Mexican Mestizo Research Articles

Interethnic variability of pharmacogenetic biomarkers in Mexican healthy volunteers: a report from the RIBEF (Ibero-American Network of Pharmacogenetics and Pharmacogenomics).

Mexico presents a complex population diversity integrated by Mexican indigenous (MI) (7% of Mexico's population) and Mexican mestizos (MMs). This composition highlights the importance of pharmacogenetic studies in Mexican populations. The aims of this study were to analyze the reported frequencies of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in healthy volunteers from Mexican populations and to assess its interethnic variability across MI and MM populations. After a literature search in PubMed, and according to previously defined inclusion criteria, 63 pharmacogenetic studies performed in Mexican healthy volunteers up to date were selected. These reports comprised 56,292 healthy volunteers (71.58% MM). Allele frequencies in 31 pharmacogenetic biomarkers, from 121 searched, are described. Nine of these biomarkers presented variation within MM and MI groups. The frequencies of CYP2D6*3, *4, *5, *10, *17, *35 and *41 alleles in the MM group were different from those reported in the MI group. CYP2C9*2 and *3 alleles were more frequent in MM than in MI populations (χ2 test, p<0.05). CYP2C19*3 allele was not found in the MM or MI populations reported. For UGT1A1*28, only one study was found. HLA-A*31:01 and HLA-B*15:02 were present in some MM and MI populations. Poor metabolizers for CYP2D6 and CYP2C9 were more frequent in MM than in MI groups (χ2 test, p<0.05). Only 26% of the relevant pharmacogenetic biomarkers searched have been studied in Mexican healthy volunteers; therefore, further studies are warranted. The frequency variation of biomarkers in MM and MI populations could be important for the clinical implementation of pharmacogenetics in Mexico.

Distribution of genetic variants of oxidative stress metabolism genes: Paraoxonase 1 (PON1) and Glutathione S-transferase (GSTM1/GSTT1) in a population from Southeastern Mexico

Background: Paraoxonase 1 (PON1) and glutathione S-transferases (GSTs) are involved in the biotransformation of xenobiotics. Variation in the enzyme concentration and activity suggests individual differences for the degree of protection against oxidative stress.Aim: This study analysed the distribution of SNPs Q192R, L55M (PON1) and variants in GSTM1 and GSTT1 genes in a population from Southeastern Mexico.Subjects and methods: One hundred and fifty-one Mexican Mestizo healthy volunteers were included. PON1 polymorphisms were determined by Taqman allele discrimination real time-PCR, whereas GSTM1 and GSTT1 genes were determined with a multiplex PCR-based method.Results: All genotypes were in Hardy-Weinberg equilibrium, except for GSTM1. The genotypic distributions of Q192R and L55M were 22% QQ, 48% QR, 30% RR, 62% LL, 34% LM and 4% MM, respectively, whereas the allele frequencies were 0.46 (Q), 0.54 (R), 0.79 (L) and 0.21 (M). The most frequent haplotype was R/L (46.7%). It was found that 31% and 9% of the individuals had the GSTM1 and GSTT1 null genotype, respectively. The frequency of the combined null genotype GSTM1*0/GSTT1*0 was 4.64%.Conclusion: The results showed that the frequencies of polymorphisms of PON1, GSTM1 and GSTT1 in the Yucatán population differ to those observed in other ethnic groups and provide useful data for epidemiological studies.

Frequency evaluation of the CYP3A4*4 polymorphism in iranian healthy volunteers

Purpose: CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) is an important enzyme in the body. The purpose of this enzyme is to oxidize small foreign organic molecules such as drugs or toxins. The different genetic variants CYP3A4 present in individuals such as CYP3A4*4. The cytochrome P450 3A subfamily have an important role in the catabolic reactions like many of peroxidative, oxadative, and reductive biotransformation reactions of common drugs such as Carbamazepine, Hydroxylations and Nevirapine. Methods: In this study, the prevalence of CYP3A4*4 in healthy subject of Iran were analyzed. Three hundred healthy unrelated subjects were chosen. After DNA extraction, genotypes were analyzed by PCR-RFL Pand PCR-sequencing. Results: No mutation was detected for CYP3A4*4 (Ile118Val) in these individuals. This study can be a background for future studies specially pharmacogenomic investigations and association studies. In addition, this data could be help clinicians optimize therapy or recognition persons who have risk of adverse drug reactions. Conclusions: Our results show that the frequencies of the CYP3A4*4 polymorphism in Iranian population were almost similar to the other populations such as Malaysian, Indian, Taiwanese, Tepehuan Amerindians and Mestizo Mexicans. CYP3A4*4 mutation causes decrease enzyme activity in vivo because the Ile118Val mutation may affect the substrate binding and cause decrease in CYP3A4 activity. Therefore, lack of the CYP3A4*4 mutation among Iranian population renders the consumption of drugs whose metabolismis done by CYP3A4, harmless.

