Mexican Mestizo Research Articles

Influence of CYP2D6 Deletion, Multiplication, –1584C→G, 31G→A and 2988G→A Gene Polymorphisms on Dextromethorphan Metabolism among Mexican Tepehuanos and Mestizos

The aim of this study was to explain the variability of CYP2D6 activity by the identification of CYP2D6 deletion and multiplications, and the single-nucleotide polymorphisms (SNPs) –1584C→G, 31G→A and 2988G→A in Mexican Mestizo and Tepehuano subjects. One hundred twelve Mestizos and 99 Tepehuano Amerindians were studied, who were previously phenotyped with dextromethorphan. The frequencies of CYP2D6*2A [–1584C→G] and *35 [–1584C→G, 31G→A] were 10.7 and 4.1%, respectively, in Mestizos, which is evidently a trend towards an extensive metabolism in carriers of the –1584G change. In Tepehuanos, *2A was identified with a frequency of 20%, and the allele *35 was not found. The frequencies of CYP2D6*5 (deletion) and *41[2988G→A] were 1.3 and 2.2% in Mestizos and 0.5 and 1% in Tepehuanos, respectively. The SNP 2988A was found to be significantly related with the intermediate metabolizer phenotype in Mestizos (R = 0.309; n = 88; p = 0.006). The multiplications had frequencies of 4.1% in Mestizos and 1.5% in Tepehuanos. Only in the Mestizos did the presence of multiplications significantly decrease the DM/DX (dextromethorphan/dextrorphan) values (R = 0.273; n = 88; p = 0.016). The polymorphisms studied had different frequencies between Tepehuanos and Mestizos (p < 0.001); however, in the Tepehuano group these had a low influence on their phenotypic expression. It helps to understand the genotype-phenotype relationships of CYP2D6 in our studied populations.

The NRF2 gene variant, -653G/A, is associated with nephritis in childhood-onset systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with oxidative stress and characterized by chronic inflammation. Kidney malfunction, an aggressive characteristic of this disease, is not present in all affected individuals. The Nrf2-Keap1 pathway is important in protecting against oxidative stress and inflammation. Mouse models and genome-wide scans have suggested NRF2 (Nuclear factor (erythroid-derived 2)-like 2) as a candidate gene for susceptibility to SLE. We therefore investigated whether NRF2 polymorphisms are associated with childhood-onset SLE in a Mexican Mestizo population. Two single nucleotide polymorphisms (SNPs) were genotyped by TaqMan((R)) assays in 362 patients with childhood-onset SLE and 379 controls. We found no significant association between susceptibility to SLE and NRF2 polymorphisms. However, after population stratification by gender, the heterozygous genotype of the -653G/A SNP was significantly associated with nephritis in females only [OR = 1.81, CI (1.04-3.12), p = 0.032]. This association was stronger in females affected with severe nephritis [classes IV-VI; OR = 2.16, CI (1.12-4.15), p = 0.019]. Our results suggest that NRF2 is not associated with susceptibility to childhood-onset SLE, but it could confer a risk for developing kidney malfunction in SLE-affected individuals.

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards

Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP subjects, respectively. In agreement with our hypothesis, CYP2C9*2 was significantly lower in the Mexican populations than in the SP (P<0.05), and among Mexicans in the MT than in the MM and MA groups (P<0.05), which presented similar frequencies. Moreover, the frequency of CYP2C9*3 was found to be lower (P<0.05) in MM (0.015) and MT (0.015) than in MA (0.06) and SP (0.08). Finally, the CYP2C9*6 allele was present just in one MM subject, and CYP2C9*4 and *5 were not found in the studied populations. Therefore, these findings add further evidence about CYP2C9 genetic diversity within Hispanic populations with regard to their ancestry. Considering that CYP2C9*2 and CYP2C9*3 alleles have altered catalytic activities relative to CYP2C9*1, the present data suggest the need for pharmacogenetic studies to optimize drug dosages in different populations.

