Novel Point Mutations and A8027G Polymorphism in Mitochondrial-DNA-Encoded Cytochrome c Oxidase II Gene in Mexican Patients with Probable Alzheimer Disease.

Mitochondrial dysfunction has been thought to contribute to Alzheimer disease (AD) pathogenesis through the accumulation of mitochondrial DNA mutations and net production of reactive oxygen species (ROS). Mitochondrial cytochrome c-oxidase plays a key role in the regulation of aerobic production of energy and is composed of 13 subunits. The 3 largest subunits (I, II, and III) forming the catalytic core are encoded by mitochondrial DNA. The aim of this work was to look for mutations in mitochondrial cytochrome c-oxidase gene II (MTCO II) in blood samples from probable AD Mexican patients. MTCO II gene was sequenced in 33 patients with diagnosis of probable AD. Four patients (12%) harbored the A8027G polymorphism and three of them were early onset (EO) AD cases with familial history of the disease. In addition, other four patients with EOAD had only one of the following point mutations: A8003C, T8082C, C8201T, or G7603A. Neither of the point mutations found in this work has been described previously for AD patients, and the A8027G polymorphism has been described previously; however, it hasn't been related to AD. We will need further investigation to demonstrate the role of the point mutations of mitochondrial DNA in the pathogenesis of AD.

Allele frequency distribution of CYP2C9 2 and CYP2C9 3 polymorphisms in six Mexican populations.

Allele frequency differences of functional CYP2C9 polymorphisms are responsible for some of the variation in drug response observed in human populations. The most relevant CYP2C9 functional variants are CYP2C9*2 (rs1799853) and CYP2C9 3 (rs1057910). These polymorphisms show variation in allele frequencies among different population groups. The present study aimed to analyze these polymorphisms in 947 Mexican-Mestizo from Mexico City and 483 individuals from five indigenous Mexican populations: Nahua, Teenek, Tarahumara, Purepecha and Huichol. The CYP2C9*2 allele frequencies in the Mestizo, Nahua and Teenek populations were 0.051, 0.007 and 0.005, respectively. As for CYP2C9 3, the allelic frequencies in the Mestizo, Nahua and Teenek populations were 0.04, 0.005 and 0.005, respectively. The CYP2C9 2 and CYP2C9 3 alleles were not observed in the Tarahumara, Purepecha and Huichol populations. These findings are in agreement with previous studies reporting very low allele frequencies for these polymorphisms in American Indigenous populations.

MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis.

MTHFR polymorphisms C677T and A1298C are associated with reduced MTHFR enzyme activity and hyperhomocysteinemia, which has been associated with osteoporosis. The A163G polymorphism in osteoprotegerin (OPG) has been studied in osteoporosis with controversial results. The objective of the present study was to investigate the association(s) among MTHFR C677T, MTHFR A1298C, and OPG A163G polymorphisms in Mexican patients with rheumatoid arthritis and osteoporosis. The femoral neck and lumbar spine bone mineral densities (BMDs) were measured in 71 RA patients, and genotyping for the three polymorphisms was performed via restriction fragment length polymorphism analysis. Patients with osteoporosis/osteopenia exhibited statistically significant differences in the genotype frequencies of MTHFR C677T as well as an association with femoral neck BMD; TT homozygotes had lower BMDs than patients with the CT genotype, and both of these groups had lower BMDs than patients with the CC genotype. The associations of the MTHFR C677T polymorphism with osteoporosis/osteopenia and femoral neck BMD suggest that these polymorphisms confer a risk of developing osteoporosis in patients with rheumatoid arthritis, a risk that may be reduced with folate and B complex supplementation.

[Improvements in the diagnosis of dystrophinopathies: what have we learnt in these last 20 years?]. / Mejoras en el diagnostico de distrofinopatias: que hemos aprendido despues de 20 anos?