Frequency distribution of interleukin-10 haplotypes (-1082 A>G, -819 C>T, and -592 C>A) in a Mexican population.

Interleukin 10 (IL-10) is an immunoregulatory cytokine with multiple roles in the immune system. Three single nucleotide polymorphisms at positions -1082 (A>G), -819 (C>T), and -592 (C>A) in the promoter region of the IL10 gene are believed to be associated with different inflammatory, infectious, and autoimmune diseases. These polymorphisms exhibit a strong linkage disequilibrium (LD) and form three principal haplotypes (GCC, ACC, and ATA). The GCC and ATA haplotypes have been associated with high and low levels of IL-10 production, respectively. The aim of this study was to establish the allele and haplotype frequencies of the IL10 polymorphisms in Mestizos from western Mexico. SNPs were analyzed in 340 healthy unrelated Mestizos from western Mexico by polymerase chain reaction-restriction fragment length polymorphism. The studied population presented significant differences, in the distribution of IL10 polymorphisms, from the Asian, African, and European populations. We also observed a strong LD within -1082 A>G, -819 C>T, and -592 C>A (100% pc = 7.735 x 10-18). The haplotypes ACC (45.4%), ATA (22.0%), GTA (14.9%), and GCC (13.9%) were most frequently observed in this population. The haplotype frequencies, however, differed from those reported previously in Mestizos from central Mexico, Asians, Africans, and European Caucasians, suggesting a differential gene flow in the Mexican Mestizo population. This could account for the genetic variability between Mexicans and populations of other ethnicities. The study of these polymorphisms and their haplotypes could help in expanding our knowledge to design future disease-risk studies on the western Mexican population.

Association between -174G/C and -572G/C interleukin 6 gene polymorphisms and severe radiographic damage to the hands of Mexican patients with rheumatoid arthritis: a preliminary report.

Several interleukin 6 gene (IL6) polymorphisms are implicated in susceptibility to rheumatoid arthritis (RA). It has not yet been established with certainty if these polymorphisms are associated with the severe radiographic damage observed in some RA patients, particularly those with the development of joint bone ankylosis (JBA). The objective of the present study was to evaluate the association between severe radiographic damage in hands and the -174G/C and -572G/C IL6 polymorphisms in Mexican Mestizo people with RA. Mestizo adults with RA and long disease duration (>5 years) were classified into two groups according to the radiographic damage in their hands: a) severe radiographic damage (JBA and/or joint bone subluxations) and b) mild or moderate radiographic damage. We compared the differences in genotype and allele frequencies of -174G/C and -572G/C IL6 polymorphisms (genotyped using polymerase chain reaction-restriction fragment length polymorphism) between these two groups. Our findings indicated that the -174G/C polymorphism of IL6 is associated with severe joint radiographic damage [maximum likelihood odds ratios (MLE_OR): 8.03; 95%CI 1.22-187.06; P = 0.03], whereas the -572G/C polymorphism of IL6 exhibited no such association (MLE_OR: 1.5; 95%CI 0.52-4.5; P = 0.44). Higher anti-cyclic citrullinated peptide antibody levels were associated with more severe joint radiographic damage (P = 0.04). We conclude that there is a relevant association between the -174G/C IL6 polymorphism and severe radiographic damage. Future studies in other populations are required to confirm our findings.

