menopausal Women

Objectives: This study aims to determine the relationship between angiotensinogen (AGT) M235T polymorphism and hypertension among post-menopausal Thai women. Materials and Methods: Case-control study was conducted. The study group was those who had hypertension or previously diagnosed and, the control were those who had no hypertension. Blood samples were taken for AGT M235T allelic characterization using allele specific oligonucleotides (ASO) PCR. Results: Of 255 post-menopausal women, 128 had hypertension, regarded as “hypertension group”, the other 127 without hypertension, regarded as “control group”. The presence of AGT M235T polymorphism was 76.5% for homozygous mutation (73.4% for hypertension group and 79.5% for control group), 21.2% for heterozygous mutation (25.0% for hypertension group and 17.3% for control group, respectively) and 2.4% for homozygous wild-type (1.6% for hypertension group and 3.2% for control group, respectively). Distribution of MM, MT and TT genotypes was not significantly different between both group (p=0.251). Conclusions: Interestingly, overall TT genotype was much higher than that of TM and MM in post-menopausal Thai women. AGT M235T polymorphism was not significantly associated with hypertension, though TT genotype tended to give a small risk. They may not serve as a good genetic marker for essential hypertension among Thai population.

Association Between the Angiotensinogen Gene Polymorphism and The Pro-Oxidant Effect in Tunisian Patients with Coronary Heart Disease

Background: Evaluation and investigation of the pro-oxidant role of the angiotensinogen (AGT) among Tunisian coronary. Materials and methods: The current study evaluated the frequency of AGT (M235T and A(-6)G) polymorphism in relation to coronary artery disease in a group of Tunisian population. AGT polymorphism was determined by Real Time PCR. These subjects (150 patients and 120 controls) beneficed also by an enzymatic determination of superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant status (TAS), catalase (CAT) activity was determined spectrophotometrically and serum lipid peroxides were measured by the fluorimetric method reaction to reveal the atherogenic effects of these radical species and investigate their interactions with AGT polymorphisms. Results: The results revealed that there was a positive risk of developing coronary artery disease when having the T allele whether in homozygous or heterozygous state. Statistical tests of the baseline correlation between oxidative stress parameters and M235T genotype groups showed a negative correlation between MM genotype group and oxidant parameters (SOD, GPX and TAS). The same result was found in TT and MT genotype groups. Conclusion: This study shows that the AGT polymorphisms were associated with the presence of coronary artery disease. In addition to its vasoconstrictor role, AGT can be considered as a pro-oxidant, these two effects combine in the genesis and the complications of cardiovascular diseases.

Association of the angiotensinogen M235T polymorphism with recurrence after catheter ablation of acquired atrial fibrillation.

Previous studies showed that genetic variants of the angiotensinogen (AGT) gene conferred higher risk for acquired atrial fibrillation (AF). The present study investigated whether AGT variants correlate with the clinical outcome in patients with acquired AF after catheter ablation (CA). A total of 150 acquired symptomatic drug-refractory AF patients (mean age 63.7±11.0 years, 24.6% non-paroxysmal AF) with acquired AF underwent a single CA procedure in our department and were included in this retrospective analysis. Eight tagging single nucleotide polymorphisms (tSNPs) in the AGT gene were genotyped. Standard electrocardiographs (ECGs) and 24-hour Holter recordings were performed during a median follow-up period of 57.5 months to detect AF recurrence. Sixty-one patients (40.7%) suffered AF recurrences after a single CA procedure during follow up. Of the eight tSNPs, the frequency of the M allele of M235T was significantly higher in the recurrence group (28%) compared to the non-recurrence group (18%) (p=0.042). The recurrence rates of patients with the TT, MT, and MM genotypes were 34.4%, 50%, and 55.6%, respectively (ptrend=0.049). After adjusting for age, sex, body mass index, hypertension, left atrial volume index (LAVI) and other covariates, M235T increased the risk of AF recurrence in additive and dominant models with odds ratios of 2.023 (95% confidence interval (CI): 1.034-3.926, p=0.033) and 2.601 (95% CI: 1.102-6.056, p=0.025), respectively. However, in multiple correction analyses, the p values of multiple comparisons were not statistically significant (pcorrect>0.05). The M allele of M235T might be associated with an increased risk of AF recurrence after CA. Genotyping may thus be helpful on identifying patients with higher risks of AF recurrence after CA and developing optimal follow-up strategies. These strategies may differ and should be individualized according to patients' genotype. Future studies are warranted to validate the potential effect of AGT M235T on AF recurrence post CA.

