Carlos Galaviz-Hernández

CYP2D6 gene polymorphisms and predicted phenotypes in eight indigenous groups from northwestern Mexico

AIM Polymorphisms in CYP2D6 impact the interindividual and interethnic variability of drug efficiency; therefore, we determined the CYP2D6 allele distribution in eight Amerindian groups from northwestern Mexico and compared them with the frequencies in Mexican Mestizos. MATERIALS & METHODS A total of 508 Amerindians were studied. Genotyping of CYP2D6*5 and multiplication alleles was performed by long-range PCR, while CYP2D6*2, *3, *4, *6, *10, *17, *29, *35, *41 and copy number were evaluated by real-time PCR. RESULTS The most frequent alleles were CYP2D6*2 (0.05-0.28), CYP2D6*4 (0.003-0.21) and multiplications (0.043-0.107). CYP2D6*5, *6, * 10 and *41 were not observed in the majority of Amerindians, and CYP2D6*3, *17, *35 and *29 were not detected. The poor metabolizer genotype ( *4/*5) was lower (0.2%) in Amerindians than in Mestizos (5%); conversely, the ultrarapid metabolizer genotype was higher (12.6%) in indigenous groups than in Mestizos (7%). CONCLUSION Our data show a lower frequency of CYP2D6 inactive alleles and a higher frequency of duplication/multiplication of CYP2D6 active alleles in indigenous populations that in Mestizos. Original submitted 14 August 2013; Revision submitted 7 October 2013.

Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico

We previously documented the lowest frequency of CYP2C9*2 in Mexican indigenous Tepehuanos followed by Mestizos and Mexican-Americans populations, suggesting a negative correlation between the CYP2C9*2 frequency and the degree of Asian ancestry in indigenous Americans. We determined the influence of ethnic admixture components on the CYP2C9 allele distribution in 505 Amerindian from eight indigenous populations through genotyping CYP2C9*2, *3 and *6 alleles by real-time PCR and molecular evaluation of ancestry. The frequencies for CYP2C9*2 were 0.026 in Seris and 0.057 in Mayos, being higher than in Asians (P<0.001). CYP2C9*3 was found in Tarahumaras (0.104), Mayos (0.091), Tepehuanos (0.075), Guarijíos (0.067), Huicholes (0.033) and Coras (0.037), with East Asians having lower frequencies than the former three groups (P<0.001). CYP2C9*6 was not found. The frequency of CYP2C9*2 was lower in Amerindians than in European populations, and higher than their Asian ancestors. The presence of this allele in ethnic groups in Mexico can be explained by European admixture.

Comparative expression profiles for KiSS-1 and REN genes in preeclamptic and healthy placental tissues

OBJECTIVE The aim of the present work was to look at differences in the placental tissue expression of KiSS-1 and REN genes from preeclamptic and healthy pregnant women, that could account for a possible synergistic function for both genes in the pathogenesis of preeclampsia. STUDY DESIGN This case-control study involved 27 preeclamptic women and 27 normoevolutive pregnant women. cDNA was obtained from placental tissue to carry out qPCR for both KiSS-1 and REN genes in order to compare mRNA expression levels in the studied groups. Statistical analysis showed expression differences that correlate with clinical and/or biochemical variables. RESULTS Higher expression for KiSS-1 in PEE vs. control woman (p=0.001) was observed, whereas no difference was observed for REN expression (p=0.300) when all the subjects were included. However, REN expression was significant higher when the samples were stratified according to preeclampsia severity. For 18 mild preeclamptic patients the p-value was p=0.001 compared to their controls, while for the remaining nine with severe preeclampsia the expression became significant (p=0.001). CONCLUSION Our results suggest that the high KiSS-1 expression seen in preeclamptic patients is in accordance with its role as an inhibitor of trophoblast invasiveness and maintained until the end of gestation. On the other hand, aggressive therapeutic management and/or severity status of patients have a direct effect on placental REN expression levels, masking the natural high expression of this gene on preeclamptic placental tissue. Therefore it was not possible to establish a real concordant expression profile for KiSS-1 and REN genes.

