AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study

We investigated the association between angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) gene polymorphisms and exercise training responses of resting and exercise blood pressure (BP). BP at rest and during submaximal (50 watts) and maximal exercise tests was measured before and after 20 wk of endurance training in 476 sedentary normotensive Caucasian subjects from 99 families. AGT M235T and ACE insertion/deletion polymorphisms were typed with PCR-based methods. Men carrying the AGT MM and MT genotypes showed 3. 7 +/- 0.6 and 3.2 +/- 0.5 (SE) mmHg reductions, respectively, in diastolic BP at 50 watts (DBP(50)), whereas, in the TT homozygotes, the decrease was 0.4 +/- 1.0 mmHg (P = 0.016 for trend, adjusted for age, body mass index, and baseline DBP(50)). Men with the ACE DD genotype showed a slightly greater decrease in DBP(50) (4.4 +/- 0.6 mmHg) than the II and ID genotypes (2.8 +/- 0.7 and 2.4 +/- 0.5 mmHg, respectively, P = 0.050). Furthermore, a significant (P = 0.022) interaction effect between the AGT and ACE genes was noted for DBP(50); the AGT TT homozygotes carrying the ACE D allele showed no response to training. Men with the AGT TT genotype had greater (P = 0.007) diastolic BP (DBP) response to acute maximal exercise at baseline. However, the difference disappeared after the training period. No associations were found in women. These data suggest that, in men, the genetic variation in the AGT locus modifies the responsiveness of submaximal exercise DBP to endurance training, and interactions between the AGT and ACE loci can alter this response.     

Adipose Angiotensinogen Secretion,Blood Pressure,and AGT M235T Polymorphism in Obese Patients

Objective: To investigate AGT secretion in cultured adipocytes from obese patients and its relationship with obesity‐related phenotypes, blood pressure, and the M235T polymorphism in the AGT gene. Research Methods and Procedures: Measurements, including anthropometry, body composition (DXA), and blood pressure, were performed in 61 overweight or obese women (BMI: 28 to 68 kg/m²). A subcutaneous abdominal adipose tissue biopsy was used for adipocyte size determination and quantification of AGT secretion in the medium of cultured adipocytes. AGT M235T genotype was determined using polymerase chain reaction‐restriction fragment length polymorphism. Results: Adipose secretion of the AGT protein (range, 140 to 2575 ng/10⁶ cells/24 h) was not significantly correlated with BMI, body fat, or blood pressure and did not vary according to the M235T polymorphism in the AGT gene. However, the AGT M235T polymorphism was associated with adipocyte size (111.6 ± 2.8, 108.8 ± 1.9, 118.2 ± 2.6 μm in MM, MT, and TT genotypes, respectively; p < 0.01) after adjustment for age and fat mass. An association between the AGT M235T polymorphism and adipocyte size (p < 0.02 adjusted for sex, age, and BMI) was found in another independent sample of 106 obese subjects (sex ratio, M/F 16/90; BMI, 29 to 70 kg/m²). Discussion: In cultured adipocytes from obese subjects, AGT secretion was not associated with body fat phenotypes, blood pressure, or fat cell size. However, results from two independent studies suggest an association between the AGT M235T polymorphism and adipocyte size.     

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.     

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.     

Angiotensinogen gene M235T variant and pre-eclampsia in Romanian pregnant women

Background. Association between the human angiotensinogen gene and essential hypertension has been confirmed in recent studies. Pre-eclampsia is a complication of pregnancy characterised by increased vascular resistance, high blood pressure, proteinuria and oedema, that appears in the second and third trimester of pregnancy. The aim of our study was the analysis of M235T mutation in the gene encoding angiotensinogen in Romanian women with different forms of hypertension during pregnancy. Methods. Fourteen women with obstetric complications were tested for M235T angiotensinogen gene mutation. Indications for testing were: severe or mild pre-eclampsia and pre-eclampsia associated with chronic hypertension. We also tested for control 6 healthy women. The M235T angiotensinogen gene mutation was analysed by polymerase chain reaction followed by enzymatic digestion with Tth 111I restriction endonuclease enzyme and agarose gel electrophoresis of the products. Results. Eleven (78.57%) of the 14 women with complications of pregnancy had M235T mutation: 9 (64.28%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 2(14.28%) were found to be homozygous carriers. In the group of women with normal pregnancy, 3 (50%) of the 6 women had M235T mutation: 2 (33.33%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 1 (16.66%) was found to be homozygous carrier. Conclusions. Our study shows that the M235T variant in the gene encoding angiotensinogen could be a risk factor in mild and severe pre-eclampsia.     