PDCD1 gene polymorphisms in different Mexican ethnic groups and their role in the susceptibility to hypersensitivity pneumonitis

Objective Hypersensitivity pneumonitis (HP) is an immunological disorder caused by antigen exposure in susceptible individuals. The PDCD1 polymorphisms, PD1.3 and PD1.5 have been associated with the susceptibility to inflammatory disorders. This study was conducted to test whether the PD1.3 and PD1.5 polymorphisms are associated with HP in Mexican patients and to explore the distribution of these polymorphisms in different Mexican ethnic groups. Design and methods We studied 98 Mexican patients with HP and 92 healthy Mexican controls. Also, 156 healthy Amerindian individuals from two ethnic groups were included (96 Mayans and 60 Mayos). Polymorphisms were determined by TaqMan 5′ nuclease assays. Results Significant differences in the distribution of the PD1.3 and PD1.5 genotypes between HP patients and healthy Mestizo controls were not found. We observed a significantly different distribution of these polymorphisms in Mexican Mestizos when compared to the Amerindians. Conclusions We found no association between PD1 polymorphism and HP; however the distribution of these polymorphisms was different in Mexican Mestizos and Amerindians.

T1314 Rates of Sepsis and Mortality Among IBD Patients With Thiopurine-Induced Leukopenia

Background: Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Among cytokines induced in UC, interleukin 1 antagonist (IL-1ra) and interleukin 1 beta (IL-1β) appears to have a central role because of its immunological up-regulatory and proinflammatory activities. Aim: To determine the association between IL-1RA and IL-1B gene polymorphisms and the clinical features of UC in the Mexican Mestizo population. Patients and Methods: Five polymorphisms in the IL-1 gene cluster members IL-1B (rs16944), IL1F10 (rs3811058) and IL-1RN (rs419598, rs315952, and rs315951) were genotyped by 5' exonuclease TaqMan genotyping assays in a group of 200 Mexican patients with UC and 248 ethnically matched unrelated healthy controls. Results: We found a significant increased frequencies of IL-1RN6/1 TC (rs315952) and RN6/2 CC (rs315951) and decreased frequency of IL-1B-511 TC (rs16944) genotypes in UC patients as compared to healthy controls. In the subgroup analysis, we found a significant association between the RN6/2 GG (rs315951) and IL-1B-511 CC (rs16944) genotypes and the presence of steroid-dependence in UC patients (pC=00001, OR=15.6 and pC=0.008, OR=4.09, respectively). Patients with UC showed increased frequencies of IL-1RN “CTC” and “TCG” haplotypes when compared to healthy controls (p=0.019, OR=1.43 and p<10-7, OR=2.63, respectively). Two haplotypes (TTG and CTG) showed decreased frequency in patients when compared healthy controls (p=9x10-7, OR=0.11 and p=8x10-6, OR=0.11, respectively). Conclusion: the IL-1 RN and IL-1B polymorphisms were associated with the genetic susceptibility to develop UC and were also associated with the presence of steroid-dependence in UC patients.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

Stimulating autoantibodies against the angiotensin II type 1 receptor are not associated with preeclampsia in Mexican–Mestizo women

Recent studies have demonstrated that stimulating autoantibodies against the angiotensin II type 1 receptor (AT1R-AA) are frequently detected in the sera from women with preeclampsia, suggesting that they may play an important role in the pathogenesis of this disease. Nevertheless, the real clinical significance of AT1R-AA in preeclampsia is still controversial due to the paucity of appropriate large comparative studies that require cumbersome, time-consuming, and expensive bioassays to detect AT1R-AA. At present, the prevalence of AT1R-AA in large populations of preeclamptic women is unknown. In an attempt to clarify this issue, we assessed the presence and potential clinical significance of AT1R-AA in a large population of Mexican-Mestizo women with preeclampsia. Using a cross-sectional design, we determined the presence of AT1R-AA in 525 pregnant women (99 healthy pregnant, 96 with mild preeclampsia, and 330 with severe preeclampsia) by a new bioassay that employs human embryonic kidney-293 cells stably expressing the recombinant rat AT1R and a 4x nuclear factor of activated T cells responsive luciferase construct as well as by the reference assay in Chinese hamster ovary (CHO) cells. We found that IgG obtained from sera of healthy pregnant women and patients with preeclampsia were unable to induce luciferase activity in both HEK-293 and Chinese hamster ovary cells expressing functional angiotensin II receptor type 1. Therefore, the frequency of patients with AT1R-AA was zero. We concluded that in Mexican-Mestizo women agonistic AT1R-AA cannot be invoked as a factor involved in the pathogenesis of preeclampsia. Whether these findings can be attributed to genetic or environmental factors remains unknown.

