Publications by authors named "Armando Reyes-Engel"

19 Publications

  • Page 1 of 1

MAOB rs3027452 Modifies Mood Improvement After Tryptophan Supplementation.

Int J Gen Med 2021 6;14:1751-1756. Epub 2021 May 6.

Department of Surgery, Biochemistry and Immunology School of Medicine, University of Malaga, Malaga, Spain.

Purpose: Tryptophan is the only precursor of serotonin, the hormone which helps regulate key human functions such as appetite, memory, mood, and sexual behavior. Connections have been identified between serotonin system dysfunction and the molecular etiology and treatment of mood disorders in a wide range of studies. Proposals have been put forward to co-administer tryptophan supplementation together with serotonin reuptake inhibitors in major depression patients, and also to exploit the sub-therapeutic depressive status in healthy populations. The reported responses, however, have been very dissimilar and this uneven effect may largely be explained by interindividual genetic differences.

Materials And Methods: We studied mood change in 138 healthy subjects using both Goldberg's General Health Questionnaire and the Profile of Mood States Questionnaire to determine the effects of a daily supplementation of 1g of tryptophan or placebo. Buccal DNA samples were provided and (rs1800532), (rs3788862 and rs979605), (rs3027452), and (rs6269 and rs4680) variants were genotyped.

Results: rs3027452 was equally associated with tryptophan supplementation efficacy in the depression subscales of both questionnaires (ΔT-Score.D; ΔT-Score.TMD and ΔPOMS.D p-values <0.01).

Conclusion: Here we provide evidence that tryptophan supplementation has an uneven effect on mood improvement in the general population.
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http://dx.doi.org/10.2147/IJGM.S305443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110250PMC
May 2021

Monoamino oxidase alleles correlate with the presence of essential hypertension among hypogonadic patients.

Mol Genet Genomic Med 2020 01 19;8(1):e1040. Epub 2019 Nov 19.

Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Málaga, Spain.

Background: Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side-effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO-inhibitory treatments in patients with psychiatric disease.

Methods: In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml.

Results: MAOB rs3027452-A allele carriers were significantly over-represented among hypertensive (HT) patients (25.49%) in comparison to either the non-HT patients (10%, OR = 3.079 CI [1.364-6.952], p = .005, Chi-square test) and the control population series of nonobese nor hypogonadic males (also 10%, p = .003 Chi-square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p = .005). When quantitative analysis was performed, hypertensive patients harboring rs3027452-A allele showed higher systolic blood pressure values (p = .038, Mann-Whitney U-test) as well as an increased Systolic-Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452-A and rs3027452-G respectively, p-value .019, Mann-Whitney U-test). Previous studies on MAOB revealed that rs3027452-A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation.

Conclusion: If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension.
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http://dx.doi.org/10.1002/mgg3.1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978270PMC
January 2020

Effects of SHBG rs1799941 Polymorphism on Free Testosterone Levels and Hypogonadism Risk in Young Non-Diabetic Obese Males.

J Clin Med 2019 Jul 31;8(8). Epub 2019 Jul 31.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

Introduction: Obesity has been associated with increased risk of presenting hypogonadism. Free testosterone (FT) is the fraction of testosterone that carries out the biological function of testosterone, and is determined from total testosterone (TT) and sex-hormone binding globulin (SHBG) levels. We aimed to study the SHBG polymorphism rs1799941 in a cohort of young non-diabetic obese males to unravel the possible implication of this polymorphism in obesity-related hypogonadism.

Methodology: 212 young (<45 years) non-diabetic obese (BMI ≥ 30 kg/m) males participated in this study. Subjects were classified according to TT and FT levels in: Eugonadal ( 55, TT > 3.5 ng/mL and FT ≥ 70 pg/mL; EuG), normal FT hypogonadism ( 40, TT < 3.5 and FT ≥ 70 pg/mL; normal FT HG) and hypogonadism ( 117, TT < 3.5 ng/mL and TL < 70 pg/mL; HG). The SHBG rs1799941 polymorphism (GG/GA/AA) was analyzed using the Taqman Open Array (Applied biosystem).