Essential arterial hypertension and polymorphism of angiotensinogen M235T gene

Several candidate genes, chosen from the renin‐ angiotensin system, were examined for their association with essential hypertension. The genes of the renin‐ angiotensin system (RAS) are good candidates for such an approach because this system is well known to be involved in the control of blood pressure. One of these candidate genes is the gene encoding for angiotensinogen (the most important gene of the RAS associated with essential hypertension in the most population, is the gene for angiotensin‐converting enzyme‐ ACE). One DNA polymorphism within exon 2‐ with threonine instead of methionine at position 235 (M235T) was found to be significantly associated with hypertension. The objective of this study is the analysis of M235T polymorphism in angiotensinogen gene in Romanian patients with essential hypertension as well as controls. We examined 38 patients with essential hypertension and 21 normotensive patients. In order to identify the M235T angioteninogen variant, we used the following methods: DNA extraction, PCR amplification and enzymatic digestion of the PCR product using Tth IIII restriction endonuclease enzyme. In the study groups, the M235T variant (Met?Thr in aminoacid position 235) was found more frequently in hypertensive patients (81,57%), than in control subjects (66,66%). We identified 52,63% M235T heterozygotes in the hypertensive group compared with 47,61% in the control group, and 28,94% T235T homozygotes in the hypertensive group compared with 19,04% in the control group. The results of our study suggest an association of the M235T polymorphism in the gene encoding angiotensinogen with essential hypertension     

Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester,Minnesota

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.     

Polymorphism of angiotensinogen gene M235T in myocardial infarction and brain infarction: a meta-analysis

The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI) and brain infarction (BI), but the results remain inconclusive. This meta-analysis was designed to clarify these controversies. Electronic databases were systematically searched before February 2013. A total of 38 studies with 17304 subjects met our inclusion criteria. In East Asian group, significant association was found between AGT M235T polymorphism and risk of MI (for dominant model: OR = 1.79; 95% CI = 1.04–3.06; for recessive model OR = 2.01; 95% CI = 1.21–3.36; for additive model OR = 1.79; 95% CI = 1.14–2.86) as well as BI (for dominant model: OR = 1.66; 95% CI = 1.22–2.27; for recessive model OR = 1.78, 95% CI = 1.29–2.46; for additive model: OR = 1.64, 95% CI = 1.34–2.00), while the M235T polymorphism did not impact the risk of MI in total population and other ethnicity. In the subgroup analyses by gender and age, there was lack of evidence for the association. This meta-analysis suggested an association between the M235T polymorphism and MI as well as BI in East Asian population. Further studies with larger numbers of worldwide participants are needed to understand the genetic basis of MI and BI.     

Role of missense mutation (M235T) in the angiotensinogen gene in development of cerebral ischemia

Possible correlation of M/T polymorphism of angiotensinogen gene with risk of ischemic stroke and basic risk factors of cerebral pathology (levels of arterial pressure and blood cholesterol; presence of diabetes mellitus, coronary heart disease, or myocardial infarction in anamnesis; and stenosis of major cerebral arteries) was studied. It was shown that M/T polymorphic variants of angiotensinogen gene were factors determining neither clinical variant of cerebral ischemia development (acute ischemic stroke or chronic brain ischemia) nor formation of main risk factors of stroke.     

Angiotensin converting enzyme I/D,angiotensinogen M235T and AT1-R A/C1166 gene polymorphisms in patients with acromegaly

Acromegaly is associated with increased morbidity and mortality related to cardiovascular disease. Hypertension is one of the most common cardiovascular risk factors in acromegalic patients. The aim of this study was to investigate association between the frequencies of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT1-R) A/C1166 gene polymorphisms and some clinical parameters of acromegalic patients. Total of 33 acromegalic patients and 63 controls were enrolled to study. We determined the ACE I/D, AGT M235T and AT1-R A/C1166 gene polymorphisms. Serum insulin, glucose, triglyceride, HDL-cholesterol, LDL-cholesterol, growth hormone and Insulin-like growth factor I (IGF-I) levels of subjects were analyzed. The frequencies of ACE and M235T AGT genotype were not significantly different between control and patients. The distribution of AT1R A/C1166 genotypes was significantly different between patients and control subjects (P = 0.016). None of the three ACE genotypes, DD, ID and II displayed significant difference in acromegalic patients. A significant difference in systolic blood pressure and the serum IGF-I levels among the three AGT genotype, MM, MT and TT genotypes was found in patient group. Individuals with MT genotypes had significantly higher serum IGF-I levels and systolic blood pressure than MM and TT genotype subjects, P < 0.05. In addition, serum triglyceride and HDL levels differed significantly between MM and MT genotypes, P < 0.05. However, systolic blood pressure of patients with CC genotypes was found to be significantly higher than AA genotypes individuals in acromegaly group, P < 0.05. It can be said that the angiotensinojen MT and AT1R CC1166 genotype carriers may have more risk than other genotypes in the development of hypertension in acromegaly.     