Epidemiology Data of Patients with Chronic Lymphocytic Leukemia in West Central Mexico

Background: chronic lymphocytic leukemia (CLL) is a rare disease in Mexican mestizos (Br J Haematol 2015;169:909-911 and Int J Hematol 1999;69:253-255). No significant data on epidemiology is available.Methods: epidemiological data from samples referred to Laboratorios Fatima de Michoacan for flow cytometry immunophenotyping for neoplastic hematological disease.Results: 229 samples were received, 52 were diagnosed as CLL (22.7 %). Male 32 and female 20, ratio 1.6 a 1. Age from 33 to 89 years, average 66; 31 to 40 one, 41 to 50 two, 51 to 60 eleven, 61 to 70 twenty four, 71 to 80 ten, more than 81 four. Expression of CD 38 and ZAP-70 in three; only CD38 in 2, only ZAP-70 in three.Conclusions: similar results in male female ratio and age of presentation are noted as compared with international data. Low frequency of expression in CD38 and ZAP-70 may be due pre-analytic phase in the management of the sample. As a regional group we are trying to have epidemiology data in non-malignant and malignant hematological diseases to form specific protocol treatments. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mexicans in the Making of America, by Neil Foley

in the Making of America, by Neil Foley. Cambridge and London: The Belknap Press of Harvard University Press, 2014. ix, 368 pp. $29.95 US (cloth). In in the Making of America, Neil Foley tells a familiar story of North Americans' love-hate relationship with Mexican immigrants and their US-born relatives. Although in Foley's intricate and readable book love is really tolerate due to a persistent and urgent need for cheap Mexican labour in the United States, and hate manifests itself from explicit and violent racist acts, to institutionalized discrimination couched as protecting the homeland from foreign contagion. Yet at the core of this tale is the vital role themselves have played in making the United States and their integral part in that country's history. Foley begins and ends his study with the oft stated demographic that by some impending decade, one in three US residents will be of Latin American and Caribbean heritage comprised overwhelmingly by those of Mexican origin. That numerical fact becomes a convincing argument for why we need to better understand the United States' southern neighbors, why they keep coming, and what they do once they arrive in the US. Foley has a salubrious take on this historical dynamic: Whether one is optimistic or pessimistic about the rapid changes wrought by unprecedented immigration from Mexico and other La tin-American countries, Latinos will be central to ensuring the future health and well-being of the nation (p. 224). Of course, not everyone would agree. In addition to the successes achieved by Mexican labourers, activists, consumers, soldiers, educators, politicians, and others, there has always been a deep seeded fear that Mexicans-like other non-white immigrants--will contaminate and forever disrupt the US's dominant narrative and power. Organized in a recognizable chronological order, in the Making of America relates a broad narrative from the precolonial era to the present, synthesizing many of the key historical junctures and punctuated by detailed, original case studies used to illustrate important themes in the Mexican-American experience. The first chapter establishes a recurring motif in the book: the encounter between peoples in varying colonial and postcolonial contexts and the ensuing construction of racialized forms of power and privilege. Just as Spanish colonists cast indigenous and African inhabitants into subordinate positions in their imperial hierarchy, so did pioneers claiming space in Northern Mexico, which they recast as the West. In this context, Foley writes, Anglo Americans thus reproduced the Spanish colonial practice of allowing certain light-skinned mestizos to become espanol, or white, and erased the mixed-race reality of Indian and mestizo Mexicans (p. 37). The volume moves quickly to the nineteenth century when, following the Invasion norteamericana (1846-48), the two young countries went their separate ways and established a relationship of deep inequality that persists until today. …

D14 repeat polymorphism of the asporin gene is associated with primary osteoarthritis of the knee in a Mexican Mestizo population.

Asporin is a novel extracellular matrix protein (ECM) with an important role in the development of osteoarthritis (OA), because it has been reported that functional polymorphisms in the aspartic acid repeat (D) of the asporin gene (ASPN) are associated with susceptibility to OA. This study was planned to investigate the association of the ASPN polymorphism with primary OA of the knee in a Mexican population, including several countryside regions. We conducted a case-control study in which 93 cases with primary OA of the knee and 118 controls were included. Cases included patients > 40 years of age, with a body mass index (BMI) ≤ 27 and a radiologic score for OA of the knee of ≥ 2. Controls were subjects > 40 years of age with a radiologic score of < 2. The D repeat polymorphism was genotyped and logistic regression was developed to evaluate risk magnitude. The D14 allele was more common in our cases and was associated with an increased risk for developing OA, while the frequencies of the remaining alleles did not exhibit differences. Our data suggest that the D14 allele of the ASPN polymorphism could exert an influence on primary OA of the knee etiology in a Mexican Mestizo population.