Refractory hyperaldosteronism in heart failure is associated with plasma renin activity and angiotensinogen polymorphism.

Refractory hyperaldosteronism is frequently observed in heart failure patients on up-to-date treatment, and holds prognostic value. Our aim was to identify which factors, either genetic or nongenetic, are associated with refractory hyperaldosteronism. We enrolled 109 consecutive patients with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) 32 ± 10%; 86% males; age 65 ± 13 years (mean ± standard deviation)] on optimized adrenergic and renin-angiotensin-aldosterone system (RAAS) antagonism, undergoing clinical and neuroendocrine characterization, and genotyping for six polymorphisms in key RAAS-regulating genes [angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE-240A>T and I/D), angiotensin II type I receptor (AGTR1 1166A>C), aldosterone synthase (CYP11B2-344C>T) and renin (REN rs7539596)]. Patients with refractory hyperaldosteronism (n = 41, 38%, with plasma concentration >180 ng/l, URL, median 283 ng/l, interquartile range 218-433), when compared with those without (106 ng/l, 74-144; P < 0.001), were not different either for treatment or LVEF, while presented with different AGT M235T genotype distribution (P = 0.047). After adjustment for several humoral, instrumental, functional and therapeutical variables, only plasma renin activity (PRA) (P < 0.001) and potassium (P = 0.027) were independently associated with refractory hyperaldosteronism. Among polymorphisms, only AGT M235T (P = 0.038) was associated with refractory hyperaldosteronism, after adjustment for nongenetic variables. In conclusion, refractory hyperaldosteronism in heart failure may be influenced by AGT M235T polymorphism, among RAAS candidate genes, and by PRA, which may represent, respectively, a constitutive (genotype dependent) and a nongenetic (phenotype-dependent) trigger for aldosterone elevation.

Renin-angiotensin system gene polymorphisms among Saudi patients with coronary artery disease.

BackgroundThe polymorphisms in the components of the renin-angiotensin system (RAS) are important in the development and progression of coronary artery disease (CAD) in some individuals. Our objectives in the present investigation were to determine whether three RAS polymorphisms, angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin receptor II (Ang II AT2 - C3123A) and angiotensinogen (AGT-M235T), are associated with CAD in the Saudi population. We recruited 225 subjects with angiographically confirmed CAD who had identical ethnic backgrounds and 110 control subjects. The polymerase chain reaction-restriction fragment length polymorphisms (RFLP) technique was used to detect polymorphisms in the RAS gene.ResultsWithin the CAD group, for the ACE I/D genotype, DD was found in 64.4%, 26.3% carried the ID genotype, and 9.3% carried the II genotype. Within the control group, the DD genotype was found in 56.4%, 23.6% carried the ID genotype, and 20% carried the II genotype. The odds ratio (OR) of the ACE DD vs II genotype with a 95% confidence interval (CI) was 2.45 (1.26-4.78), with p = 0.008. For the Ang II AT2 receptor C3123A genotype, within the CAD group, CC was found in 39.6%, 17.8% carried the CA genotype, and 42.6% carried the AA genotype. Within the control group, CC was found in 39.1%, 60.9% carried the CA genotype, and there was an absence of the AA genotype. The OR of the Ang II AT2 receptor C3123A CC vs AA genotypes (95% CI) was 0.01, with p = 0.0001. A significant association with CAD was shown. For the AGT-M235T genotype, within the CAD group, MM was found in 24.0%, 43.6% carried the MT genotype and 32.4% carried the TT genotype. Within the control group, MM was found in 26.4%, 45.5% carried the TT genotype and 28.2% carried the MT genotype. The OR of MM vs TT (95% CI) was 0.79 (0.43 to 1.46), which was insignificant.ConclusionsThere is an association between the ACE I/D and Ang II AT2 receptor C3123A polymorphisms and CAD, however, no association was detected between the AGT M235T polymorphism and CAD in the Saudi population.