Body Fat,Resting and Exercise Blood Pressure and the Angiotensinogen M235T Polymorphism: The Heritage Family Study

RANKINEN, T., JACQUES GAGNON, LOUIS PÉRUSSE, TREVA RICE, ARTHUR s. LEON, JAMES s. SKINNER, JACK H. WILMORE, D. C. RAO, AND CLAUDE BOUCHARD. Body fat, resting and exercise blood pressure and the angiotensinogen M235T polymorphism: the Heritage family study. Obes Res. Objective: The association of resting and exercise blood pressure (BP) and fat mass with the angiotensinogen (AGT) M235T polymorphism was investigated in 522 sedentary Caucasian subjects from 99 families. Research Methods and Procedures: Resting BP was measured on two separate days, three times each day, and the mean of six valid measurements was used. Exercise BP was measured during a cycle ergometer test at a constant power output (50 W). Body composition was derived from underwater weighing and the AGT M235T polymorphism was typed with a polymerase chain reaction-based method. Results: Neither resting nor exercise BP was associated with the AGT genotypes. In mothers, the homozygotes for the T allele showed 8. 8 kg and 7. 1 kg greater (p = 0. 017) age-adjusted body fat mass (FM) than the MM homozygotes and heterozygotes, respectively. Sixty-nine percent of all TT homozygotes were found in the highest FM tertile, whereas only 16% of the MM homozygotes fell in the same tertile (p = 0. 008). Moreover, a significant interaction was seen between FM and T-allele carrier status in women with regard to resting diastolic BP (p = 0. 002). Among women with a FM≥24 kg, carriers of the T allele showed a 6. 3 mmHg higher diastolic blood pressure (DBP) than non-carriers whereas no difference was found in women with a FM less than 24 kg. A similar trend toward an interaction term was evident with resting systolic blood pressure (p = 0. 011) and exercise DBP (p = 0. 012). Body fat was not associated with the AGT polymorphism in fathers or in offspring. Discussion: These data suggest that the AGT M235T polymorphism is associated with body fatness in women, and that the relationship between DBP and AGT M235T polymorphism is dependent on FM in middle-aged sedentary normotensive women.     

Diapause induction in Ephestia cautella: An interaction between genotype and crowding

Larval diapause induction in Ephestia cautella (Walker) (Lepidoptera: Pyralidae) is a function of the interaction between genotype and larval crowding. A diapause stock in which 79% of the larvae diapaused under crowded conditions and 40% diapaused under uncrowded conditions was maintained by selection. Outbreeding of adults from this diapause stock to those from a non-diapause stock resulted in 36% diapause under crowded conditions and 6% diapause under uncrowded conditions. The rate of termination of larval diapause is inheritable and temperature dependent. These data seem to explain the seasonal trends in percentage larval diapause among E. cautella infesting citrus pulp during storage.Larval diapause was induced in groups of larvae by crowding in mass cultures and in single larvae by rearing on a small amount of fresh diet or on a larger amount of fresh diet containing residual diet from crowded cultures. The diapause-inducing effects of this residual diet could be removed by extraction with lipid solvents. Some activity was demonstrated when the extract was dried onto fresh diet.

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Resume L'induction de la diapause larvaire d'Ephestia cautella (Walker) dépend du génotype et de la densité larvaire.Des croisements à l'intérieur de la souche diapausante donnent 79% de diapause aux fortes densités larvaires et 40% aux faibles densités. Les croisements des adultes de cette souche avec ceux de la souche non-diapausante donnent 36% de diapause aux fortes densités et 6% aux faibles densités. La fréquence de fin de diapause est héréditaire et dépend de la température. Ces résultats peuvent expliquer les variations saisonnières du taux de diapause E. cautella dans la pulpe de citron stockée.La diapause larvaire a été induite chez des groupes de chenilles par surpeuplement dans des élevages standards, et chez des chenilles isolées par élevage sur une quantité limitée d'aliments frais ou sur une quantité abondante d'aliments frais contenant des résidus alimentaires provenent d'élevages surpeuplés. Les effets inducteurs de ces résidus alimentaires disparaissent après extraction avec les solvants de lipides. Une certaine action est observée par de l'extraint sec sur de l'aliment frais.