Results: The rs1799941 frequencies were different among the groups. Higher proportion of the allele (A) was found in HG, compared to EuG and normal FT HG. Among the genotypes, the rare homozygous (AA) were found in the normal FT HG group and higher levels of serum SHBG and lower of FT were observed. The presence of the allele A was related (according to lineal regression models) to an increased of SHBG levels ((GA) β = 3.28; (AA) β = 12.45) and a decreased of FT levels ((GA) β = -9.19; (AA) β = -18.52). The presence of the allele (A) increased the risk of presenting HG compared to normal FT HG (OR = 2.54).

Conclusions: The rs1799941 of the SHBG gene can partially determine the presence of obesity-related hypogonadism in young non-diabetic males and whether these subjects have normal FT HG.
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http://dx.doi.org/10.3390/jcm8081136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722847PMC
July 2019

Dysmorphic contribution of neurotransmitter and neuroendocrine system polymorphisms to subtherapeutic mood states.

Brain Behav 2019 02 17;9(2):e01140. Epub 2019 Jan 17.

Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Malaga, Spain.

Objective: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state.

Materials And Methods: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self-report measures of mood states using POMS and GHQ-28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR).

Results: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = -0.168, p-value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ-28 depression scores among males (beta = -0.196, p-value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores.

Conclusion: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism.
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http://dx.doi.org/10.1002/brb3.1140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379594PMC
February 2019

Sperm count and motility are quantitatively affected by functional polymorphisms of HTR2A, MAOA and SLC18A.

Reprod Biomed Online 2018 May 2;36(5):560-567. Epub 2018 Feb 2.

Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Malaga, 29071, Malaga, Spain. Electronic address:

Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction.
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http://dx.doi.org/10.1016/j.rbmo.2018.01.007DOI Listing
May 2018

Fetal alpha 5-reductase Val89Leu mutation is associated with late miscarriage.

Reprod Biomed Online 2017 Jun 21;34(6):653-658. Epub 2017 Mar 21.

Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Malaga, 29071 Malaga, Spain. Electronic address:

The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy.
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http://dx.doi.org/10.1016/j.rbmo.2017.03.011DOI Listing
June 2017

Differential behavior of serum and red blood cell folate during a treatment with levofolinic acid. Gender differences.

Clin Lab 2014 ;60(9):1579-84

Background: Folates are essential nutrients that maintain nucleotide synthesis and methylation reactions. Folate levels depend essentially on the diet. In the present work, the changes in the folate-homocysteine (Hcy) metabolic axis were studied in response to treatment with levofolinic acid.

Methods: 49 college students (23 men and 26 women) underwent a treatment voluntarily with 5 mg/day levofolinic acid for one month. Serum and red blood cell folate, vitamin B12, and Hcy levels were determined on days 2, 5, 10, and 30 during treatment and 30 days after completion of treatment.

Results: Serum folate and Hcy levels showed a plateau beginning on day 10, while red blood cell folate increased towards treatment completion. Gender differences were found in basal levels of Hcy, these differences remaining until the 10th day of treatment and reappearing 30 days after the treatment was finished. Between gender differences in treatment evolution were found only in percentage changes in red blood cell folate in women and men at day 30 of treatment.

Conclusions: There is a compartmentalization of folates in the body that presents a plateau in serum and an erythrocyte reservoir. Folate metabolism presents differential features between genders. The greater physiological need for folate in women of childbearing age could be the determining factor in this difference.
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http://dx.doi.org/10.7754/clin.lab.2013.130914DOI Listing
October 2014

Genetic polymorphisms of serotonin transporter and receptor 1A could influence success during embryo implantation and maintenance of pregnancy.

Fertil Steril 2013 Jun 13;99(7):2009-16.e2. Epub 2013 Mar 13.

Instituto de Fertilidad Clínica Rincón, IVF Laboratory and I+D+i Unit, Malaga, Spain.

Objective: To explore whether serotonin-related gene polymorphisms influence clinical outcomes of IVF treatment in recipients using donated oocytes.

Design: Nested case-control study.

Setting: University-affiliated infertility clinic.

Patient(s): Two hundred forty-five women undergoing IVF treatment with donated oocytes.

Intervention(s): None.