DETERMINING M235T POLYMORPHISM OF ANGIOTENSINOGEN GENE (AGT) IN NORMOTENSIVE AND PREECLAMPTIC/ECLAMPTIC PREGNANT WOMEN

Background: The 235T allele of AGT gene has been reported to be associated with higher AGT level and abnormal remodeling of the uterine spiral arteries, which is an early cause preeclampsia/eclampsia (PE/E). The aim of this study was to: (1) determine the frequencies of 235MM, 235MT and 235TT genotypes of AGT gene in normotensive and preeclamptic/eclamptic pregnant women, and (2) survey the association between AGT M235T polymorphism and PE/E. Patients and methods: 68 preeclamptic pregnant women and 272 normotensive pregnant women were determined M235T genotypes of AGT gene by allele – specific PCR technique with DNA samples extracted from whole blood. Results: The frequencies of 235MM, 235MT and 235TT genotypes in normotensive pregnant women were 1.8%; 15.8% and 82.4%, respectively, the distribution of these genotypes was in Hardy – Weinberg equilibrium. These frequencies in preeclamptic/eclamptic pregnant women were 1.5%; 14.7% and 83.8%, respectively. The frequencies of 235T allele in two groups were 90.3% and 91.2%, respectively. There was no association between the M235T polymorphism and PE/E in all of models, including 235TT/(235MT + 235MM), (235TT + 235MT)/235MM, 235TT/235MM and 235T allele/235M allele. Conclusion: The frequencies 235T allele in both groups were very high. There was no association between M235T polymorphism and preeclampsia/eclampsia. Keywords: Preeclampsia, M235T polymorphism, AGT gene

Interaction of six candidate genes in essential hypertension.

We explored the interaction of 6 candidate genetic mutations in essential hypertension (EH). The mutations AGT M235T, ACE I/D, eNOS Glu298Asp, ET-2 A985G, ANP T2238C, and NPRC A-55C were detected using a genechip microarray in 100 patients with EH and 97 controls from the Han population living in the Yunnan Province of China. Risks of EH were evaluated with respect to a combination of these genotypes. Interactions were analyzed using multifactor dimensionality reduction (MDR). P values were corrected using Bonferroni's adjustment. Results showed that CC genotype frequencies for NPRC A-55C (0.540) in EH were significantly higher than those in controls (0.237, Pc < 0.01; odds ratio (OR) = 3.777; 95% confidence interval (CI) = 2.050-6.960). The OR for NPRC A-55C CC combined with ET-2 A985G GG increased to 4.673 and to 5.529 when the MT genotype of AGT M235T, the EE genotype of eNOS Glu298Asp, the GG genotype of ET-2 A985G, and the CC genotype of NPRC A-55C were combined. MDR showed that ET-2/NPRC is the best model (OR = 4.002; 95%CI = 2.1597-7.4159). The CC genotype for NPRC A-55C and the G allele for ET-2 A985G were associated with susceptibility to EH. Although the contributions of the candidate genes differ, they may have cooperative effects on conferring risk for EH. Moreover, potential gene-gene interactions were found between ET-2 A985G and NPRC A-55C in EH.

KRAS mutations in non-small-cell lung cancer and colorectal cancer: Implications for EGFR-targeted therapies

BackgroundKRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and methodsTumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined. ResultsKRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<0.001), smoking-associated G>T transversions (73% versus 27%; p<0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%). ConclusionIn this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.

