M235T Variant Research Articles

Relationship between the AGT M235T genetic variant and the characteristics and prognosis of coronary atherosclerosis in patients with acute myocardial infarction.

Along with environmental components, genetic factors play an essential role in the pathophysiology and progression of acute myocardial infarction (AMI). There is limited and conflicting data on the influence of the AGT M235T genetic variant on coronary atherosclerosis and death in AMI patients. We carried out a prospective cohort study among 504 Vietnamese AMI patients selected between January 2020 and May 2021. All patients underwent invasive coronary angiography, had AGT M235T genetic variant genotyped using the polymerase chain reaction method, and were followed up for 12-month all-cause mortality. The proportions of the MM, MT, and TT genotypes were 0.4%, 20.8%, and 78.8%, respectively. There was no significant difference between the TT genotype and the MM + MT genotype groups regarding the position and number of stenosed coronary artery branches and the Gensini score. The AGT M235T genetic variant did not affect 12-month mortality (hazard ratio of TT vs. MM + MT: 1.185; 95% confidence interval: 0.596-2.354; P = 0.629). Subgroup analyses by age, sex, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy also did not reveal an association between the AGT M235T variant and all-cause mortality. In summary, the AGT M235T genetic variant was not found to be associated with coronary atherosclerosis characteristics and 12-month mortality in Vietnamese patients with AMI. Further multicenter studies with larger sample sizes and extended follow-up periods are needed to investigate this issue.

Angiotensinogen Gene M235T and T174M Polymorphisms in Diabetic Nephropathy in a Bangladeshi Population

Background: Marker gene polymorphisms linked with the renin-angiotensin-aldosterone system (RAAS) have been broadly studied in diabetic nephropathy (DN) patients considering that RAAS is a potential drug target to slow down kidney disease progression. Objectives: The aim of the present study was to determine the link between M235T and T174M variants of angiotensinogen (AGT) gene and DN. Methods: A total of 93 patients with DN, mean age of 56±8 years, systolic blood pressure (SBP) of 141±14, and diastolic blood pressure (DBP) of 84±7 mm Hg (mean±SD) were investigated, among whom 59 patients had a family history of type 2 diabetes mellitus. A total of 96 healthy subjects served as the control group with no family history of diabetic nephropathy (FHDN) and type 2 diabetes mellitus, a mean age of 47±10 years, SBP of 126±11, and DBP of 76±6 mm Hg. PCR–restriction fragment length polymorphism was employed for genotyping M235T and T174M molecular variants. Results: Genotype frequencies of the variants M235T (χ2=2.038, P=0.361) and T174M (χ2=2.952, P=0.229) did not show any statistically significant association with type 2 diabetic nephropathy (T2DN) compared to the control. Based on FHDN and family history of diabetes mellitus (FHDM), the frequency of genotypes of M235T marker (P=0.360) in FHDN, and (P=0.886) FHDM; T174M marker (P=0.641) in FHDN, and (P=0.425) FHDM also did not show any statistically significant association with T2DN compared to the controls. Conclusion: M235T and T174M variants were not associated with DN in a Bangladeshi population.

Genetic Polymorphism in Angiotensinogen and Its Association with Cardiometabolic Diseases.

Angiotensinogen (AGT) is one of the most significant enzymes of the renin-angiotensin-aldosterone system (RAAS) which is involved in the regulation and maintenance of blood pressure. AGT is involved in the production of angiotensin I which is then converted into angiotensin II that leads to renal homeostasis. However, various genetic polymorphisms in AGT have been discovered in recent times which have shown an association with various diseases. Genetic polymorphism increases the level of circulating AGT in blood which exaggerates the effects produced by AGT. The associated diseases occur due to various effects produced by increased AGT levels. Several cardiovascular diseases including myocardial infarction, coronary heart disease, heart failure, hypertrophy, etc. are associated with AGT polymorphism. Other diseases such as depression, obesity, diabetic nephropathy, pre-eclampsia, and liver injury are also associated with some variants of AGT gene. The most common variants of AGT polymorphism are M235T and T174M. The two variants are associated with many diseases. Some other variants such as G-217A, A-6G, A-20C and G-152A, are also present but they are not as significant as that of M235T and T174M variants. These variants increase the level of circulating AGT and are associated with prevalence of different diseases. These diseases occur through various pathological pathways, but the initial reason remains the same, i.e., increased level of AGT in the blood. In this article, we have majorly focused on how genetic polymorphism of different variants of AGT gene is associated with the prevalence of different diseases.