INTRODUCTION. Dystrophinopathies are X-linked genetic disorders caused by mutations in the DMD gene. Genetic tests are of utmost importance for management and genetic counseling of these diseases. However, the complexity of the DMD gene is a challenge for diagnosis. AIM. To describe recent advances in the diagnosis of dystrophinopathies, after 20 years since the firsts molecular assays for genetic screening for these diseases. DEVELOPMENT. Currently, a variety of strategies such as automated mutation detection, cell-based methods and high throughput haplotyping have been developed to facilitate diagnosis of dystrophinopathies, carrier detection, prenatal and preimplantation diagnosis. CONCLUSION. New technologies have improved early detection and optimal management of dystrophinopathies and have established the basis for future molecular medicine. The most significant advances in dystrophinopathy diagnosis are reviewed herein.

Mejoras en el diagnóstico de distrofinopatías: ¿qué hemos aprendido después de 20 años? / Improvements in the diagnosis of dystrophinopathies: what have we learnt in these last 20 years?

Introducción. Las distrofinopatías son trastornos genéticos ligados al cromosoma X causados por mutaciones en el gen DMD. Las pruebas genéticas son de suma importancia para la gestión y el asesoramiento genético de estas enfermedades. Sin embargo, la complejidad del gen DMD es un desafío para el diagnóstico. Objetivo. Describir los avances recientes en el diagnóstico de distrofinopatías, después de 20 años de los primeros ensayos moleculares para la detección genética de estas enfermedades. Desarrollo. En la actualidad, se han desarrollado una variedad de estrategias, como la detección de mutaciones automatizada, los métodos basados en células y la haplotipificación de alto rendimiento, para facilitar el diagnóstico de distrofinopatías, la detección de portadoras, el diagnóstico prenatal y preimplantacional. Conclusión. Las nuevas tecnologías han mejorado la detección temprana y el manejo óptimo de distrofinopatías, y han establecido la base para la medicina molecular en el futuro. Los avances más importantes en el diagnóstico de distrofinopatías se revisan en este documento (AU)

Introduction. Dystrophinopathies are X-linked genetic disorders caused by mutations in the DMD gene. Genetic tests are of utmost importance for management and genetic counseling of these diseases. However, the complexity of the DMD gene is a challenge for diagnosis. Aim. To describe recent advances in the diagnosis of dystrophinopathies, after 20 years since the firsts molecular assays for genetic screening for these diseases. Development. Currently, a variety of strategies such as automated mutation detection, cell-based methods and high throughput haplotyping have been developed to facilitate diagnosis of dystrophinopathies, carrier detection, prenatal and preimplantation diagnosis. Conclusion. New technologies have improved early detection and optimal management of dystrophinopathies and have established the basis for future molecular medicine. The most significant advances in dystrophinopathy diagnosis are reviewed herein. (AU)

FCGR3A V(176) polymorphism for systemic lupus erythematosus susceptibility in Mexican population.

The objective of this study is to establish whether there is an association between the presence of FCGR3A V(176) polymorphism with SLE or its manifestations. We included 94 patients according to the 1982 ACR criteria as well as 98 controls matched by age and gender. The 11 ACR diagnostic criteria were analyzed on the clinical files. The polymorphism FCGR3A V(176) was determined by direct sequencing. There was not an association between the polymorphism FCGR3A V(176) with SLE or its main manifestations. The allelic frequency for F(176) was: 0.80 and 0.72 in cases and controls, respectively (P = 0.09, IC95%: 0.42-1.07); and the genotypic frequency in the group of cases was: 0.65 for homozygotes F(176)/F(176), 0.30 for heterozygotes and 0.05 for the homozygotes V(176)/V(176), while for the control group it was 0.53, 0.39 and 0.08, respectively. The polymorphism FCGR3A V(176) is not associated with SLE or any of its manifestations in patients with SLE from the West of Mexico.

Renin gene haplotype diversity and linkage disequilibrium in two Mexican and one German population samples.