The Glu298ASP polymorphism of the endothelial nitric oxide synthase gene is associated with premature ST elevation myocardial infarction in Mexican population

Background The polymorphism Glu298Asp of endothelial nitric oxide ( eNOS) gene has been associated with hypertension and coronary artery disease in several populations worldwide, but results are still controversial. We examined the possible association of the Glu298Asp with premature ST elevation myocardial infarction (STEAMI) in young Mexican population. Methods In a case–control study 180 unrelated patients with STEAMI ≤ 45 years who were admitted to a cardiovascular intense care unit and 180 apparently healthy controls matched by age and gender were recruited from January 2006 to June 2009. The polymorphism Glu298Asp was determined in all participants by a polymerase chain-reaction-restriction fragment length polymorphism assay (PCR-RFLP). Results There was a significant difference in the genotype distribution between 2 groups ( P = 0.001). The allele Asp occurred more frequently in the patients group ( P = 0.001). There were independent factors for STEAMI: the Asp allele (OR 2.2, 95% CI 1.1–3.5, P = 0.03), smoking (OR 5.0, 95% CI 3.1–8.2, P < 0.001), hypertension (OR 2.0, 95% CI 1.0–3.5, P = 0.03), family history of cardiovascular disease, (OR 3.7, 95% CI 2.0–4.6, P = 0.02), and dyslipidemia (OR 3.4, 95% CI 2.0–6.3, P = 0.02). Conclusions The Asp allele from the Gu298Asp polymorphism represents an independent risk factor for premature STEAMI in Mexican Mestizo population.

Distribution of HLA Class II Alleles and Haplotypes in Mexican Mestizo Population: Comparison with Other Populations

We describe the analysis of the Major Histocompatibility Complex (MHC) class II polymorphism in Mexican Mestizo population. The study provides the HLA-DRB1, DQA1 and DQB1 allele frequencies in 99 Mexican Mestizos. DNA from these individuals was typed by PCR followed by hybridization using sequence specific oligonucleotides (PCR-SSO). The relationship with other worldwide populations was studied by using HLA data from 69 different populations and calculating neighbor-joining dendrograms and correspondence multidimensional values. The highest frequencies were for DRB1*0802 (allele frequency = 0.151), DRB1*0701 (allele frequency = 0.111) and DRB1*0407 (allele frequency = 0.106). Among the eight DQA1 alleles detected, the most frequent were DQA1*03011 (allele frequency = 0.257), DQA1*0501 (allele frequency = 0.227) and DQA1*0401 (allele frequency = 0.166). Twelve DQB1 alleles were found and four of them, DQB1*0302 (allele frequency = 0.237), DQB1*0301 (allele frequency = 0.176), DQB1*0201 (allele frequency = 0.166) and DQB1*0402 (allele frequency = 0.166) showed the highest frequencies. The haplotype DRB1*0802-DQA1*0401-DQB1*0402 (0.151) predominated clearly, followed by DRB1*0701-DQA1*0201-DQB1*0201 (0.111) and DRB1*0407-DQA1*03011-DQB1*0302 (0.101). Both genetic distances and correspondence analyses showed that Mexicans clustered with Amerindian population. These results suggest that the Mexican Mestizo population be principally characterized by haplotypes presents in Amerindian and Caucasian populations with a low frequency of Black haplotypes. In summary, the HLA class II haplotype frequencies demonstrated the tri-racial component existing in Mexican Mestizos.