A115 - Comparative Study of Epigenetics In Adipose Tissue and Liver From Diabetic and Non-Diabetic Obese Patients: A Differential Dna Methylation Analysis In A Mexican Mestizo Population

A115 - Comparative Study of Epigenetics In Adipose Tissue and Liver From Diabetic and Non-Diabetic Obese Patients: A Differential Dna Methylation Analysis In A Mexican Mestizo Population

Genetic Risk Determinants for Cigarette Smoking Dependence in Mexican Mestizo Families.

Tobacco smoking is a leading cause of mortality in developed and developing countries. Despite antitobacco and smoke-free policies, the prevalence of active smokers in Mexican urban populations has remained stable. Mexican smokers differ from Caucasian and other ethnic groups, probably due to sociocultural and genetic background characteristics. This study explored the effect of known genetic variants on smoking behavior in Mexico City residents. Three hundred sixty-four Mexican Mestizo Mexico City residents from 87 families with at least one smoker were assessed for association of 12 gene variants of six candidate genes (CHRNA4, CHRNB2, DRD2, ANKK1, SLC6A3, and CYP2A6) with cigarette consumption, age of initiation and smoking duration. The Family Based Association Test, an extension of the Transmission Disequilibrium Test, was used to perform family-based association analysis. The Family Based Association Test showed statistically significant association between the rs2072658 polymorphism of the CHRNB2 gene and smoking-related phenotypes such as: smoking status (SS), age of onset (AO), years of smoking, and psychological dependence (PD) evaluated by the Glover-Nilsson Smoking Behavior Questionnaire. After Bonferroni correction, only the association with AO remained significant (P = .003). Statistically significant association was also observed for the CYP2A6 rs28399433 T allele with SS (P = .003) and PD (P = .003). Our results indicate effects of the rs2072658 CHRNB2 and rs28399433 CYP2A6 gene variants on AO, SS and PD in Mexican Mestizo smokers. A mild effect of other analyzed gene variants, which may contribute to a putative polygenic predisposition for smoking, is suggested. The understanding of genetic and environmental determinants in the Mexican population is important for other Latin American populations as well, living in their own countries or moving to other ones, particular due to the current migration characteristics and particular genetic background like the Mexican Mestizo and other Central American populations with similar characteristics and migrating to neighbor developed countries, introducing their own smoking behavior and contributing importantly to the genetic pool of the receptor country.

Adenoid Cystic Carcinoma in a Mexican Population.

To analyze the demographic data, clinical behavior, management (surgery/radiotherapy), disease-free survival (DFS) and overall survival (OS) in Mexican Mestizos with adenoid cystic carcinoma (ACC). A retrospective study comprising all cases with histologic diagnosis of ACC of the head and neck treated from 1986 to 2012. There were 101 cases (69 women and 32 men), with a mean age of 50years; mean evolution time before diagnosis was 25months (range 1-180 months). Most tumors involved maxillary sinus (25.8%), followed by hard palate (15.9%) and parotid gland (10.9%). Surgery was the treatment in 81 cases (80.2%), radiotherapy alone in 3 cases (3%), chemo-radiotherapy in 4 cases (4%) and 13 cases (12.9%) did not receive any treatment. Post-surgery adjuvant radiotherapy was used in 58 cases (57.4%); 6 cases (5.9%) had adjuvant chemo-radiotherapy after surgery and 37 (36.6%) cases did not receive any adjuvant treatment. Mean follow-up time was 52months (range 1-288 months). Histologic patterns were cribriform (50.5%), solid (28.7%), and tubular (11.9%) types. OS was 57.6% and 42.3% at 5 and 10years respectively. DFS was 57.8% at 5years and 49.7% at 10years. Initial management in most cases within this series was surgery followed by radiotherapy. There is more to learn about real benefits of molecular therapies. There were no significant differences in DFS and OS depending on site of involvement. OS did not show statistically significant differences amongst patients with positive and negative lymph nodes.

Differences in body mass index according to fat mass- and obesity-associated (FTO) genotype in Mexican patients with bipolar disorder.