INTRODUCTION: Renin is the main rate-limiting enzyme in the renin-angiotensin-aldosterone system. Its gene, REN, is a candidate crucial factor in essential hypertension and cardiovascular disease. The aim of this study was to evaluate allele and haplotype distributions of REN polymorphisms, and to estimate normalised linkage disequilibrium (D') in Mexican and German populations. MATERIALS AND METHODS: Four groups were studied for the REN single nucleotide polymorphisms (SNPs) 1205C>T, 1303G>A, and 10607G>A, in population samples of Mexican Mestizo (n = 86), Mexican Huichol (n = 49), German (n = 39), and individuals with hypertension diagnosis (n = 66). Polymorphisms were detected by PCR-RFLP. Genotype, allele and haplotype frequencies were estimated. RESULTS: SNP 1205C>T and 10607G>A allele and genotype distribution showed inter-group differences. The 1205T and 10607A allele showed a significance difference in hypertensive population. Haplotype analysis also showed some inter-group differences, especially in 1205C-1303G-10607G, 1205C-1303G-10607A and 1205T-1303G-10607G haplotypes. The segregation analysis disclosed complete linkage disequilibrium between 1205 and 1303 loci. CONCLUSION: These results provide an example of genetic diversity in related populations and illustrate the convenience of increasing the number of loci in associative studies between diseases and candidate genes.

Association between polymorphisms of the androgen and vitamin D receptor genes with prostate cancer risk in a Mexican population.

INTRODUCTION: Prostate cancer (PCa) is a worldwide health issue, because of its high incidence and mortality. Its etiology is complex and includes certain risk factors such as age, hormonal status, ethnic origin and family history of PCa. Genetic predisposition is proposed as a major risk factor and there are several controversial reports on the association of PCa and gene polymorphism such as the receptors of the androgen receptor (AR) and the vitamin D (VDR). Objective. To evaluate the CAG triplet repeats in the first exon of the AR and polymorphisms in the restriction site Taql in the VDR in Mexicans with PCa. MATERIAL AND METHODS: A total of 68 Mexicans with histopathological diagnosis of PCa and 48 healthy Mexican with normal prostate-specific antigen and rectal exam where included. 10ml of peripheral blood were extracted to isolate DNA and the polymorphisms were evaluated with specific primers for the AR and VDR. RESULTS: The allelic and genetic distributions of the AR and VDR polymorphisms were consistent with the Hardy-Weinberg equilibrium, and there were no statistical differences between the PCa patients and controls (p > 0.05). However, there was a statistical difference between the number of CAG repeats in younger patients with PCa compared to controls (p = 0.045) but when the young patient group was compared versus the elder group there was not stadistically difference (p = 0.085), but the results showed a tendency towards less repetitions of CAG in elder patients. Concerning the VDR, when we analyzed the patients with PCa and a bad pathological prognosis they had a less frequent genotype of TT (p = 0.03). CONCLUSIONS: Our results suggest an association between the VDR and AR gene polymorphisms, and the histopathological score and age at diagnosis in Mexican patients with PCa, respectively. However, it is important to confirm these results in a larger scale study.

Association between polymorphisms of the androgen and vitamin D receptor genes with prostate cancer risk in a Mexican population / Asociación entre polimorfismo de andrógenos y receptores de vitamina D con riesgo de cáncer prostático en una población mexicana

Introduction. Prostate cancer (PCa) is a worldwide health issue, because of its high incidence and mortality. Its etiology is complex and includes certain risk factors such as age, hormonal status, ethnic origin and family history of PCa. Genetic predisposition is proposed as a major risk factor and there are several controversial reports on the association of PCa and gene polymorphism such as the receptors of the androgen receptor (AR) and the vitamin D (VDR). Objective. To evaluate the CAG triplets repetitions in the first exon of the AR and polymorphisms in the restriction site Taql in the VDR in Mexicans with PCa. Material and methods. A total of 68 Mexicans with histopathological diagnosis of PCa and 48 healthy Mexican with normal prostate specific antigen and rectal exam where included. 10ml of peripheral blood were extracted to isolate DNA and the polymorphisms were evaluated with specific primers for the AR and VDR. Results. The allelic and genetic distributions of the AR and VDR polymorphisms were consistent with the Hardy-Weinberg equilibrium, and there were no statistical differences between the PCa patients and controls (p > 0.05). However, there was a statistical difference between the number of CAG repeats in younger patients with PCa compared to controls (p = 0.045) but when the young patient group was compared versus the elder group there was not stadistically difference (p = 0.085), but the results showed a tendency towards less repetitions of CAG in elder patients. Concerning the VDR, when we analyzed the patients with PCa and a bad pathological prognosis they had a less frequent genotype of TT (p = 0.03). Conclusions. Our results suggest an association between the VDR and AR gene polymorphisms, and the hystopathological score and age at diagnosis in Mexican patients with PCa, respectively. However, it is important to confirm these results in a larger scale study.

