Dataset Information

Analysis of polymorphisms in genes (AGT, MTHFR, GPIIIa, and GSTP1) associated with hypertension, thrombophilia and oxidative stress in Mestizo and Amerindian populations of Mexico.

ABSTRACT: Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1)} polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using chi square tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups.

SUBMITTER: Juarez-Velazquez R

PROVIDER: S-EPMC3833604 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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Analysis of polymorphisms in genes (AGT, MTHFR, GPIIIa, and GSTP1) associated with hypertension, thrombophilia and oxidative stress in Mestizo and Amerindian populations of México.

Juárez-Velázquez Rocio R Canto Patricia P Canto-Cetina Thelma T Rangel-Villalobos Hector H Rosas-Vargas Haydee H Rodríguez Maricela M Canizales-Quinteros Samuel S Velázquez Wong Ana Claudia AC Ordoñez-Razo Rosa María RM Vilchis-Dorantes Guadalupe G Coral-Vázquez Ramón Mauricio RM

Disease markers 20100101 5

Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1)} polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele ...[more]

PMID: 20592457

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Project description:CYP3A5 metabolizes endogenous substrates and ~30% of prescription drugs. The CYP3A5 gene contains an active CYP3A5*1 allele, and a non-functional version, the CYP3A5*3 (rs776746), with consequences for drug therapeutic responses and side effects. Both CYP3A5*1 and *3 have been associated with hypertension. The frequency of CYP3A5*3 varies between populations of different ancestries, with Europeans having the highest allele frequency (> 90%). Given the importance of CYP3A5*3 in drug response and hypertension development, the aim of the present study was to evaluate the frequency of this polymorphism and its association with hypertension in vulnerable indigenous populations in Mexico. A total of 372 subjects were recruited from eight ethnic groups in Northwest Mexico. Systolic (SBP), diastolic (DBP), and median (MBP) blood pressures as well as body mass index (BMI) were measured. Ancestry was evaluated through STR analysis, and the CYP3A5*1/*3 polymorphisms were identified using real-time PCR with TaqMan® probes. Higher frequencies of CYP3A5*1 and *3 were observed in groups with higher (>90%) and lower (<90%) Amerindian ancestry, respectively. The CYP3A5*3/*3 genotype was more frequent in indigenous women with higher SBP and DBP values. On the other hand, the *1 allele showed a protective effect against both high SBP (OR, 0.38; 95% CI, 0.17-0.83, p = 0.001) and DBP (OR 0.38, 95% CI 0.18-0.81, p = 0.007) in women. This association remained significant after adjusting for BMI and age for diastolic (OR, 0.38; 95% CI, 0.17-0.84, p = 0.011) and systolic BP (OR, 0.33; 95% CI, 0.15-0.76, p = 0.005) BP levels in women. Thus, the frequency of CYP3A5*3 varies between groups and seems to depend on ancestry, and CYP3A5*1 decreases the risk of hypertension in Mexican indigenous women. This population analysis of CYP3A5*1/*3 has profound implications not only for the susceptibility to diseases, such as hypertension, but also for safer drug administration regimens, assuring better therapeutic responses and fewer side effects.

Project description:Due to their continuing geographic isolation, the Amerindian populations of the Brazilian Amazon present a different genetic profile when compared to other continental populations. Few studies have investigated genetic variants present in these populations, especially in the context of next-generation sequencing. Knowledge of the molecular profile of a population is one of the bases for inferences about human evolutionary history, in addition, it has the ability to assist in the validation of molecular biomarkers of susceptibility to complex and rare diseases, and in the improvement of specific precision medicine protocols applied to these populations and to populations with high Amerindian ancestry, such as Brazilians. DNA polymerases play essential roles in DNA replication, repair, recombination, or damage repair, and their influence on various clinical phenotypes has been demonstrated in the specialized literature. Thus, the aim of this study is to characterize the molecular profile of POLA1, POLE, POLG, POLQ, and REV3L genes in Amerindian populations from the Brazilian Amazon, comparing these findings with genomic data from five continental populations described in the gnomAD database, and with data from the Brazilian population described in ABraOM. We performed the whole exome sequencing (WES) of 63 Indigenous individuals. Our study described for the first time the allele frequency of 45 variants already described in the other continental populations, but never before described in the investigated Amerindian populations. Our results also describe eight unique variants of the investigated Amerindians populations, with predictions of moderate, modifier and high clinical impact. Our findings demonstrate the unique genetic profile of the Indigenous population of the Brazilian Amazon, reinforcing the need for further studies on these populations, and may contribute to the creation of public policies that optimize not only the quality of life of this population, but also of the Brazilian population.

