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We previously reported that the -2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the -1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the -2518 MCP-1 genotype GG and the -1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.

The etiology of lichen planus (LP) is still unknown and previous studies have found an association between LP and HLA-DR1, DR2, DR3, DR9 and DR10 in different populations. The aim of this study was to analyze the distribution of the HLA-DRB1 alleles in Mexican Mestizo patients with LP. The aim of this study was to determine the gene frequency of HLA-DR locus in Mexican Mestizo patients with LP. We studied 20 patients with LP and 99 healthy Mexican Mestizo controls. HLA-DRB1 was performed by PCR-SSO reverse dot blot hybridization. High resolution HLA typing was performed by PCR-SSP. The HLA-DRB1*0101 allele was associated significantly in LP patients compared with healthy controls (pC = 0.0007, OR = 5.46, 95% CI = 1.86-16.06). HLA-DRB1*0101 is a marker for the development of LP in Mexican Mestizo population, yet another gene or HLA marker within MHC region may be the causatively associated gene.

Background: It may be difficult to distinguish type 1 diabetes mellitus (T1DM) from type 2 diabetes mellitus (T2DM) in the pediatric population. Autoantibodies may help to differentiate both types of diabetes, but sometimes these are positive in patients with T2DM and negative in patients with T1DM. The human leukocyte antigen (HLA)-DR genotype has been associated with T1DM and with T2DM only in adults and in determined cases., Aim: To determine the differences in HLA class II allele frequencies in Mexican children with T1DM and T2DM., Methods: We included 72 children with T1DM, 28 children with T2DM, and 99 healthy controls. All were Mexican, and diabetes was diagnosed according to the clinical and laboratory criteria established by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. The HLA-DRB1 typing was performed using polymerase chain reaction-sequence-specific oligonucleotide probe and polymerase chain reaction sequence-specific primers., Results: We found an increased frequency of HLA-DRB1*08 and a decreased frequency of HLA-DRB1*04 in the group with T2DM vs. T1DM [p = 0.0001, odds ratio (OR) = 10.58, 95% confidence interval (CI) = 3-40.8 and p = 0.0006, OR = 0.24, 95% CI = 0.11-0.53, respectively]. No significant differences were found between HLA-DRB1 alleles in T2DM vs. controls. In the group with T1DM, there was a significantly increased frequency of the HLA-DR4 and HLA-DR3 alleles relative to controls (p = 0.0000001, OR = 3.59, 95% CI = 2.2-5.8 and p = 0.00009, OR = 4.66, 95% CI = 2.1-10.3, respectively)., Conclusion: There are significant differences in the HLA profile in Mexican children with T1DM and T2DM. HLA typing could play a role in the differentiation between both types of diabetes in this population.

Aim: To determine the HLA-DQ locus in Mexican patients with Chronic gastritis and gastric adenocarcinoma., Methods: Oligotyping for HLA-DQ locus was performed in 45 Mexican patients with chronic gastritis and 13 Mexican patients with diffuse-type gastric adenocarcinoma, and was then compared with 99 clinically healthy unrelated individuals. H pylori infection and CagA status were assessed in patients by enzyme-linked immunosorbent assay (ELISA) method., Results: We found a significant increased frequency of HLA-DQB1*0401 allele in H pylori-positive patients with chronic gastritis when compared with healthy subjects [19 vs 0%, P = 1 x 10(-7), odds ratio (OR) = 4.96; 95% confidence interval (95% CI), 3.87-6.35]. We also found a significant increased frequency of HLA-DQB1*0501 in patients with diffuse-type gastric carcinoma in comparison with healthy individuals (P = 1 x 10(-6), OR = 13.07; 95% CI, 2.82-85.14)., Conclusion: HLA-DQ locus may play a different role in the development of H pylori-related chronic gastritis and diffuse-type gastric adenocarcinoma in the Mexican Mestizo population.