Polymorphisms of Alcohol Metabolizing Enzymes in Indigenous Mexican Population: Unusual High Frequency of CYP2E1*c2 Allele

Alcohol abuse represents the major identified etiological factor of cirrhosis in México. ADH1B, ALDH2, and CYP2E1 have been considered candidate genes in alcohol-related diseases. Controversial results probably due to ethnic differences, among other factors, have been reported. Mexican Mestizos (MES) derive from the combination of indigenous, Spaniard, and African genes. Huichols (HUI) constitute an indigenous group from western Mexico with no racial admixture. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy HUI and MES from western Mexico. Lipid and hepatic profile were also carried out. One hundred and one HUI and 331 MES subjects were studied. Genotype and allele frequency were assessed through polymerase chain reaction-restriction fragment length polymorphism after DNA isolation from peripheral leukocytes. Commercial kits for lipid and hepatic determinations were used. Polymorphic allele distribution in HUI was: 0%ADH1B*2, 0.5%ALDH2*2, 51.5%CYP2E1*c2; in MES: 3.4%ADH1B*2, 0%ALDH2*2, 16.1%CYP2E1*c2. Frequency of ADH1B*2 was statistically (p < 0.001) lower in HUI than MES. CYP2E1*c2 polymorphic allele was significantly higher (p < 0.0001) in HUI than MES. Hepatic profile was normal in both groups. HUI showed a better lipid profile than MES independently of genotype. Huichols exhibited the highest CYP2E1*c2 allele frequency of the world documented up to this date; meanwhile, ADH1B*2 and ALDH2*2 were practically absent. This feature could be useful in the understanding of Mexican population gene composition, alcohol metabolism, and alcoholic liver disease development. However, further association studies are necessary. The heterogeneity of Mexican population was evidenced by the significantly different distribution of CYP2E1*c2 allele observed among different regions of the country. Lipid and hepatic values were not associated to genotype. This report constitutes the first study dealing with gene polymorphisms of alcohol metabolizing enzymes conducted in HUI.

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5'UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction-restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.16-0.78; P = 0.007) with gene-dosage effect (additive model) reaching significance (P = 0.0001) in the Welsh case-control group. This association was replicated in the second case-control group from Mexico (OR (recessive model) = 0.49, 95% CI = 0.24-0.96; P = 0.03), and the pooled analysis yielded a strong association (Mantel-Haenszel OR = 0.43, 95% CI = 0.27-0.69, P = 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P = 0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case-control group from Wales (adjusted P = 0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

A COL2A1 gene polymorphism is related with advanced stages of osteoarthritis of the knee in Mexican Mestizo population

Primary osteoarthritis (OA) is a multifactorial disease with several genetics factors involved. The COL2A1 gene is of particular interest because it encodes for the most abundant protein in articular cartilage. The aim was to evaluate the association of COL2A1 gene polymorphism with OA of the knee in Mexican Mestizo patients. A case-control study was conducted; cases comprised patients with a radiologic scoring > or = 2 and controls with a radiologic scoring <2. DNA was extracted from a peripheral blood sample, the polymorphic site of the COL2A1 gene was submitted to polymerase chain reaction (PCR), and the products were digested using PvuII restriction enzyme. For statistical analysis, a non-conditional logistic regression was developed. There were no associations among alleles in the overall sample, nevertheless, a significant association was found with p (Pp/pp) allele and OA of the knee grade 4 [odds ratio (OR), 95% confidence interval (CI 95%) 4.1 (1.2-14.6)] adjusted by gender, age, and body mass index (BMI). These results suggest an association of a COL2A1 gene polymorphism with advanced stages of OA of the knee in Mexican Mestizo population.

Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

17alpha-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene. This condition shows considerable clinical and biochemical variation. Molecular characterization of novel mutations in the CYP17A1 gene and detailed study of their structural, enzymatic, and clinical consequences are required to fully understand enzyme behavior. Here, we present the first molecular characterization of two novel mutations in CYP17A1 in a 15-year-old female Mexican mestizo 46,XY female with primary amenorrhea and lack of pubertal development and severe hypertension that manifested only after surgery. A complete clinical and biochemical evaluation was compatible with 17OHD. Structural anomalies in the CYP17A1 gene were discovered by direct automated sequencing, which revealed a novel compound heterozygous K110X/R362H mutation that leads to a complete lack of enzyme activity. Immunohistochemical analyses performed to determine protein expression and localization showed that cytochrome P450 17A1 was completely absent in the patient's testicular tissue. Studies of novel mutations, such as those described here, provide important information that allows us to better understand the effect of a given mutation on enzyme function and to observe the impact of the mutation on clinical phenotype.

HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever

Host genetics in dengue hemorrhagic fever (DHF) pathophysiology has not been extensively investigated. Most studies have focused on HLA in different populations; however these reported associations have not been replicated. We performed a case–control study to analyze possible associations of HLA-A, HLA-B, HLA-Cw, HLA-DRB1 and HLA-DQB1 alleles with clinical disease severity caused by dengue virus infection. Our population consisted of 39 individuals (DF: 23, DHF: 16) and 34 healthy controls from the State of Morelos, Mexico. HLA loci were genotyped by nucleotide sequencing method. Statistical analyses revealed associations in three alleles: HLA-B*35 was negatively associated with symptomatic disease ( p < 1 × 10 −4, p c = 0.01, OR = 0.12, 95%CI = 0.037–0.39), and DF ( p = 0.0007, p c = 0.03, OR = 0.13, 95%CI = 0.031–0.51). HLA-DQB1*0302 was positively associated with DHF ( p = 0.018, p c = NS, OR = 5.02, 95%CI = 1.05–25.34), and negatively with DF ( p = 0.011, p c = NS, OR = 0.23, 95%CI = 0.06–0.84). HLA-DQB1*0202 was positively associated with DF only ( p = 0.012, p c = NS, OR = 7.0, 95%CI = 1.11–73.8). We identified possible associations of HLA-B and HLA-DQB1 alleles with the risk of developing symptomatic disease, DF and DHF in a Mexican Mestizo population.

Genetic Association of Monocyte Chemoattractant Protein 1 (MCP-1)-2518 Polymorphism in Mexican Patients With Transitional Cell Carcinoma of the Bladder

To investigate the role of MCP-1-2518, stromal cell-derived factor-1 (SDF-1)-G801A and chemokine receptors CCR5-Delta32, CCR5-59 029, and CCR2-64I gene polymorphisms in transitional cell carcinoma of the bladder in Mexican Mestizo patients. Forty-seven unrelated consecutive patients with non-muscle-invasive transitional cell carcinoma (TCC) and 126 unrelated healthy individuals were studied. Genomic extraction was carried out from complete blood samples using the salting out method. The PCR-RFLP method was used to amplify the following polymorphisms: MCP-1-2518, SDF-1-G801A, CCR5-Delta32, CCR5-59 029, and CCR2-64I. The patients were divided according to low, intermediate, and high risk of progression and treated accordingly with surveillance or immunotherapy with BCG. SDF-1-G801A, CCR5-Delta32, CCR5-59 029, and CCR2-64I polymorphisms were not associated with the genetic susceptibility to non-muscle-invasive TCC of the bladder in Mexican patients. The distribution of AA, AG, and GG genotypes of MCP-1-2518 was significantly different in bladder cancer patients compared with controls (P = .006). There was a significant decrease both in the frequency of the G mutant allele (P = .021, OR = 1.752; C 95% CI 1.088-2.828) and in the GG genotype (P = .001, OR = 6.097 95% CI 1.885-19.570) in TCC patients, compared with controls. This preliminary study shows that MCP-1 polymorphism is associated with TCC.

Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico

Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. We evaluated genetic diversity, linkage disequilibrium patterns, and extent of haplotype sharing using genomewide data from Mexican Mestizos from regions with different histories of admixture and particular population dynamics. Ancestry was evaluated by including 1 Mexican Amerindian group and data from the HapMap. Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.

Identification of B*9550, a novel B*15 allele, in a Mexican bone marrow donor from Veracruz State

Human leukocyte antigen-B*9550 is a novel allele identified in a Mexican Mestizo bone marrow donor from Veracruz.