Project description:BACKGROUND:Since the 1990s, there have been a lot of research on single-nucleotide polymorphism (SNP) and different diseases, including many studies on 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and essential hypertension (EH). Nevertheless, their conclusions were controversial. So far, six previous meta-analyses discussed the internal relationship between the MTHFR polymorphism and EH, respectively. However, they did not evaluate the credibility of the positive associations. To build on previous meta-analyses, we updated the literature by including previously included papers as well as nine new articles, improved the inclusion criteria by also considering the quality of the papers, and applied new statistical techniques to assess the observed associations. OBJECTIVES:This study aims to explore the degree of risk correlation between two MTHFR polymorphisms and EH. METHODS:PubMed, EMBASE, the Cochrane Library, CNKI, and Wan Fang electronic databases were searched to identify relevant studies. We evaluated the relation between the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and EH by calculating the odds ratios (OR) as well as 95% confidence intervals (CI). Here we used subgroup analysis, sensitivity analysis, cumulative meta-analysis, assessment of publication bias, meta-regression meta, False-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and Venice criterion. RESULTS:Overall, harboring the variant of MTHFR C677T was associated with an increased risk of EH in the overall populations, East Asians, Southeast Asians, South Asians, Caucasians/Europeans, and Africans. After the sensitivity analysis, positive results were found only in the overall population (TT vs. CC: OR = 1.14, 95% CI: 1.00-1.30, P h = 0.032, I 2 = 39.8%; TT + TC vs. CC: OR = 1.15, 95% CI: 1.01-1.29, P h = 0.040, I 2 = 38.1%; T vs. C: OR = 1.14, 95% CI: 1.04-1.25, P h = 0.005, I 2 = 50.2%) and Asian population (TC vs. CC: OR = 1.14, 95% CI: 1.01-1.28, P h = 0.265, I 2 = 16.8%; TT + TC vs. CC: OR = 1.17, 95% CI: 1.04-1.30, P h = 0.105, I 2 = 32.9%; T vs. C: OR = 1.10, 95% CI: 1.02-1.19, P h = 0.018, I 2 = 48.6%). However, after further statistical assessment by FPRP, BFDP, and Venice criteria, the positive associations reported here could be deemed to be false-positives and present only weak evidence for a causal relationship. In addition, when we performed pooled analysis and sensitivity analysis on MTHFR A1298C; all the results were negative. CONCLUSION:The positive relationships between MTHFR C677T and A1298C polymorphisms with the susceptibility to present with hypertension were not robust enough to withstand statistical interrogation by FPRP, BFDP, and Venice criteria. Therefore, these SNPs are probably not important in EH etiology.

Project description:BACKGROUND: Hyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes--methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-β-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18-60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length-polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [β(SE β), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [β(SE β), -0.56(0.58) and -0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was -1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6-28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34-0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level. CONCLUSIONS: Gene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population.

Dataset Information

Analysis of polymorphisms in genes (AGT, MTHFR, GPIIIa, and GSTP1) associated with hypertension, thrombophilia and oxidative stress in Mestizo and Amerindian populations of Mexico.

Publications

Analysis of polymorphisms in genes (AGT, MTHFR, GPIIIa, and GSTP1) associated with hypertension, thrombophilia and oxidative stress in Mestizo and Amerindian populations of México.

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