Main Outcome Measure(s): Genotype and haplotype analysis of the serotonin transporter-linked polymorphic region (5-HTTLPR), rs1800532, rs6295, rs6313, and rs3813929, between recipients grouped according to the results of the oocyte donation for IVF treatment.

Result(s): No differences were found between genotype distribution of the tryptophan hydroxylase 1, serotonin receptor 2A, and serotonin receptor 2C polymorphisms. Recipients carrying the LL genotype for 5-HTTLPR had lower clinical pregnancy rates (PR) and higher biochemical pregnancy loss (BPL) events. Lower implantation rates were found in CC carriers for 5-HT1A.rs6295 who also presented higher BPL rates. A lower incidence of clinical pregnancy was observed for LC haplotypes, corresponding to an increase in BPL rates.

Conclusion(s): A strong association was found between early pregnancy loss and recipients carrying the 5-HTTLPR and rs6295 genetic variants. Identifying biological processes involving serotonin and embryo implantation may help to understand the dynamics of the maternal-embryo dialogue.
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http://dx.doi.org/10.1016/j.fertnstert.2013.02.026DOI Listing
June 2013

Changes in CDKN2D , TP53, and miR125a expression: potential role in the evaluation of human amniotic fluid-derived mesenchymal stromal cell fitness.

Genes Cells 2012 Aug 2;17(8):673-87. Epub 2012 Jul 2.

Department of Immunology, Carlos Haya Regional University Hospital, Malaga 29010, Spain.

Human amniotic fluid-derived mesenchymal stromal cells (hAMSC) have become one of the main cell populations used in regenerative medicine and for the study of various clinical disorders. These cells have a great capacity for proliferation and differentiation and do not form teratomas when transplanted into animal models, and their stemness seems to be between embryonic cells and adult mesenchymal cells. Before their use in cell therapy, they must be cultured and expanded in vitro, but the effect this process has on their fitness, a determining factor for the success or failure of cell therapy, is unknown. We undertook a follow-up of gene and microRNAs (miRNAs) expression using microarray of hAMSC for the first 15 passages. Significant changes were noted in the expression of various mRNAs and miRNAs, particularly down-regulation of TP53, increased expression of hsa-miR-125a and up-regulation of CDKN2D . The variations in TP53 and hsa-miR-125a may act as an indicator of the stemness of the hAMSC, whereas CDKN2D may indicate the begging of early senescence process in a p53-independent mechanism. The genes described in this study will help evaluate the fitness of hAMSC, thus guaranteeing their biological quality for use in regenerative medicine.
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http://dx.doi.org/10.1111/j.1365-2443.2012.01623.xDOI Listing
August 2012

Evaluation of a low cost cryopreservation system on the biology of human amniotic fluid-derived mesenchymal stromal cells.

Cryobiology 2012 Jun 20;64(3):160-6. Epub 2012 Jan 20.

Department of Immunology, Carlos Haya Regional University Hospital, Malaga 29010, Spain.

Background: Human amniotic-derived mesenchymal stromal cells (hAMSC) are a novel population of multipotent stem cells that have been shown to have great potential for use in regenerative medicine. However, procedures to store and preserve hAMSC for future clinical applications have not been explored extensively.

Methods: In this study, we analyzed the influence of cryopreservation, using a protocol based on freezing rate of 1 °C/min, 10% dimethyl sulfoxide as cryoprotectant and a thawing rate >100 °C/min, on hAMSC morphology, proliferation rates, viability, cell cycle, karyotype, immune phenotype and multilineage differentiation potential.

Results: This study found that this cryopreservation protocol does not affect the biological properties of hAMSC.

Discussion: This shows that this protocol is a viable system for banking hAMSC, with the associated advantages that has a low cost in terms of expense, time and personnel involved and is easy to implement.
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http://dx.doi.org/10.1016/j.cryobiol.2012.01.003DOI Listing
June 2012

Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder.

BMC Med Genet 2011 May 26;12:75. Epub 2011 May 26.

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Málaga, Spain.

Background: Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD.

Methods: A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated.

Results: Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161).

Conclusions: Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.
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http://dx.doi.org/10.1186/1471-2350-12-75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129576PMC
May 2011

Lifespan of human amniotic fluid-derived multipotent mesenchymal stromal cells.