The prevalence of obesity has dramatically increased in many countries and it is particularly high in patients with bipolar disorder (BD). A region in the first intron of the fat mass- and obesity-associated (FTO) gene, encompassing markers rs9939973, rs8050136, and rs9939609, has been consistently associated with obesity and body mass index (BMI) in different populations. We sought to determine whether FTO is associated with BMI and/or obesity in patients with BD. The sample included 129 Mexican Mestizo patients with bipolar I or bipolar II disorder. After obtaining informed consent, participants were evaluated with the Structured Clinical Interview for DSM-IV Axis I Disorders and weight, height, and body measurements were recorded. DNA was extracted from a 5-mL blood sample and real-time polymerase chain reaction was performed. The results were analyzed with Haploview v4.2 and SPSS v21. Differences in mean BMI were explained by rs8050136 and rs9939609 genotypes, especially by comparing non-carriers and carriers of two copies of the risk allele (Tukey's p ≤ 0.019), with a mean difference in BMI as high as 7.81 kg/m(2) . Differences in BMI were also explained by the interaction of the genotype (rs8050136 and/or rs9939609), the use of second-generation antipsychotics, and the use of mood stabilizers (p ≤ 0.41). Obesity was also associated with these two markers when patients with and without obesity were compared. In patients with BD, differences in BMI may be affected by the presence of FTO risk alleles, especially in homozygous individuals for these variants. Besides evaluating the possible metabolic effects of certain antipsychotics or mood stabilizers, it is important to evaluate the role of other factors such as FTO risk alleles.

Presence of the HLADR13 allele among Mexican Mestizos suggests a protective factor against relapsing-remitting multiple sclerosis (RRMS)

Background and objectiveMultiple sclerosis (MS) is a chronic demyelinating disease that affects the central nervous system. Researchers have looked for an association between relapsing-remitting MS (RRMS) and human leukocyte antigen (HLA) as risk or protective factor associated to ethnicity, which may add a partial explanation to disease heterogeneity and geographical variations. We described the frequency of the HLA-DR alleles in Mexican Mestizo (RRMS) patients. Patients and methodsWe included 143 RRMS patients and 377 healthy controls, both Mexican Mestizos. Previous signing informed consent, we record demographic and clinical characteristics of the participants. Genetic profile was made, and HLA frequencies in both groups were compared. ResultsRRMS patients were 39.8% male and 60.2% female, mean age was 35 years. While, controls were 48%male and 52% women, mean age was 38 years. The most frequent allele found in subjects with RRMS was DR 15 (p=0.006, OR=2.2, 95% CI: 1.3–3.6). DR 13 allele was more frequent among healthy subjects than RRMS patients (p=0.050) with a protective OR 2.6, (95% CI: 1.3–5.2, p=0.050). ConclusionIn our study we found HLA DR 13 was more frequent in healthy controls than in RRMS patients, suggesting a protective factor among Mexican Mestizo population

IL2 polymorphisms have no impact on risk, but genetic variants in IFNG have a protective role in acute lymphoblastic leukemia and are associated with gender in Mexican children

Aim Acute lymphoblastic leukemia (ALL) is the most common cancer in children (26%). ALL patients present a defective immune system with deregulation of cytokine production. A lower population of IL-2 and INF- γ producer cells Th1 and Tc1 are evident in ALL patients. These cytokines promote cellular immunity and its protein production may be altered by inherited polymorphisms. The aim of this study was to evaluate the role of IFNG(+874 A/T) and IL2(−330 G/T) SNPs in the expression of ALL in Mexican children and the gender influence in susceptibility to the disease. Methods ALL patients (N = 148) were genotyped for INFG and 110 for IL2; 376 healthy controls were included for comparison. All individuals are Mexican Mestizos, born in Mexico. The patients’ age ranged between 1 and 17 years; 59.4% were males and 40.6% females. DNA was obtained from peripheral blood samples using the Maxwell16 instrument. Allele discrimination of IFNG +874A/T(rs2430561) and IL2 −330 G/T(rs2069762) was performed using a Taqman real time PCR assay and an ABI 7500 Real-Time PCR equipment. Results A protective role of IFNG(+874A/T) SNP was shown for the expression of ALL. The frequency of the T allele (OR = 0.482; p = 0.00005) and TT genotype (OR = 0.052 p = 0.000006) were found decreased in the patients, while AA genotype was increased (OR = 1.86; CI 1.25–2.76; (p = 0.003). Upon sex-stratification, TT was protective in both, males (OR = 0.087; p = 0.003) and females (OR = 0.127; p = 0.02). IL2(−330G/T) SNP did not show any statistical deviation between cases and controls. Conclusions IL2(−330 G/T) was not associated with the development of childhood ALL. However, our results support the role of IFNG (+874 A/T) in surveillance against tumor cells in ALL in Mexican Mestizo children, IFNG +874 TT genotype has been associated with high cytokine production, since +874T matches with the transcription factor NF- κ B binding site that may enhance IFNG transcription. The cytokine has antitumor and anti-proliferative properties; and our data agree with other reports emphasizing the role of IFN- γ alleles in immune surveillance and its possible effect as an immunotherapeutic agent in certain forms of ALL. Moreover, recent data suggest the association of TT genotype on age at clinical onset in B-lineage ALL, in older children expressing the TT high producing IFN- γ genotype.