Polimorfismo 677CT del gen de la metilentetradihidrofolato reductasa y cardiopatias congenitas aisladas en poblacion mexicana

INTRODUCTION AND OBJECTIVES The frequency of the 677C>T mutation in the methylenetetrahydrofolate reductase gene in Mexico is one of the highest worldwide. Some studies have shown that both the homozygous state of this mutation and a high homocysteine concentration are associated with congenital heart disease. The aim of this study was to determine whether this association exists in the Mexican population. METHODS Genotypes were analyzed in 60 patients with congenital heart disease and in their mothers, and the levels of homocysteine were determined in the latter group. The genotypes were compared with those of a control group (n=62) and of their mothers. All the possible mother-child genotype combinations were also compared. RESULTS There were no significant differences in allele or genotype frequencies between the patients with congenital heart disease and the controls or their respective mothers (P>.05). Although no significant differences were observed when the homocysteine concentrations in the presence of the CC or the TT genotype were compared, a clear trend was observed (P=.0621). We found no significant differences in homocysteine concentrations in relation to folic acid intake. The study cases and controls did not differ in terms of the possible combinations of mother-child genotypes. CONCLUSIONS The frequencies obtained were consistent with those reported for Mexico. No significant differences were found between groups. Nor did we find any association between TT mutations in both the mother and child and hyperhomocysteinemia. There was no evidence of an association between any of the mother-child genotype combinations and congenital heart disease. Similar studies with larger numbers of patients are required to confirm or refute some of the trends observed in this report.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

Association of the intronic polymorphism rs12540874 A>G of the GRB10 gene with high birth weight

BACKGROUND High birth weight (HBW) is considered a key predictor of the development of chronic diseases, such as Type 2 Diabetes (T2D). Foetal growth depends on many factors, among which placental function is critical. Some genes with expression in the placenta, such as GRB10, are known to be involved in the regulation of insulin receptor pathways and the size of mouse littermates. AIM To evaluate whether the intronic polymorphism rs12540874 A>G of the GRB10 gene is associated with HBW in term newborns. STUDY DESIGN A total of 51 healthy term newborns were enrolled in a nested case-control study. The case group was defined by the presence of HBW (n=17) and the control group by newborns with normal birth weight (NBW n=34). Maternal and foetal factors influencing HBW were considered as exclusion criteria. The polymorphism was determined through real-time PCR using TaqMan technology. Categorical variables were evaluated with descriptive statistics, and multivariate logistic regression analysis was used to evaluate the association between polymorphism and HBW. RESULTS The newborns in the case group had a longer gestation period (39. 7 ± 1.0 and 38.8 ± 1.8 weeks) and higher insulin levels at birth (9.5 ± 4.0 and 5.7 ± 3.4 μU/mL) than the newborns in the control group. The multivariate regression analysis, adjusted for weeks of gestation, showed a significant association between the SNP rs12540874 A>G of the GRB10 gene with HBW (OR 4.9; CI95% 1.10-22.10 p=0.02). CONCLUSIONS Our results suggest that the SNP rs12540874 A>G, an intronic SNP of the gene GRB10, is associated with HBW.

Association of the polymorphisms 292 C>T and 1304 G>A in the SLC38A4 gene with hyperglycaemia

The SLC38A4 gene is related to system ‘A’ activity, which seems to be related to impaired gluconeogenesis. The objective of this study was to determine whether the 292 C>T and 1304 G>A polymorphisms of SLC38A4 gene are associated with hyperglycaemia in humans.