Association of rs699 (M235T) Polymorphism in the AGT Gene With Power but Not Endurance Athlete Status

Thus far, genetic studies of the renin-angiotensin system (RAS) with respect to athletic performance or athlete status have mainly focused on the angiotensin-converting enzyme gene and its insertion/deletion polymorphism. The aim of this study was to investigate the functional rs699 (M235T) polymorphism in angiotensinogen (AGT), the second most important gene of the RAS, for association with athletic status and level of performance. The study included 123 endurance athletes and 100 power-oriented athletes, who were classified as elite or sub-elite according to competitive achievements at the international level, and 354 unrelated sedentary control subjects. The M235T genotype and allele distributions differed significantly between power and endurance athletes (p < 0.0001 and p < 0.0002, genotypes and alleles, respectively) and between power athletes and control subjects (p < 0.0001 and p < 0.0002, genotypes and alleles, respectively). The frequency of the CC genotype in the power athlete group was 2.2 times higher and 3.1 times higher than in the control and endurance groups, respectively. No difference was found in M235T allele distribution between elite and sub-elite athletes, either in power- or endurance-oriented athletes. We conclude that the CC genotype of the M235T polymorphism is overrepresented in Polish power athletes, suggesting that the AGT M235T variant is associated with power athletes' status.

Genotypes of renin-angiotensin system and plasma adiponectin concentration in kidney transplant patients

Low plasma adiponectin concentration was recently recognized as a novel risk factor for new-onset diabetes after transplantation. Pharmacological modulation of the renin-angiotensin system activity and genetic predisposition were shown to have an influence on plasma adiponectin level. Therefore the aim of this study is to analyze the association between angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT1R) A1166C and angiotensinogen (AGT) M235T genotypes and plasma adiponectin concentration as well as insulin resistance in a cohort of kidney transplant patients. AGT M235T, ACE I/D and AT1R A1166C genotyping and plasma adiponectin and insulin concentrations assessment were performed in 372 patients with functioning kidney allograft (eGFR >20 ml/min/1.73 m2) from 2 transplant centres. Females with II ACE I/D genotype had a significantly higher plasma adiponectin concentration than the ID+DD subgroup, which could partially be explained by a lower BMI in the II subgroup. Males with TT genotype of the AGT M235T gene polymorphism (and higher BMI) had higher plasma concentration of insulin and HOMAIR values than those in the MT+MM subgroup. A multiple regression analysis revealed that only female sex (b=0.239), BMI (b=–0.208) and ACE II genotype (b=0.129) were significantly associated with plasma adiponectin concentration variability. A similar analysis for HOMA-IR showed that its variability was associated with BMI (b=0.333), eGFR (b=–0.115) and plasma adiponectin concentration (b=–0.064) irrespective of any of the analyzed genotypes. Plasma adiponectin concentration, but not insulin resistance, seems to be modulated only by ACE I/D polymorphism in kidney transplant patients. Polymorphisms of the other renin-angiotensin system components do not influence plasma adiponectin concentration or insulin resistance in these patients.

Genophenotypic Analysis of Angiotensinogen Gene M235T Polymorphism and Preeclampsia

We studied phenotypes of the circulating renin-angiotensin-aldosterone system and circadian BP during preeclampsia depending on polymorphism of angiotensinogen gene M235T. The TT genotype or T allele of angiotensinogen M235T gene polymorphism is associated with the risk of preeclampsia. Plasma renin activity significantly decreases under conditions of preeclampsia. The TT genotype of angiotensin M235T gene polymorphism is associated with highest renin activity and highest 24-h diastolic BP in comparison with MT and MM genotypes in patients with preeclampsia. Plasma aldosterone level is lower in patients with preeclampsia, but this is not related to angiotensinogen M235T gene polymorphism.

Association of Angiotensinogen (M235T) Gene Polymorphism with Blood Pressure Lowering Response to Angiotensin Converting Enzyme Inhibitor (Enalapril)