IL6 (−174G/C) SNP but not IL4 (−590C/T) polymorphisms contributes to the development of acute lymphoblastic leukemia, and is involved in gender specific risk in Mexican children

The characteristic of acute lymphoblastic leukemia (ALL) is the clonal proliferation and accumulation of immature lymphoid cells. About 80% of children are cured with the nowadays treatment. IL-6 contributes to the systemic effects of inflammation in innate immunity but in adaptive immunity, it stimulates the growth of B-cells and acts as a growth factor for myeloma cells. IL-4 suppresses cellular immunity stimulating the development of TH2/Tc2 cells. ALL patients present high populations of IL-4 producer cells, with higher levels of IL-6. Variation in SNPs may lead to differential gene transcription, translation and protein structure. The purpose of this study was to evaluate the role of IL6 (−174G/C) and IL4 (−590C/T) SNPs in the development of ALL in Mexican children. A total of 149 (58.4% were males) and 145 (58.6% were males) ALL patients and 376 controls were genotyped for IL4 and IL6 respectively. The patients were aged 1–17 and all of them are Mexican Mestizos born in Mexico. DNA was obtained from blood samples using a Maxwell16 instrument. Allele discrimination of IL6 −174G/C (rs1800795) and IL4-590C/T (rs2243250) was performed using a Taqman real time PCR assay on an ABI 7500 Real-Time PCR System. The study meets the criteria of the declaration of Helsinki. A low risk for ALL development may be associated with IL6 (−174 G/C) SNP, since the GC genotype was decreased in the patients(OR = 0.53; CI 0.31–0.91; p = 0.02). The frequency of IL6 (−174G/C) stratified by sex, showed a higher risk for the CC genotype in males (OR = 5.16; CI 1.02–26.21; p = 0.02). No association was found with ALL and IL4 (−590C/T) alleles/genotypes. The allele distribution of healthy controls is in Hardy–Weinberg equilibrium. We suggest a protective role of IL6 (−174 GC) GC genotype that confers a lower risk for the development of ALL in Mexican Mestizo children and a higher risk for males carrying the CC genotype, agreeing with published data. IL-6 is a pro-inflammatory cytokine that regulates immune reactions in acute phases. The GC genotype that produces higher levels of IL-6 may confer a lower risk for the development of ALL, whilst CC genotype which is a low IL-6 producer may be of high risk in males, as pointed out by others. These data together with HLA results, may be helpful in transplantation

HLA-B∗, C∗, DRB1∗ AND DQB1∗ alleles contribute to susceptibility to acute myeloblastic leukemia in Mexican Mestizo adult patients