Transcriptomic Profiling of Adipose Tissue in Obese Women in Response to Acupuncture Catgut Embedding Therapy with Moxibustion

OBJECTIVE Complementary and alternative medicine, such as Traditional Chinese Medicine, represents an efficient therapeutic option for obesity control. It was previously reported that acupuncture catgut embedding therapy (ACET) with moxibustion reduces body weight and reverts insulin resistance in obese women. This study aimed to evidence changes in adipokines and gene expression in adipose tissue that could explain the effects of ACET with moxibustion. DESIGN Overweight/obese women were treated with ACET with moxibustion or sham acupuncture as control. Peripheral blood samples and fat biopsies were taken before and after intervention. Circulating adipokines (leptin, adiponectin, tumor necrosis factor alpha, and resistin) were quantified by enzyme-linked immunosorbent assay. Gene expression in adipose tissue was determined by cDNA microarray assays and assessed by quantitative reverse transcription real-time polymerase chain reaction. RESULTS ACET with moxibustion did not modify circulating adipokines levels. However, correlations with anthropometric and biochemical parameters were affected. Interestingly, transcriptional changes in adipose tissue revealed the modulation of genes participating in homeostasis control, lipid metabolism, olfactory transduction, and gamma-aminobutyric acid signaling pathway. CONCLUSIONS The effects of ACET with moxibustion on body weight and insulin resistance were associated with the regulation of biochemical events that are altered in obesity.

Influence of CYP1A1*2C on High Triglyceride Levels in Female Mexican Indigenous Tarahumaras

BACKGROUND AND AIMS High triglyceride levels are closely related to cardiovascular disease. Its development lays on age, diet, physical activity, ethnicity and genetic factors. Among the last, the CYP1A1*2C allele has an influence on the metabolism of cholesterol and other fatty acids. We undertook this study to determine the frequency of CYP1A1*2C and its association with triglyceride levels in Mexican indigenous Tarahumaras and Tepehuanos. METHODS Anthropometric and biochemical data were recorded. Genotyping of CYP1A1*2C by RT-PCR was done in 110 Tepehuano, 69 Tarahumara and 64 Mestizo. RESULTS Significant differences in age, waist diameter, BMI, creatinine, glucose, cholesterol, triglycerides, HDL and VLDL measurements were found between Tarahumaras and Tepehuanos (p <0.05). Additionally, Tarahumara women showed the highest values of waist diameter, BMI and triglycerides (p <0.05). It was found that Tarahumaras showed a significant association between high triglyceride levels and CYP1A1*2C allele (OR = 2.57; 95% CI 1.12-5.88, p = 0.024) under a recessive inheritance model. However, the Tepehuano group showed a significant protective association between normal triglyceride levels and CYP1A1*2C polymorphism (OR = 0.28; 95% CI 0.10-0.80, p = 0.015) following a dominant inheritance model. The same pattern was observed after analysis with females of both ethnicities. CONCLUSION A significant association between CYP1A1*2C and high triglyceride levels in Amerindian Tarahumaras from Chihuahua has been found; this allele was significantly associated with normal triglyceride levels in Tepehuanos from Durango, Mexico. Further studies are needed to elucidate the genetic role of CYP1A1 in cardiovascular disease susceptibility.

Vascular Dysfunction in Mother and Offspring During Preeclampsia: Contributions from Latin-American Countries

Pregnancy is a physiologically stressful condition that generates a series of functional adaptations by the cardiovascular system. The impact of pregnancy on this system persists from conception beyond birth. Recent evidence suggests that vascular changes associated with pregnancy complications, such as preeclampsia, affect the function of the maternal and offspring vascular systems, after delivery and into adult life. Since the vascular system contributes to systemic homeostasis, defective development or function of blood vessels predisposes both mother and infant to future risk for chronic disease. These alterations in later life range from fertility problems to alterations in the central nervous system or immune system, among others. It is important to note that rates of morbi-mortality due to pregnancy complications including preeclampsia, as well as cardiovascular diseases, have a higher incidence in Latin-American countries than in more developed countries. Nonetheless, there is a lack both in the amount and impact of research conducted in Latin America. An impact, although smaller, can be seen when research in vascular disorders related to problems during pregnancy is analyzed. Therefore, in this review, information about preeclampsia and endothelial dysfunction generated from research groups based in Latin-American countries will be highlighted. We relate the need, as present in many other countries in the world, for increased effective regional and international collaboration to generate new data specific to our region on this topic.