It has been suggested that genetic backgrounds, which have an association with essential hypertension, may also determine the responsiveness to ACE inhibitor. We determined the association of angiotensinogen (M235T) gene polymorphism with essential hypertension and the relationship between polymorphism in the angiotensinogen (M235T) gene and blood pressure response to ACE inhibitor (Enalapril) in patients with essential hypertension from northern Indian subjects. 250 patients with essential hypertension and 250 normal healthy controls from Delhi and surrounding areas were recruited for the investigation. Blood pressure was recorded before and after 6 weeks of treatment with ACE inhibitors, Enalapril. Genotyping were carried out by polymerase chain reaction and Restriction fragment length polymorphism technique. Statistically significant association of T allele was observed with essential hypertension [x2 = 14.67, p = 0.00013, Odds ratio = 1.76 (1.3-2.32) at 95% CI], the relative risk at 95% CI being 1.28 (1.2-1.54). The decrease in systolic blood pressure and diastolic blood pressure after six weeks of treatment of the patients carrying TT genotype (SBP = 26 ± 17.4 mmHg, DBP = 14.83 ± 7.6 mmHg) were greater than the groups carrying MT (SBP = 3.0 ± 7.8 mmHg, DBP = 6.2 ± 3.0 mmHg) and MM genotypes (SBP = 1.2 ± 0.8 mmHg, DBP = 0.10 ± 12.1 mm Hg. The angiotensinogen (M235T) gene polymorphism is significantly associated with essential hypertension. Patients carrying TT genotype had higher blood pressure lowering response when treated with ACE inhibitor, Enalapril than those carrying MM and MT genotypes suggesting that the T allele may be a possible genetic marker for essential hypertension.

Association Between Gene Polymorphisms of the Components of the Renin-Angiotensin-Aldosteron System, Graft Function, and the Prevalence of Hypertension, Anemia, and Erythrocytosis After Kidney Transplantation

Introduction Genetic predisposition, including polymorphisms of the renin–angiotensin system (RAS) genes, are among the potential factors that may affect the occurrence of hypertension, anemia, or erythrocytosis as well as transplanted kidney function. However, the association of the RAS genes polymorphism and the kidney transplant outcomes is controversial. The aim of this study was to analyze the association between polymorphic variants of the angiotensin-converting enzyme (insertion/deletion [I/D]), angiotensinogen (M235T), and angiotensin II receptor type 1 (A1166C) genes, and the early and long-term kidney graft outcomes, as well as the prevalence of hypertension, anemia and erythrocytosis after kidney transplantation. Patients and Methods We included 331 consecutive kidney transplant patients performed between 1998 and 2003. Of the total, 87.9% of patients completed a 5-year follow-up. Subjects were genotyped for the I/D, M235T, and A1166C polymorphisms. Results None of the examined polymorphism affected early or long-term graft function or was associated with hypertension before or after kidney transplantation. There was no significant difference in genotype distribution between patients with and without posttransplant erythrocytosis. However, posttransplant anemia (PTA) seemed to be significantly more common among kidney recipients with TT and MT than MM angiotensinogen genotypes (35.7% vs 20.7%; P = .03). The T allele was associated with the risk of development of PTA (odds ratio, 2.12; 95% confidence interval, 1.12–3.99; P = .02). Conclusion Our results do not support the hypothesis that polymorphism of the genes coding RAS components may by an independent risk factor for the development of interstitial fibrosis/tubular atrophy, posttransplant hypertension, or PTE. Further studies are necessary to investigate the association between angiotensinogen M235T genotypes and PTA.

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

Background: Diabetic nephropathy (DN) is a leading cause of diabetes-related morbidity and mortality. The aim of this study was to evaluate the relationship of AGT M235T and apoprotein E (APO E) gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, non-DN patients, and healthy controls. Methods: AGT M235T and APO E genotype and allele analysis were performed in 111 DN patients, 108 non-DN patients, 106 healthy control subjects for APO E genotype, and 100 for AGT M235T genotype polymorphism. APO E and AGT M235T genotype were determined by RFLP-PCR. Results: The frequencies of APO E ε2/3, ε 3/3, ε 3/4 genotypes were 22.7%, 60%, 60%, respectively, among DN patients and 6.6%, 80%, 10.4%, respectively (p < 0.001), in the non-DN patients. The frequencies of AGT M235T MM, MT, TT genotypes among the same groups were 17%, 46%, 37% and 21%, 63%, 16%, respectively (p < 0.02). Having the ε2/3 genotype and TT genotype increased the risk for DN nephropathy [4.8-fold (95% CI: 1.94–11.67), 2.9-fold (95% CI: 1.27–6.69), respectively]. Conclusion: Our study has shown that AGT M235T TT genotype and APO E ε 2/3 genotype may be linked to a risk for DN among Turkish population.