Cytotherapy 2011 May 5;13(5):572-81. Epub 2011 Jan 5.

Immunology Service, Regional University Hospital Carlos Haya, Malaga, Spain.

Background Aims: Human multipotent mesenchymal stromal cells (hMSC) have become one of the main interests in regenerative medicine because of their ability to differentiate into different lineages. Human amniotic fluid is reported to contain MSC (hAMSC) and therefore may be a useful source of cells for clinical applications. However, our understanding of the behavior of these cells in indefinite in vitro culture conditions is very limited.

Methods: We systematically evaluated and characterized, throughout their whole lifespan, the expansion potential, chromosomal stability, surface and intracellular phenotype and differentiation potential of fibroblastoid hAMSC (F-type hAMSC).

Results: Nine F-type hAMSC cultures could be expanded in in vitro culture conditions for 223.25 ± 24.44 days (mean ± SD), during which time 28.96 ± 1.5 passages were made giving rise to 54.95 ± 3.17 population doublings (PD) and an estimated number of accumulated cells of between 1.0 × 10(22) and 9.7 × 10(23), with no visible alterations in the chromosome during their lifespan. All the cultures showed unchanged percentages of strongly positive expressions of the surface markers CD29, CD44, CD73, CD90, CD95, CD105 and HLA-ABC, as well as the embryonic intracellular markers Nanog and Sox2, during their lifespan, whereas the expression of the embryonic surface markers SSEA3, SSEA4, TRA-1-60 and TRA-1-81 fell until it disappeared with progression of the culture. These cells retained their differentiation capacities to adipogenic, chondrogenic and osteogenic lineages throughout their lifespan.

Conclusions: F-type hAMSC exhibit reproducible biologic characteristics, confirming that these cells are ideal candidates for use in regenerative medicine.
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http://dx.doi.org/10.3109/14653249.2010.547466DOI Listing
May 2011

Human genetic selection on the MTHFR 677C>T polymorphism.

BMC Med Genet 2008 Nov 28;9:104. Epub 2008 Nov 28.

Department of Biochemistry and Molecular Biology, University of Malaga, Malaga 29071, Spain.

Background: The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA).

Methods: A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman probes. A section of our population (n = 276) born in 1980-1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period.

Results: An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980-1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98.

Conclusion: Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.
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http://dx.doi.org/10.1186/1471-2350-9-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610030PMC
November 2008

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss.

Hum Reprod 2007 Dec 25;22(12):3249-54. Epub 2007 Oct 25.

Department of Biochemistry, Hospital Costa del Sol, Marbella, Spain.

BACKGROUND Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, including spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS 342 samples of fetal tissues, selected from SA occurring during the 1980s, 230 samples from subjects born in the 1980s and a third set of samples from 204 subjects born in the 1950s, were genotyped by using TaqMan probes. RESULTS The wild CC genotype of the C677T polymorphism showed a strong protective effect against abortion (0.03 in SA versus 0.47 in 1950s and 0.43 in 1980s) (P < 0.0001). Genotypes of three mutations in the combinations of polymorphisms for C677T and A1298C showed a very low frequency in the living population; however, the three mutations genotypes were over expressed in the SA group (0.02 in 1950s; 0.03 in 1980s and 0.17 in SA) (P < 0.0001). Samples with four mutations (n = 2) were found only in the SA group. CONCLUSIONS There is no linkage disequilibrium between C667T and A1298C polymorphisms. Fetal viability is directly related to the CC genotype as a protector while the three and four mutation MTHFR genotypes appear to be a determinant on fetal non-viability and SA.
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http://dx.doi.org/10.1093/humrep/dem337DOI Listing
December 2007

[Mild hyperhomocysteinemia, low folate levels and prognosis of acute coronary syndrome without ST elevation].

Med Clin (Barc) 2007 Sep;129(8):281-6

Servicio de Cardiología, Hospital Universitario Virgen de la Victoria, Málaga, España.

Background And Objective: The influence of homocysteine metabolism on the prognosis of acute coronary syndrome without ST elevation is controversial.