Association of gene polymorphisms of ACE, AGT, and ARNT-like protein 1 with susceptibility to gestational diabetes

Background and aimsGestational diabetes mellitus is well-defined as glucose intolerance first documented during pregnancy. In this study, we examined the possible associations between I/D polymorphism of the angiotensin-converting enzyme gene, the M235T variant of angiotensinogen gene, and the rs7950226 polymorphism of the ARNT-like protein-1 (BMAL1) gene and the risk for diabetes in Egyptian pregnant women.Subjects and methodsThis study recruited 160 gestational diabetes cases and 165 controls. Genomic DNA was derived from peripheral blood leukocytes and ACE gene (I/D) genotyping was performed using the method of polymerase chain reaction and the polymerase chain reaction-based restriction fragment length polymorphism was used for identifying the M235T variant of AGT gene and the rs7950226 polymorphism of the BMAL1.ResultsThe II, ID, and DD genotypes of the ACE gene have significant differences in cases compared to controls (P = 0.000 and X2 = 81.77). The M235T polymorphism of the AGT gene was increased with gestational diabetes risk. Furthermore, the AA genotype of the BMAL1 rs7950226 gene was significantly related to the gestational diabetes risk (P = 0.000 and X2 = 52.82). Furthermore, the allele frequencies of the three variants have significant variances between cases and control.ConclusionThis study suggested significant associations between ACE (DD), AGT (TT), and BMAL1 rs7950226 (AA) gene polymorphisms with gestational diabetes susceptibility and there was a possibility to identify that II + MM + GG as protective haplotypes and DD + TT + AA as risk haplotypes for gestational diabetes.

ASSOCIATION OF AGT GENE M235T AND ACE GENE I/D POLYMORPHISMS WITH HYPERTENSION IN MONGOLIAN POPULATION

Objective: In Mongolia, hypertension is major public health problem due to its high prevalence of stroke and mortality rate. The objective of this study was to analyse the relationship between AGT M235T gene variant and ACE I/D gene variant with hypertension in a sample of the Mongolian population of the Ulaanbaatar city. Design and method: Design and Method: A case-control study has been performed in 146 subjects including 96 hypertensives and 50 normo-tensive subjects, aged 18–60 years. Hypertension was defined as systolic BP =>130 mm Hg and/or diastolic BP=>80 mm Hg). After isolation DNA from peripheral blood, the following specific primers were used for polymerize chain reaction (PCR). PCR purification kit and QIAquick Gel extraction kit were used to establish nucleic acid sequence. Results: The mean age of the participants was 39.6 years and 54.7% were men. The M235T variant of AGT gene was identified in 97.9% of all participants (96.8% of hypertensive patients and 100% of normotensive subjects). According to the genotype results, the frequencies of the AGT TT, MT and MM genotypes were 57.3%, 39.6%, and 3.1% in cases and 64.0%, 36.0% and 0.0% in controls respectively. The genotypic distribution of the M235T variant of the AGT gene did not differ in hypertensives and normotensives group (p > 0.328). In this study, we did not observe any significant differences in blood pressure levels with regard to ACE gene I/D polymorphism in both hypertensive and normotensive groups (40% vs 38%, p > 0.543). Conclusions: Conclusion: This is the first report on the frequency of AGT and ACE gene polymorphisms among Mongolian population. About 97.9% of Mongolians carry the M235T variant of the AGT gene that makes them more prone to hypertension when they eat too much sodium.