     

The angiotensinogen gene M235T polymorphism and acute myocardial infarction risk: a meta-analysis of 22 studies

Angiotensinogen, one of the most important proteins in the renin–angiotensin system, plays a key role in the progress of coronary heart disease and myocardial infarction (MI). Many studies have investigated the association between angiotensinogen gene M235T polymorphism and MI risk, but the results were inconsistent. We performed a meta-analysis of 22 studies on M235T polymorphism and MI risk published before November 2012. This meta-analysis included a total of 4,606 MI cases and 4,918 controls. Overall, the per-allele odds ratio (OR) of the 235T variant for total MI risk was 1.04 (95 % CI 0.92–1.17). When a recessive model was evaluated, the OR was 1.06 (95 % CI 0.96–1.17) and under a dominant model, the OR was 0.96 (95 % CI 0.82–1.11). Under pairwise comparisons, non-significant associations were found between M235T polymorphism and MI risk (MT vs. MM, OR, 0.96, 95 % CI 0.87–1.06; TT vs. MM, OR, 1.03, 95 % CI 0.83–1.28). Subgroup analyses in the different ethnic groups and different control sources were performed and no significant association was found also. Based on the available evidence, no association between M235T polymorphism and MI risk was observed, even in the sub-analysis concerning different races and control sources. The direction of further research should focus not only on the simple relationship of M235T polymorphism and MI risk, but also on gene–gene and gene-environment interaction.     

Females with paired occurrence of cancers in the UADT and genital region have a higher frequency of either Glutathione S-transferase M1/T1 null genotype

Upper Aero digestive Tract (UADT) is the commonest site for the development of second cancer in females after primary cervical cancer. Glutathione S-transferase (GSTM1 and / or T1) null genotype modulates the risk of developing UADT cancer (primary as well as second cancer). The aim of this study was to evaluate the difference in GST null genotype frequencies in females with paired cancers in the UADT and genital region as compared to females with paired cancers in the UADT and non-genital region. Forty-nine females with a cancer in the UADT and another cancer (at all sites-genital and non-genital) were identified from a database of patients with multiple primary neoplasms and were analyzed for the GSTM1 and T1 genotype in addition to known factors such as age, tobacco habits, alcohol habits and family history of cancer. Frequencies of GSTM1 null, GSTT1 null, and either GSTM1/T1 null were higher in females with paired occurrence of cancer in the UADT and genital site (54%, 33% and 75% respectively) in comparison to females with paired occurrence of cancer in the UADT and non-genital sites (22%, 6% and 24% respectively). The significantly higher inherited frequency of either GSTM1/T1 null genotype in females with a paired occurrence of cancers in UADT and genital region (p = 0.01), suggests that these females are more susceptible to damage by carcinogens as compared to females who have UADT cancers in association with cancers at non-genital sites.     

Sex-specific effects of <Emphasis Type="Italic">ACE</Emphasis> I/D and <Emphasis Type="Italic">AGT</Emphasis>-M235T on pulse pressure: the HyperGEN Study

Evidence shows that an elevated pulse pressure (PP) may lead to an increased risk of cardiovascular morbidity and mortality. There is also evidence that PP is a sexually dimorphic trait, and that genetic factors influence inter-individual variation in PP. The aim of this project was to assess the genotype-by-sex interaction on PP in a sample of mostly hypertensive African American and White participants using candidate genes involved in the renin–angiotensin–aldosterone system. Subjects were participants in the HyperGEN Study, including men (43%) and women (57%) over the age of 55 years (mean age = 65). Candidate gene polymorphisms used were ACE insertion/deletion (1,789 subjects genotyped) and AGT-M235T (1,800 subjects genotyped). We employed linear regression methods to assess the genotype-by-sex interaction. For ACE, genotype-by-sex interaction on PP was detected (P = 0.04): the “D/D” genotype predicted a 2.2 mmHg higher pulse pressure among women, but a 1.2 mmHg lower PP among men, compared to those with an “I” allele, after adjusting for age, weight, height, ethnicity, and antihypertension medication use. A similar interaction was found for systolic blood pressure. The genotype-by-sex interaction was consistent across ethnicity. The interaction was evident among those on antihypertensive medications (P = 0.05), but not among those not taking such medications (P = 0.55). In our analysis of AGT, no evidence of a genotype-by-sex interaction affecting PP, SBP, or DBP was detected. This evidence for a genotype-by-sex interaction helps our understanding of the complex genetic underpinnings of blood pressure phenotypes.