In Mexicans, (Acute myeloid leukemia) AML comprises 15% of all AL cases. (1/100,000). The contribution of MHC markers to its expression has been suggested. Copy neural loss of heterozygosity for all parts of one haplotype, or somatic mutations in the nucleotide sequences of common A∗ or B∗ alleles, was shown. A∗03, B∗35 was reported in Turkish patients and B∗40 in a small group of Mexicans. We looked for the HLA MHC I & II pattern to unravel the genetic HLA background of AML. We included 282 high risk AML young patients, classified according to their chromosomal rearrangements, undergoing HSC transplantation & 348–708 healthy controls (C). All of them were Mexican Mestizos. Typing was done for: HLA-A∗ P = 70; C = 139; B∗ P = 94 vs. C = 105; C∗; P = 63 vs. C = 106); DRB1∗ (P = 105 vs. C = 299); and DQB1∗ (P = 354) loci, that were typed by PCR-SSOP/SBT. AF, Chi2, p & ORs were calculated with the SPSS17 software. Estimated Haplotypes Frequency was done (Arlequin software). We found associated in AML: B∗44:03(OR = 5.73); C∗16:01 (OR = 3.40); DRB1∗01:03 (OR = 6.39); DQB1∗02:02 (OR = 2.47); QB1∗05:01 (OR = 1.65); DQB1∗06:03 (OR = 2.08). One protective allele was shown: DQB1∗03:01 (OR = 0.51). DRB1∗07 was not found associated, suggesting that susceptibility is linked to the DQ2 and to the B∗44:03-C∗16:01 haplotype. Two haplotypes involving A∗02:01 were significantly increased in the patients. particularly A∗02-B∗07:02-DRB1∗15-DQB1∗06:02 (1.55 %) & A∗02-B∗39:05-DRB1∗04:07-DQB1∗03:02(1.55%); the prevalent aplotypes in C were: A∗02:01-B∗35:12-DRB1∗08:02-DQB1∗04:02 & A∗02:06-B∗35:01-DRB1∗04-DQB1∗03:02(1.5%). A recent meta-analysis of differential gene expression in AML, found that only 9.6% of the reported genes were replicated in more than one study. They identified 5 major clusters of prognostic genes, none of them involving HLA. A complex genetic etiology is clear suggesting that the interaction of specific amino acids in the HLA groove with different infectious agents and environmental factors, are related to AML expression. Epidemiological studies in Mexico have shown that the incidence of AML is higher in people living in crowded households, having more risk of infections. We provided evidence of HLA association with AML with diverse alleles contribute to the risk, and one involved in protection

CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy.

We aimed to explore the possible influence of CYP2C9 (*2, *3 and IVS8-109 A>T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C>T, 2677G>A/T and 3435C>T) on phenytoin (PHT) plasma concentrations in 64 Mexican Mestizo (MM) patients with epilepsy currently treated with PHT in mono- (n=25) and polytherapy (n=39). Genotype and allele frequencies of these variants were also estimated in 300 MM healthy volunteers. Linear regression models were used to assess associations between the dependent variables (PHT plasma concentration and dose-corrected PHT concentration) with independent variables (CYP2C9, CYP2C19 and ABCB1 genotypes, ABCB1 haplotypes, age, sex, weight, and polytherapy). In multivariate models, CYP2C9 IVS8-109 T was significantly associated with higher PHT plasma concentrations (t(64)=2.27; P=0.03). Moreover, this allele was more frequent in the supratherapeutic group as compared with the subtherapeutic group (0.13 versus 0.03, respectively; P=0.05, Fisher's exact test). Results suggest that CYP2C9 IVS8-109 T allele may decrease CYP2C9 enzymatic activity on PHT. More research is needed to confirm findings.

Association of KIR3DL1/S1 and HLA-Bw4 with CD4 T cell counts in HIV-infected Mexican mestizos.

Certain genotypic combinations of killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) have been associated with favourable outcomes after exposure to human immunodeficiency virus in Caucasoid and African populations. Human immunodeficiency virus (HIV) infection is characterized by a rapid exhaustion of CD4 cells, which results in impaired cellular immunity. During this early phase of infection, it is thought that the natural killer (NK) cells represent the main effector arm of the host immune response to HIV. This study investigates whether KIR and HLA factors are associated to CD4 T cell numbers after HIV infection in Mexican mestizos as assessed at the time of initial medical evaluation and subsequent clinical follow-up. KIR and HLA-B gene carrier frequency differences were compared between groups of patients stratified by CD4 T cell numbers as assessed during their first medical evaluation (a point in time at which all patients were anti-retroviral therapy naïve). In addition, the influence that these genetic factors have on averaged historical CD4 cell counts in patients subjected to follow-up (mostly therapy-experienced) was also evaluated. Our results suggest a protective role for the HLA-Bw4 and KIR3D + Bw4 combination in both therapy-naïve and therapy-experienced patients. This report furthers our understanding on the way that immune genes modulate HIV disease progression in less-studied human populations such as the Mexican mestizos with a special focus on CD4 T cell number and behaviour.

Identification of genetic variants in the TNF promoter associated with COPD secondary to&amp;nbsp;tobacco smoking and its severity

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of “contig” alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.

Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66% and 97 vs. 98%, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15%), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p=0.02). Haplotype analysis showed strong linkage disequilibrium D'=0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r=-0.64, p<0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.