Associations Between Polymorphisms of Endothelial Nitric Oxide Synthase, Matrix Metalloproteinase 3, Angiotensinogen, and Angiotensin II Type 1 Receptor and Risk of Restenosis After Percutaneous Coronary Intervention: A Meta-analysis

PurposePrevious studies have reported controversial results regarding the risk of restenosis with polymorphisms of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase 3 (MMP-3), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) after percutaneous coronary intervention (PCI). This study aimed to summarize the association between these polymorphisms and risk of restenosis after PCI. MethodsWe searched the electronic databases of PubMed, Embase, Cochrane's Library, and ClinicalTrials.gov for studies on the association of eNOS, MMP-3, AGT, and AT1R polymorphisms with restenosis. FindingsA total of 17 studies (7781 patients) were analyzed, including 5 studies on eNOS G298A (n = 912), 5 studies on MMP3 5A/6A (n = 4519), 6 studies on AGT M235T (n = 1801), and 7 studies on AT1R A1166C (n = 2477). For the G298A variant of the eNOS gene, the allele odds ratio (OR) was 1.685 (95% CI, 1.269–2.338; P < 0.001), the heterozygote OR was 2.144 (95% CI, 1.490–3.085; P < 0.001), the dominant OR was 2.078 (95% CI, 1.462–2.954; P < 0.001), and the overdominant OR was 0.496 (95% CI, 0.348–0.706; P < 0.001). For the 5A/6A variant of the MMP3 gene, the heterozygote OR was 0.839 (95% CI, 0.722–0.975; P = 0.022), the dominant OR was 0.846 (95% CI, 0.733–0.976; P = 0.022), and the overdominant OR was 1.141 (95% CI, 1.001–1.301; P = 0.049). For the M235T variant of the AGT gene, the heterozygote OR was 1.594 (95% CI, 1.179–2.155; P = 0.002), the dominant OR was 1.437 (95% CI, 1.077–1.918; P = 0.014), and the overdominant OR was 0.694 (95% CI, 0.555–0.869; P = 0.001). Positive results were observed in the AT1R gene A1166C polymorphism under 3 models (homozygote OR = 2.009; 95% CI, 1.433–2.816; P < 0.001; recessive OR 1.874; 95% CI, 1.353–2.595; P < 0.001; and dominant OR = 1.350; 95% CI, 1.105–1.649; P = 0.003). ImplicationsThe G298A variant of eNOS, the 5A/6A variant of MMP3, the M235T variant of AGT, and the A1166C variant of A1TR may increase the risk of restenosis after PCI.

Contribution of angiotensinogen M235T and T174M gene variants and haplotypes to preeclampsia and its severity in (North African) Tunisians.

Background:Preeclampsia (PE) is a pregnancy-associated hypertensive disorder and a leading cause of maternal and neonatal morbidity and mortality. While its pathogenesis remains ill defined, several candidate genes for PE have been identified, but results remain inconclusive. We investigated the association of the angiotensinogen (AGT) gene variants M235T and T174M with PE, and we analyzed the contribution of both variants to the severity of PE.Methods:This case-control study enrolled 550 Tunisian pregnant women: 272 with PE, of whom 147 presented with mild, and 125 with severe PE, along with 278 unrelated age- and ethnically matched control women. AGT genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism.Results:Significantly higher M235T minor allele frequency (MAF) was associated with increased risk of PE (p < 0.001). Decreased frequency of heterozygous T174M genotype carriers were found in control women (p = 0.015), suggesting a protective effect of this genotype (odds ratio (95% confidence interval) = 0.51 (0.29–0.89)). Two-locus haplotype analysis demonstrated MM and TT haplotypes to be negatively and positively associated with PE, respectively. MAF of M253T, but not T174M, was higher in the severe PE group, and carrying M235T or T174M minor allele was associated with increased body mass index (p < 0.001) among unselected PE women.Conclusions:AGT M235T and T174M variants contribute to an increased risk of developing PE, and for M235T to PE severity.

Association study between some renin-angiotensin system gene variants and essential hypertension in a sample of Algerian population: case control study.