Introducción. El cáncer de próstata (PCa) es un problema de salud mundial, tanto por su elevada incidencia como mortalidad. Su etiología es compleja e incluye factores de riesgo reconocidos como la edad, estado hormonal, origen étnico y antecedentes familiares de PCa. El fondo genético es un factor de riesgo y existen reportes controversiales de la asociación de PCa y polimorfismos en los genes como son los receptores de vitamina D (VDR) y el de andrógenos (AR). Objetivo. Evaluar las repeticiones de tripletes de CAG en el primer exon del AR y polimorfismos en el sitio de restricción Taql en el VDR en mexicanos con PCa. Material y métodos. Se incluyeron 68 mexicanos con diagnóstico histopatológico de PCa y 48 mexicanos con niveles normales de antígeno prostático y tacto rectal normal. Se les extrajo 10 mL de sangre periférica para aislar DNA y mediante olígos específicos se evaluaron los polimorfismos mencionados. Resultados. La distribución alélica y genotípica de los polimorfismos en el AR y VDR fueron consistentes con el equilibrio de Hardy-Weinberg, y no mostraron diferencias significativas entre los casos y controles (p > 0.05). Sin embargo, el número de repeticiones de CAG en el AR fueron estadísticamente diferentes en pacientes jóvenes con PCa comparados con los controles (p = 0.045), cuando se comparó el grupo de pacientes de jóvenes contra aquellos mayores de 60 años no se encontró diferencia estadísticamente significativa (p - 0.085); sin embargo, se observó una tendencia de un número menor de repetidos CAG en pacientes mayores con PCa. Por otra parte, al comparar VDR en los pacientes con PCa de mal pronóstico por el patrón histológico tenían menor frecuencia de genotipos TT (p - 0.03). Conclusiones. Nuestros resultados sugieren una asociación entre los polimorfismos de los genes del VDR y AR, y el patrón histológico y la edad al diagnóstico en pacientes mexicanos con PCa, respectivamente. Sin embargo, es necesario confirmar estos resultados en un estudio con mayor número de pacientes.

Association of beta-defensin 1 single nucleotide polymorphisms with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic multifactorial allergic disease with unclear etiology. The antimicrobial human beta-defensin 1 is chemotactic for dendritic cells, which are important regulators of allergic immune responses. In an attempt to identify useful markers that could predict susceptibility to AD, we investigated single nucleotide polymorphisms (SNPs) of the beta-defensin 1 gene (DEFB1) with potential functional consequences. METHODS: Four SNPs of the DEFB1 gene were genotyped either by real-time polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphisms in 59 patients with AD and 151 controls from the Mexican population. Correlation analyses were carried out between genetic, environmental and clinical variables in AD patients. RESULTS: The genotypes associated with susceptibility to AD and no other allergy were 692 GG (OR = 3.21, 95% CI 1.37-7.34) and 1654 AA (OR = 17.37, 95% CI 1.62-860.83). The allele 668 C is a risk factor for AD (OR = 2.23, 95% CI 1.22-4.01) and the allele A in site 1836 correlates with earlier age at onset (Spearman's rho = 0.232; p = 0.03). The prolonged duration of breastfeeding correlates with earlier age at onset as well as with the severity of AD. CONCLUSIONS: The DEFB1 gene is probably involved in the incidence and development of AD, but additional functional studies will be necessary to understand the biological role of these SNPs.

Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamic-pituitary-adrenal axis activation in mice.