Patients And Method: Prospective study of 109 patients admitted because of acute coronary syndrome without ST elevation. Basal plasmatic levels of homocysteine and folates were obtained. Clinical features and survival data on follow-up were registered.

Results: Both two years-free-of-events and total survival were lower in patients with low folate levels (36.5% vs 72.5%, p = 0.02; 48% vs 94%, p < .001). Patients with high homocysteine levels had lower two years-free-of-events survival (57.4% vs 89.1%, p < .01); but no difference in the total survival was observed (86.3% vs 97.3%, p = 0.11). The multivariate analysis showed that low folate levels was an independent predictor of mortality (odds ratio [OR] = 8.33; 95% confidence interval [CI], 1.88-33.33; p < 0.01), and moderate high homocysteine was an independent predictor of events on follow-up (OR = 4.34; 95% CI, 1.47-12.50; p < 0.01).

Conclusions: Patients with high homocysteine or low folate levels have a poor prognosis compared with those with normal levels. On the other hand, low folate levels and moderate hyiperhomocysteinemia are independent predictors of bad prognosis in the follow-up.
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http://dx.doi.org/10.1157/13109705DOI Listing
September 2007

Influence of 677 C-->T polymorphism of methylenetetrahydrofolate reductase on medium-term prognosis after acute coronary syndromes.

Tex Heart Inst J 2007 ;34(2):142-7

Cardiology Department, Hospital Universitario Virgen de la Victoria, School of Medicine, University of Málaga, 29010 Málaga, Spain.

Various common genotypes of the polymorphism 677 C-->T of the methylenetetrahydrofolate reductase enzyme result in lower activity of the enzyme and in a subsequent increase in homocysteine levels. Many studies have analyzed the connection between this polymorphism and the beginning of coronary artery disease. However, conclusions have been controversial, and evidence of a connection between this polymorphism and the prognosis of coronary artery disease has been poorly evaluated. This prospective study evaluated the prognostic relevance of genotype TT in a cohort of 155 patients admitted to our hospital for treatment of an acute coronary syndrome accompanied by evidence of coronary atherosclerosis on coronary angiography. We found that patients with the genotype TT had higher homocysteine levels than did patients with the CT and CC genotypes (15.72 +/- 6.92 micromol/L vs 12.11 +/- 5.40 micromol/L and 12.01 +/- 4.25 micromol/L, P=0.01). After a mean follow-up of 13.4 +/- 7.4 months, we observed similar rates of major adverse cardiovascular events (CC, 29%; CT, 22%; and TT, 25%) and cardiovascular death (CC, 11%; CT, 7%; and TT, 8%). No difference in cardiovascular-death-free survival (log-rank analysis, 0.81; P=0.66) or event-free survival (log-rank analysis, 0.76; P=0.68) was found. The presence of genotype TT was not an independent predictor of prognosis after multivariate analysis by means of the Cox regression survival model. In conclusion, the presence of the TT genotype of the 677 C-->T polymorphism of the methylenetetrahydrofolate reductase enzyme was not related to prognosis in patients admitted to the hospital after an acute coronary syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894727PMC
August 2007

Influence of gender and genetic variability on plasma angiotensin peptides.

J Renin Angiotensin Aldosterone Syst 2006 Jun;7(2):92-7

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Málaga, Malaga, 29080, Spain.

Introduction: We analysed the influence of three polymorphisms of the renin-angiotensin system (RAS) (I/D from angiotensin-converting enzyme [ACE], M235T from angiotensinogen gene [ATG] and A1166C from AT1 receptors) on plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)].

Materials And Methods: The study population consisted of a homogeneous group of 93 healthy subjects (43 men and 50 women, mean age: 20.67+/-2.75 years). The mean blood pressure (BP) was 126+/-7/76+/-5 (SD) mmHg and the mean body mass index (BMI) was 22.4+/-2.5 kg/m2. Angiotensin peptides were separated by high performance liquid chromatography (HPLC) and quantified by radio immuno assay (RIA). Genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme analysis.