Essential hypertension is an important risk factor for the development of cardiovascular disease. We aim in this study to analyse the relationship between AGT M235T gene variant and ACE I/D gene variant with essential hypertension in a sample of the Algerian population of the Oran city. A case-control study has been performed in 145 subjects including; 75 hypertensives and 70 controls from Algerian population of Oran city. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to detect the M235T variant of angiotensinogen (AGT) gene and a nested PCR to determine ACE I/D gene variant. The genotypic and allelic distribution of the M235Tvariant of the AGT gene did not differ in hypertensives and normotensives group (X(2) =7.81, P<0.05; X(2) =4.67, respectively) thus there was no association between the T allele and hypertension (OR=1.64; 95%CI [1.01-2.69]). The genotypic and allelic frequencies of the ACE I/D variant did differ significantly between hypertensives and controls (X(2)=13.98, P<0.05; X(2) =12.66, P<0.05, respectively) where a significant association between the D allele of the ACE I/D gene and essential hypertension has been observed (OR=0.46; 95%CI [0.27-0.75]). We reported a high prevalence of the D and T allele in hypertensives female. This study shows that the M235T variant of the AGT gene is not associated with essential hypertension while a significant association has been reported with the D allele in this sample of Algerian population of the Oran city.

Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04–1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

Gender specific association of RAS gene polymorphism with essential hypertension: a case-control study.

Renin-angiotensin system (RAS) polymorphisms have been studied as candidate risk factors for hypertension with inconsistent results, possibly due to heterogeneity among various genetic and environmental factors. A case-control association study was conducted to investigate a possible involvement of polymorphisms of three RAS genes: AGT M235T (rs699), ACE I/D (rs4340) and G2350A (rs4343), and AGTR1 A1166C (rs5186) in essential hypertensive patients. A total of 211 cases and 211 controls were recruited for this study. Genotyping was performed using PCR-RFLP method. The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (OR-CI = 2.62 (1.24–5.76), P = 0.006; OR-CI = 0.699 (0.518–0.943), P = 0.018), respectively. When the samples were segregated based on sex, the 235TT genotype and T allele were predominant in the female patients (OR-CI = 5.68 (1.60-25.10), P = 0.002; OR-CI = 0.522 (0.330–0.826), P = 0.005) as compare to the male patients (OR-CI = 1.54 (1.24–5.76), P = 0.34; OR-CI = 0.874 (0.330–0.826), P = 0.506), respectively. For ACE DD variant, we found overrepresentation of “I”-allele (homozygous II and heterozygous ID) in unaffected males which suggest its protective role in studied population (OR-CI = 0.401 (0.224–0.718); P = 0.0009). The M235T variant of the AGT is significantly associated with female hypertensives and ACE DD variant could be a risk allele for essential hypertension in south India.

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.

AGT M235T variant is not associated with risk of cancer

The angiotensinogen (AGT) gene has been considered to be implicated in the development of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of AGT M235T variant with cancer risk. Published literature from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using a fixed- or random-effects model. A total of seven articles including eight studies (3639 cancer cases and 6684 controls) for AGT M235T variant were included. The present meta-analysis showed that AGT M235T variant was marginally associated with cancer risk under dominant model (OR=1.12, 95% CI=1.02-1.24). However, the positive association was not stable after sensitivity analysis. Further subgroup analysis by cancer type did not suggest any association of AGT M235T variant with various cancers (all p>0.05). The present meta-analysis demonstrated that AGT M235T variant was not associated with risk of all cancer or various cancers. Further well-designed studies with large sample size should be conducted to confirm or refute the non-significant association.

The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease

Little is known about the contribution of genetics and lipoprotein subclasses to the development of coronary artery calcification (CAC) in asymptomatic, first-degree relatives of patients with CAD. We evaluated 100 asymptomatic, non-smoking, lipid-lowering therapy-naïve, first-degree relatives of patients with obstructive CAD through testing for 27 biomarkers, 15 single nucleotide polymorphisms in 12 candidate genes, and CAC and compared them to matched controls without family history. We compared prevalence of CAC in those with and without family history and biomarkers between those with and without CAC. Mean age was 41.6 ± 9 years; 58% were female. Significantly more subjects with family history had non-zero CAC (median Agatston: 13, range 1–1107) compared to those without family history (median Agatston: 43; range 1–345) (21% vs. 9%; p = 0.028). Among subjects with family history, in subjects with positive vs. negative CAC, multivariable analysis showed significantly lower HDL-2A (999 ± 333 vs. 1262 ± 397 nmol/L) and higher frequency of a substitution of threonine for methionine at codon 235 in the angiotensinogen gene (AGT M235T) (75% vs. 54%; p < 0.05; odds ratio of 2.6 for CAC). Population attributable risk of one copy of the risk allele at the AGT locus was 16%, highest of any variable tested. In conclusion, in this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC independent of blood pressure, raising the possibility of an alternative biological pathway.