Hypothalamic-pituitary-adrenal (HPA) axis activation-induced immunosuppression is associated with increased concentration of circulating corticosterone and impaired cellular immune responses. The purpose of this study was to investigate the effect of chronic HPA axis activation on the cellular immune response, Th1/Th2 cytokine profile, and concentration of corticosterone. Mice were divided into two groups: a control group comprised of healthy, untreated mice that received no stress, and an HPA axis-activated group that received stress through electric shock (ES). The delayed-type hypersensitivity reaction to dinitrofluorobenzene, splenocyte proliferative response to mitogens Concanavalin A and lipopolysaccharide, Th1 and Th2 profile, and TGF-beta1 production were measured in plasma and in culture supernatants. The corticosterone concentration was also measured in plasma. In the ES group, elevated plasma corticosterone concentration was associated with immunosuppression and a significant decrease in plasma concentrations of IL-2, IL-4, and TGF-beta1. In vitro IL-2 production in response to Con A was significantly lower in the ES group than in the control group. TGF-beta1 production in nonstimulated and stimulated cultures in response to either mitogen was significantly lower in the ES group than in the control group. Plasma concentrations of IFN-gamma and IL-10 did not differ significantly between groups. The concentrations of IFN-gamma, IL-4, and IL-10 in the supernatants of splenocytes stimulated with either mitogen and IL-4 production by nonstimulated cells were significantly higher in the ES group than in the control group. These results suggest that corticosterone mediates the immunosuppression induced by HPA axis activation, and induces dysregulation of the Th1/Th2 cytokine profile.

Effect of Ginkgo biloba extract EGb 761 on the nonspecific and humoral immune responses in a hypothalamic-pituitary-adrenal axis activation model.

We evaluated the immune response of healthy control and stressed Wistar rats submitted to hypothalamic-pituitary-adrenal (HPA) axis activation. Rats were treated with Ginkgo biloba extract (EGb 761) orally (100 mg/kg per day for 7 days). EGb 761 stimulated the digestion index of peritoneal and alveolar macrophages (PM and AM) of stressed rats. Likewise, the cellular immune response measured using the delayed-type hypersensitivity response to sheep red blood cells (SRBC) and the humoral immune response (measured through an anti-SRBC response), were also restored in stressed rats. Thus, this G. biloba extract possesses immunostimulatory activity in addition to its broad spectrum of pharmacological effects.

Linkage disequilibrium between IDUA kpnI-VNTR Haplotype in mexican patients with MPS-I

Background. The MPS-I is an autosomal recessive disorder caused by mutations in the IDUA gene that induce to a deficiency of glycosidase Ó-L-iduronidase that is required for degradation of heparan and dermatan sulfate. This disorder expresses a wide range of clinical symptoms. Methods. Kpnl (k) and VNTR (V) intragenic polymorphisms at the IDUA gene were studied in mestizo and Huichol Indian Mexican populations as well in 13 MPS-I patients. Data from Australian normal and MPS-I (2-4) individuals were also studied. Results. Genotypes for IDUA K and V sites in Mexicans were in agreement with hardy-Weinberg expectations, except for stie K in Huichols, Individually, allele frequency distributions were different (p< 0.05) in the two normal groups for the V site. K-V haplotype frequency distributions (HFDs) in these two normal groups were also different as compared with normal Australians. In Mexican MPS-I patients, HFD was different (p <0.05) with or MPS-I Australians. This can be taken as evidence of linkage disequilibrium between K-V polymorphism and MPS-I gene mutation(s) at the IDUA region. A similar finding was reported. However, disequilibrium in Mexicans was determined by haplotypes different from those in Australia. In Mexican MPS-I patients, haplotype K2-V1 is increased and K1-V3 decreades with respect to the Mexican mestizo (p < 0.05), while in Australians, MPS-I patients had an increase of haplotypes K2-V2 and K1-V2 with respect to expected frequency. Conclusions. The similar HFD between Mexican and australian MPS-I patients suggests a common genetic origin, that MPS-I mutations were introduced to Mexico by Spaniards, and that such mutations predate the dispersion between Mexican and Australian Caucasian ancestors. The differences in disequilibrium are explained rather by genetic drift