Hypoalphalipoproteinemia in populations of Native American ancestry: an opportunity to assess the interaction of genes and the environment

Our aim is to review the environmental and genetic factors associated with hypoalphalipoproteinemia in populations of Native American ancestry. We examine the strength of the association and outline the population-specific genetic factors that lead to a higher susceptibilty for this condition. Low HDL is the most common lipid abnormality in populations of Native American ancestry. Population-based surveys carried out in Latin America and in Mexican Americans shows that 40-60% of adults have hypoalphalipoproteinemia. The contribution of this trait to the metabolic syndrome is greater in individuals with Native American ancestry than in other ethnic groups. Several environmental factors have contributed to this phenomenon (i.e. high dietary content of carbohydrates and fat due to cultural factors and a growing incidence of obesity). In addition, results from recent genetic studies show that certain hypoalphalipoproteinemia susceptibility alleles are ethnic specific for Native Americans. The variant R230C of the ATP-binding cassette transporter subfamily A member 1 gene (ABC-A1) is common among mestizos (10.9% in Mexican mestizos) and its presence has a significant negative effect on HDL cholesterol levels (-4.2%). An additional noteworthy finding is that the R230C variant appears to be specific for the Amerindian populations. Its allele frequency is 0.28 in Mayans, 0.214 in Purepechas, 0.203 in Yaquis and 0.179 among Teenek. In contrast, the C230 allele has not been found in African, European, Chinese or South Asian populations. The assessment of the genetic and environmental determinants of hypoalphalipoproteinemia in populations of Native American origin provides an opportunity to assess the population-specific interactions between genes and the environment

DD genotype of angiotensin‐converting enzyme in type 2 diabetes mellitus with renal disease in Mexican Mestizos

The DD genotype of angiotensin-converting enzyme (ACE) has been suggested as a major contributor of diabetic nephropathy in several populations. The purpose of the present study was to determine whether micro/macroalbuminuria is associated with ACE insertion/deletion (I/D) polymorphism in Mexican Mestizos with type 2 diabetes mellitus. A total of 435 patients with type 2 diabetes mellitus, of whom 233 had albuminuria, were characterized for the ACE I/D polymorphism by the polymerase chain reaction method. Clinical and biochemical characteristics and frequencies according to DD, ID and II genotypes in patients with and without albuminuria showed no significant differences. However, only females with micro/macroalbuminuria showed higher frequency of a DD genotype than those without albuminuria (27.9%, 21.2% and 10.5%, respectively; P <or= 0.044). In addition, female patients with macroalbuminuria without dialysis showed no significant differences with patients undergoing dialysis. The ACE DD genotype is a risk factor for the development of renal disease in Mexican Mestizo females with type 2 diabetes, indicating a possible DD genotype-associated sex effect in renal disease.

HLA-DR Allele Frequencies in Mexican Mestizos with Autoimmune Liver Diseases Including Overlap Syndromes

Autoimmune liver diseases are sometimes difficult to differentiate from hepatic overlap syndromes (OS). The objective of this study was to use polymorphic genetic markers to better distinguish clinical heterogeneity in autoimmune liver disease. Since autoimmunity is the result of autoantibody production we studied HLA-DR alleles in 20 patients with autoimmune hepatitis (AIH), 16 with primary biliary cirrhosis (PBC), 10 with OS, and in 99 ethnically matched healthy individuals. Patients with OS had significantly higher alkaline phosphatase and total bilirubin levels than patients with AIH. OS patients had a higher prevalence of positive antinuclear antibodies and a higher AIH score than patients with PBC. Patients with OS also had higher total immunoglobulin levels (IgG isotype) as compared to patients with PBC. We found in PBC patients a higher gene frequency of HLA-DR4 and DR1 as compared to healthy controls (p = 0.03, OR = 2.2 and p = 0.004, OR = 4.3, respectively) and to OS patients (p = 0.01, OR = 6.8, and p = 0.004, OR = 10.0, respectively). On the other hand, the gene frequency of HLADR5 was significantly decreased in the total group of patients as compared to healthy controls suggesting a protective role of this allele for developing autoimmune liver disease.