A study of the M235T variant of the angiotensinogen gene and hypertension in a sample population of Calabar and Uyo, Nigeria

A common molecular variant of the angiotensinogen gene had been reported to predispose some ethnic groups to hypertension. This case–control study was designed to determine the frequency and association of the angiotensinogen M235T allele with hypertension in residents of Calabar and Uyo cities, south–south Nigeria.The study involved 1308 subjects, 612 patients and 696 controls. The M235T variant was investigated using an allele specific polymerase chain reaction and enzymatic digestion to determine allele frequencies. Hypertensinogenic factors such as dietary habits, physical activity, smoking and drinking habits were assessed using questionnaires. Descriptive statistics, chi-square and multiple regression analysis were used to analyze the data obtained.The M235T allele frequency was high (0.94 for hypertensives and 0.96 for controls) though it was not associated with hypertension status. The odds ratio for hypertension was 0.64 (95% confidence interval: 0.39–1.06) there were no significant differences between the genotype frequency of hypertensives and controls. By multiple regression, Hypertension was observed to be associated with age and was a predictor for systolic blood pressure in both patient r2=0.359; p<0.05 and control groups r2=0.26.Age and body mass index were predictors for diastolic blood pressure in the control group, r2=0.28.Although the frequency of the M235T variant was high, it was not a significant risk factor for hypertension in the study population.

Gender-Related Association of AGT Gene Variants (M235T and T174M) with Essential Hypertension—A Case-Control Study

Introduction. The human angiotensinogen (AGT) is a promising candidate gene for evaluating susceptibility to essential hypertension (EH). We aimed to assess the association of the variants of AGT gene and the extent of risk involved in developing EH. Methods. A case-control study was designed to compare 279 hypertensive patients with 200 normotensive subjects. The frequency distribution of M235T and T174M polymorphisms of AGT gene was assessed by polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) method. A haplotype analysis was done to determine the risk conferred by the combination of alleles of the two polymorphisms for EH. Results. The genotype distribution of the T174M variant differed significantly between hypertensives and normotensives, whereas genotypes of M235T variant did not show such difference. For M235T, MM genotype conferred an increase in risk for hypertension in women (odds ratios (OR) = 2.82; 95% confidence interval (CI) = 1.22–6.49). For the variant T174M, the TM genotype frequency was elevated in hypertensive females (36.5%) as compared to controls (18.8 %; P = .034). The 174M allele was more prevalent among female hypertensives than among female controls (0.20 vs. 0.12; P = .059). The haplotype analysis showed a significant association for the haplotypes of paired markers (M235 and 174M) with a χ2 value of 8.037 (P = .045). Conclusion. Our findings suggest that the polymorphic variants of AGT gene—M235T and T174M—show association with hypertension.

Endothelial Nitric Oxide Synthase and Angiotensinogen Gene Polymorphism in Coronary Artery Diseases in Egypt

Genetic factors contribute to the pathogenesis of coronary artery disease (CAD). We studied 100 patients with CAD and 50 healthy individuals to assess the association of endothelial nitric oxide (eNOS) polymorphism (Glu298Asp) and angiotensinogen polymorphisms (M235T) and CAD in an Egyptian population. Serum nitric oxide (NO) and angiotensin I levels were also measured. The frequency of Glu298Asp and M235T polymorphisms were higher in the CAD group compared with controls. The mean level of NO was significantly lower (P < .05) while angiotensin I was significantly higher (P < .05) in patients CAD than in controls. The frequency of eNOS TT allele of M235T variant was significantly higher in patients with CAD (20% vs 6%). The frequency of angiotensinogen (AGT) TT and T allele in patients with CAD was significantly higher (P < .05) than in controls (22% vs 6%and 47% vs23%, respectively). Homozygosity for Glu298Asp and M235T polymorphisms may predispose to CAD.