We examined the distribution of single nucleotide polymorphisms (SNPs) in nitric oxide synthase 2A, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein-1alpha genes in tuberculosis patients and healthy controls from Mexico. The odds of developing tuberculosis were 2.3- and 5.4-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Cases of homozygous GG had the highest plasma levels of MCP-1 and the lowest plasma levels of IL-12p40, and these values were negatively correlated. Furthermore, stimulation of monocytes from healthy carriers of the genotype GG with Mycobacterium tuberculosis antigens yielded higher MCP-1 and lower IL-12p40 concentrations than parallel experiments with monocytes from homozygous AA. Addition of anti-MCP-1 increased IL-12p40 levels in cultures of M. tuberculosis-stimulated monocytes from homozygous GG, and addition of exogenous MCP-1 reduced IL-12p40 production by M. tuberculosis-stimulated monocytes from homozygous AA. Furthermore, we could replicate our results in Korean subjects, in whom the odds of developing tuberculosis were 2.8- and 6.9-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Our findings suggest that persons bearing the MCP-1 genotype GG produce high concentrations of MCP-1, which inhibits production of IL-12p40 in response to M. tuberculosis and increases the likelihood that M. tuberculosis infection will progress to active pulmonary tuberculosis.

Objectives: To determine gene frequencies of HLA-DR alleles in 22 Mexican patients with focal epithelial hyperplasia and compare them with those present in ethnically matched healthy subjects, as well as to determine the types of human papillomavirus present in the lesions., Design: Prospective and retrospective observational study., Setting: Dermatology outpatient clinic in a general hospital., Patients: Twenty-two patients with clinically and histologically confirmed focal epithelial hyperplasia seen within a 10-year period., Interventions: None., Main Outcome Measures: Results of high-resolution DNA typing for HLA-DR alleles and biopsy for viral typing., Results: HLA-DR4 (DRB1*0404) was significantly increased (P<.001; odds ratio, 3.9; 95% confidence interval, 1.86-8.03). Seventeen (85%) of 20 patients had human papillomavirus subtype 13. The data on human papillomavirus differed from reports elsewhere that described association with human papillomavirus type 32., Conclusions: The HLA-DRB1*0404 allele suggests that Amerindian populations are at risk, and in this group, the Mexican population studied was affected only by human papillomavirus type 13.

The risk to develop rheumatoid arthritis (RA) has been associated with the presence of HLA-DRB1 alleles encoding the "shared epitope" (SE). Additionally, HLA-DRB1 alleles encoding an aspartic acid at position 70 (D70+ ) have been associated with protection against the development of RA. In this study we tested the association between either SE or D70+ and rheumatoid arthritis in Mexican Mestizos. We included 84 unrelated Mexican Mestizos patients with RA and 99 unrelated healthy controls. The HLA-typing was performed by PCR-SSO and PCR-SSP. We used the chi-squared test to detect differences in proportions of individuals carrying at least one SE or D70+ between patients and controls. We found that the proportion of individuals carrying at least one HLA-DRB1 allele encoding the SE was significantly increased in RA cases as compared to controls (p(c) = 0.0004, OR = 4.1, 95% CI = 2.2-7.7). The most frequently occurring allele was HLA-DRB1*0404 (0.161 vs 0.045). Moreover, we observed a significantly increased proportion of HLA-DRB1 SE+ cases with RF titers above the median (p = 0.005). Conversely, the proportion of individuals carrying at least one HLA-DRB1 allele encoding the D70+ was significantly decreased (p(c) = 0.004, OR = 0.4, 95% CI 0.2-0.7) among RA patients compared with controls. In conclusion, the SE is associated with RA in Mexican Mestizos as well as with the highest titers of RF.

Myasthenia gravis is an autoimmune, heterogeneous disorder, characterized by the presence of antibodies against acetylcholine receptors at the neuromuscular junction. There is a strong evidence that an individual's genetic composition is an important predisposing factor for the development of the disease. To correlate HLA class II genotypes with thymic pathology in Mexican Mestizo patients who had been subjected to thymectomy. HLA class II genes were analyzed in 60 patients and in 99 healthy ethnically matched controls. Thymic hyperplasia, atrophy, thymoma, and normal histology were encountered in 56, 33, 8 and 2% of patients, respectively. HLA-DR11 was significantly increased in patients with thymoma compared with healthy controls (pC = 0.001, OR = 13.35, 95% CI 3.5-51.3), compared with the subgroup of hyperplasia patients (pC = 0.005, OR = 15.5, 95% CI 2.78-95.58) and with the atrophy subgroup (pC = 0.04, OR = 10.5, 95% CI 1.75-70.95). This study provides the evidence of an association between HLA class II alleles with clinical and genetic heterogeneity in myasthenia gravis, particularly in those with thymoma (HLA-DR11).

We tested the association of MHC ancestral haplotypes with rapid or slow progression to AIDS by comparing their frequencies in the French genetics of resistance/susceptibility to immunodeficiency virus cohort with that reported in a control French population. Seven ancestral haplotypes were identified in the genetics of resistance/susceptibility to immunodeficiency virus cohort with a frequency >1%. The 8.1 (odds ratio (OR) = 3, p = 0.006), 35.1 (OR = 5.7, p = 0.001), and 44.2 (OR = 3.4, p = 0.007) ancestral haplotypes were associated with rapid progression, whereas the 35.2 (OR = 3.6, p = 0.001), 44.1 (OR = 5.4, p < 10(-4)), and 57.1 (OR = 5.8, p < 10(-4)) ancestral haplotypes were associated with slow progression to AIDS. Although the frequency of each ancestral haplotype is low in the population, the OR were quite higher than those previously obtained for single HLA allele associations, with some p values as low as 10(-4). The analysis of the recombinant fragments of these haplotypes allowed the identification of the MHC regions in the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression to AIDS and the MHC regions of the 44.1 and 57.1 haplotypes associated with slow progression to AIDS. Previous studies have identified single HLA alleles associated with disease progression. Our results on recombinant fragments confirm the direct role of HLA-B35 in rapid progression. Associations with HLA-A29 and -B57 might be due to linkage disequilibrium with other causative genes within the MHC region.

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Genetic factors implied on its onset and severity may include genes located within the class II major histocompatibility complex (MHC) region. The aim of this study was to determine the relationship between human leukocyte antigen (HLA)-DRB1 alleles with the clinical disease patterns of UC in Mexican Mestizo patients. High-resolution HLA typing was performed by polymerase chain reaction-sequence specific oligonucleotide (PCR)-SSO reverse dot blot and PCR-single-strand polymorphism in 67 patients with UC and 99 ethnically matched healthy controls. UC patients overall showed an increased frequency of HLA-DR1 as compared with healthy controls (17.1% versus 5%, [pC = 0.003, OR = 3.9]). Patients with extensive colitis showed increased frequencies of HLA-DR1 (pC = 1 x 10(-10), OR = 13.9), HLA-DRB1*0103 (pC = 1 x 10(-3), OR = 21.7), HLA-DRB1*0102 (pC = 0.007, OR = undetermined), and HLA-DR15 (pC = 1 x 10(-3), OR = 8.5) when compared with healthy controls. We also found a statistically increased frequency of HLA-DR15 in UC patients with extensive colitis compared with UC patients with only distal colitis (18.7% versus 1.8%, pC = 0.03; OR = 12.2). When patients who underwent proctocolectomy were compared with those who did not, an increased frequency of HLA-DRB1*0103 was observed (21.8% versus 4.9%; pC = 0.03; OR = 5.4; 95% confidence interval, 1.39-21.93). Also, patients with proctocolectomy showed increased frequencies of HLA-DR1 (pC = 1 x 10(-3), OR = 24.2) and HLA-DRB1*0103 (pC = 1 x 10(-3), OR = 50.6) when compared with healthy controls. We concluded that HLA-DR1 is associated with genetic susceptibility to UC in the Mexican Mestizo population. HLA-DR15 distinguishes a subgroup of patients with extensive colitis and the HLA-DRB1*0103 allele distinguishes a subgroup of severe form of disease that might require surgical management.

Low molecular weight polypeptide (LMP) genes are located within the major histocompatibility complex and have been associated with autoimmune diseases such as ankylosing spondylitis. In order to define the distribution of LMP genes in Mexican populations, the LMP2 and LMP7 polymorphism was analyzed in 312 Mexican individuals (95 Mexican Mestizos, 48 Nahuas, 56 Mazatecans, 50 Teenek, and 63 Mayos) belonging to different ethnic groups. In Mexican populations both Mestizos and Amerindians presented similar distribution of LMP2 and LMP7 polymorphisms, except Nahuas and Mayos who presented the higher frequencies of LMP2-H/H and the lowest frequencies of LMP2-H/R genotypes (P < 0.05 when compared with Mexican Mestizos). The LMP7-K/K genotype was absent in Nahuas, Teenek and Mayos and only one Mazatecan individual presented this genotype. Differences with other populations were found in Mexicans. An increased frequency of LMP2-H and a decreased frequency of LMP2-R alleles were observed in Mexican Amerindians (Nahuas and Mayos) when compared with Brazilian Amerindians (Kaingang and Guarani) and Caucasians (Spaniards) (P < 0.05). All Mexican populations (Mestizos and Amerindians) presented an increased frequency of LMP7-Q allele and a decreased frequency of LMP7-K allele when compared to Brazilian Amerindians (Kaingang), Caucasians (United States) and Asian (Japan) populations (P < 0.05). Genetic distances showed that Mexican Mestizos have an important relation with Spaniards and with all Mexican Amerindians. The present data corroborate the influence of Spaniard and Amerindian genes in the Mexican Mestizo population and could help to define the true significance of LMP polymorphism as genetic and evolutive marker in the Amerindian populations.

Several studies have been done regarding the genetic susceptibility to autoimmune thyroid disease, particularly those related to the role of Major Histocompatibility Complex (MHC) genes in the etiology of the disease. In the present study, we report class I and class II MHC haplotypes in nine individuals affected by Hashimoto thyroiditis and Graves' disease who belong to two distinct Mexican families. In one of the families, Hashimoto thyroiditis was associated with the Human Leukocyte Antigen (HLA) HLA-DR3 allele whereas in the other family the disease was associated with homozygosity for the HLA-DR4 (DRB1*0407), HLA-DQ3 (DQB1*0302) haplotype. On the other hand, Graves' disease was found to be associated in one of the families with HLA-DR2 (DRB1*1501) and in the other with homozygosity for the HLA-DR7 (DRB*0701) and HLA-DQ2 (DQB1*0201) haplotype. These results confirm that in Mexicans as in other ethnic groups, genes located within the MHC region are related to the genetic susceptibility to develop autoimmune thyroid disease.

Background: This study was undertaken in order to analyze the genetic incidence of human lymphocyte antigen diabetic retinopathy (HLA-DR) and its influence in proliferative diabetic retinopathy (PDR)., Methods: We designed a case-control study in which 127 mestizo Mexican patients with DM II and diabetic retinopathy were studied. DNA was extracted and HLA-DR regions were amplified using PCR. Alleles were determined by DNA hybridization. Diagnosis was assessed clinically and by fluorescein angiography. Incidence of HLA-DR alleles in patients was compared with an ethnically matched control group of healthy subjects (n = 98). Statistical significance was established with non-parametric tests., Results: Patients with diabetic retinopathy showed less frequency of HLA-D11 compared with the control group (p = 0.043). NPDR patients with 10 or more years of DM II showed an increase of HLA-DR7 (p = 0.01)., Conclusions: Our results suggest that the presence of HLA-DR7 protects against the development of proliferative disease in the diabetic Mexican population.

Class I and class III major histocompatibility complex (MHC) antigen frequencies were analyzed in 130 haplotypes from 33 families belonging to a group of Amerindians culturally and linguistically isolated for more than 12 centuries in Mexico: the Tarascos. The most frequent antigens in this ethnic group of the HLA-A locus are: A2 (gf 0.353), A24 (gf = 0.223), A31 (gf = 0.184), and A28 (gf = 0.161); and the most frequent of the HLA-B locus are: B35 (gf = 0.230), B39 (gf = 0.192), B15 (gf = 0.146), and B5 (gf = 0.123). On the other hand, class III antigens demonstrated relatively high frequencies of the SC31 (frequency = 0.561), SC01 (frequency = 0.076), and SC42 (frequency = 0.069) complotypes. Also important was the relatively high frequency of the HLA-B27 antigen (gf 0.061) and the SC33 complotype (frequency = 0.046), which are either absent or found infrequently in other Amerindian groups. Analysis of MHC haplotypes revealed that four of them have relatively high frequencies, these were the following: [B39;SC31] (11.6%), [B35;SC31] (11.6%), [B15;SC31] (8.0%), and [B5;SC31] (5.8%). Other MHC haplotypes had frequencies lower than 5.0%. The decreased frequency of BF alleles other than BF*S and the presence of the SC33 and SC32 complotypes suggest long time preservation from genetic admixture. This information withstands the basis for population genetic analysis and disease association studies in Mexican mestizos.