Results: Mean peptide levels were 92.48+/-102.12 pg/ml for Ang I, 22.35+/-10 pg/ml for Ang II, and 31.65+/-27.46 pg/ml for Ang-(1-7). Men had significantly higher levels of Ang-(1-7) (37.76+/-36.47 pg/ml) than women (26.04+/-13.98 pg/ml) (p<0.05). Among genotypes of each polymorphism, men with the T allele showed higher Ang- (1-7) levels compared with those with the MM genotype (p<0.05). Genotype analysis in women showed that higher Ang I levels were related with the DD genotype. When both genders were compared according to genotype, higher values of Ang-(1-7) levels and its molar ratios were found in men, and there was significantly greater Ang I levels in DD genotypes in women than men (136.72+/-112.43 vs . 65.36+/-46.83 pg/mL).

Conclusions: Significant correlations were found between Ang I and Ang II as well as between Ang II and Ang-(1-7) in the different study group distributions. No correlation was found between levels of Ang I and Ang-(1-7). Certain genotypes exert an influence on angiotensin peptide plasma levels which can only be seen when the population is divided according to gender.
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http://dx.doi.org/10.3317/jraas.2006.015DOI Listing
June 2006

Influence of high homocysteine and low folate plasmatic levels in medium-term prognosis after acute coronary syndromes.

Int J Cardiol 2007 May 4;118(2):220-6. Epub 2006 Oct 4.

Cardiology Department, Hospital Universitario Virgen de la Victoria, School of Medicine, University of Malaga, Spain.

Background: To test prospectively whether moderate hyperhomocysteinemia and low folate levels could have an influence in the prognosis of 155 patients who presented with an acute coronary syndrome.

Methods And Results: After a mean follow-up of 13.4+/-7.4 months, patients with low folate levels had higher percentages of cardiovascular death and major cardiovascular events (33% vs. 5%, p<0.001; 44% vs. 22%, p<0.05) and patients with high homocysteine levels had a higher percentage of major cardiovascular events (31% vs. 14.5%, p<0.03). Kaplan-Meier survival estimates analysis showed that patients with low folate levels had a significantly higher probability of cardiovascular death and lower free-of-events survival (log rank statistic: 21.17, p<0.001 and 6.59, p=0.01). Patients with high homocysteine levels had a lower free-of-events survival (log rank statistic: 4.95, p=0.02). Different survival multivariate analysis model showed that the presence of low folate levels was an independent predictor of cardiovascular death (hazard ratio 8.85, 95% confidence interval 2.6-29.3, p<0.000) and high homocysteine levels was identified as independent predictor of major cardiovascular events (hazard ratio 2.34, 95% confidence interval 1.07-5.12, p<0.03).

Conclusions: Low folate levels and moderate hyperhomocysteinemia were identified as independent predictors of cardiovascular events in the follow-up.
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http://dx.doi.org/10.1016/j.ijcard.2006.06.053DOI Listing
May 2007

Differential transcriptional expresión of the polymorphic myxovirus resistance protein A in response to interferon-alpha treatment.

Pharmacogenetics 2004 Mar;14(3):189-93

Immunology Service Carlos Haya Hospital, Málaga and Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Málaga, Málaga, Spain.

Levels of myxovirus resistance protein A (MxA) mRNA were studied for a single nucleotide polymorphism in the promoter region at nucleotide position -88 of the gene to identify individual-specific responses to interferon (IFN)-alpha2 that might predict responsiveness to IFN-alpha therapy. We quantified MxA expression by reverse transcription and real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMC) in vitro, induced by IFN-alpha2, from 22 healthy donors, in relation with G/T polymorphism located in the promoter of the MxA. MxA mRNA was significantly upregulated in all subjects (mean of 53-fold) in response to IFN-alpha2 in vitro (P < 0.01). Comparison of the inducibility of MxA mRNA expression in relation with G/T polymorphism showed a 4.26-fold higher induction of MxA mRNA levels in PBMC from carriers of the mutant allele (GT or TT) than homozygotes with the wild-type allele (GG) (P < 0.001). We propose that expression of the IFN-inducible MxA is affected by a single nucleotide polymorphism in the MxA promoter which can identify an individual response to IFN-alpha2.
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http://dx.doi.org/10.1097/00008571-200403000-00007DOI Listing
March 2004