Linkage of angiotensinogen gene polymorphisms with hypertension in a sibling study of Hong Kong Chinese

The angiotensinogen gene has been linked with human essential hypertension in whites but the relationship in Asian populations has been less consistent. This study aimed to examine genetic associations between hypertension and the M235T, T174M, and G-217A polymorphisms of the angiotensinogen gene in Chinese siblings. We studied members of 126 families with a hypertensive proband, including 434 siblings, of which 178 were hypertensive. Parental history of hypertension was recorded. The M235T, T174M, and G-217A polymorphisms were examined using a microarray method, validated by sequencing. The transmission disequilibrium test was applied to identify whether the genetic polymorphism loci were related to hypertension. Haplotype analysis of the combined polymorphisms was applied using the TRANSMIT program. Linkage study was conducted by applying the affected pedigree member method. A significant overtransmission was observed for the T235 allele at the M235T polymorphism and hypertension (chi2 = 4.41, P = 0.036) but not for the T174M and G-217A polymorphisms. The haplotype analysis showed a significant association with the haplotypes of paired markers (T174 and T235) with chi2 value of 8.131 (P = 0.004; global test chi2 = 9.131, P = 0.028). Linkage between M235T and hypertension was detected (T = -2.25, P = 0.019), and a tendency for linkage with central obesity-related hypertension was found for the M235T and T174M polymorphisms (P = 0.0087 and P = 0.01). The M235T and T174M variants, especially the T235 allele, contribute to an increased risk of hypertension in these Chinese patients.

The Angiotensinogen AGT p.M235T Gene Polymorphism May Be Responsible for the Development of Severe Anaphylactic Reactions to Insect Venom Allergens

Background: Insect venom allergy (IVA) is present in 1–3% of the population. A group of patients with high specific IgE do not react to stings. In contrast, a proportion of patients with IVA have low specific IgE levels. These findings indicate that factors other than specific IgE may also be involved in IVA. Dysfunction of the renin-angiotensin system (RAS) has been described as a potential factor in IVA. The objective of this study was to determine the prevalence of angiotensin AGT p.M235T and angiotensin-converting enzyme ACE I/D, I/I, D/D gene polymorphisms in patients with IVA and to relate the presence of these gene variants to the course of IVA and the safety of treatment. Methods: A total of 107 patients with IVA and 113 controls were studied. AGT p.M235T and ACE (ID, I/I, D/D) gene polymorphisms were examined, and angiotensin I levels were measured by immunoassay. Results: The frequency of the AGT MM M235T variant was significantly higher in IVA patients (29.9%) than in controls (17%, p = 0.02). The presence of the MM M235T genotype increased the risk of grade IV reactions (odds ratio = 2.5 and 95% confidence interval 1.04–6.08). There were no differences in the prevalence of the ACE I/D polymorphism and angiotensin I levels between control groups and patients with different grades of anaphylactic reactions or patients with side effects of venom immunotherapy. Conclusion: The AGT M235T MM variant may be responsible for severe anaphylactic reactions to insect venom allergens in some patients.

Angiotensinogen T174M and M235T Variants and Hypertension in the Hani and Yi Minority Groups of China

A case-control study of 538 individuals investigated whether the angiotensinogen gene (AGT) might be implicated in the pathogenesis of essential hypertension in the Hani and Yi populations of China. Genotypes for two diallelic DNA polymorphisms observed at amino acid residues 174 (T174M) and 235 (M235T) within the coding sequence were determined. M235T and T174M genotyping with PCR-RFLP was performed in 267 normotensive subjects and 271 hypertensive subjects. No significant difference was found between normotensives and hypertensives in genotype distribution and allele frequency for either M235T or T174M in the Hani or the Yi populations (P > 0.05). Relative to carriers of the 235T/235T and 174T/174T combination, the others had a significantly elevated risk of hypertension (OR = 1.62, 95% CI 1.02-2.59; P = 0.043) in the Hani population. The AGT M235T and T174M variants in combination may play a role in the genetic predisposition to develop essential hypertension in the Hani minority of China.

The M235T Polymorphism in the AGT Gene and CHD Risk: Evidence of a Hardy-Weinberg Equilibrium Violation and Publication Bias in a Meta-Analysis

BackgroundThe M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD).Methodology/Principal FindingsA case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias.Conclusions/SignificanceThe pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases.