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Type I interferon (IFN-I) pathway plays a central role in the systemic lupus erythematosus (SLE) pathogenesis. Recent data suggest that SLE is associated with variants in IFN-I genes, such as tyrosine kinase 2 (TYK2), which is crucial in anti-viral immunity. Here, five TYK2 single nucleotide polymorphisms (SNPs) were genotyped in 368 childhood-onset SLE Mexican patients and 516 sex-matched healthy controls. Allele frequencies were also estimated in four indigenous groups. SLE protection was associated with TYK2 risk infection variants affecting residually its catalytic domain, rs12720356 (OR = 0.308; p = 0.041) and rs34536443 (OR = 0.370; p = 0.034), but not with rs2304256, rs12720270, and rs280500. This association was replicated in a 506 adult-onset SLE patients sample (OR = 0.250; p = 0.005, and OR = 0.277; p = 0.008, respectively). The minor alleles of both associated SNPs had a lower frequency in Mestizos than in Spaniards and were absent or rare in indigenous, suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards. For the first time, we report genetic variants with a protective effect in childhood- and adult-onset SLE Mexican population. Our results suggest that the frequency of IFN-I alleles associated with SLE, may have been shaped in populations exposed to infectious diseases for long periods, and this could be an explanation why Native American ancestry is associated with a higher SLE prevalence and an earlier onset.

Chronic inflammation causes target organ damage in patients with systemic autoimmune diseases. The factors that allow this protracted response are poorly understood. We analyzed the transcriptional regulation of PPP2R2B (B55β), a molecule necessary for the termination of the immune response, in patients with autoimmune diseases. Altered expression of B55β conditioned resistance to cytokine withdrawal–induced death (CWID) in patients with autoimmune diseases. The impaired upregulation of B55β was caused by inflammation-driven hypermethylation of specific cytosines located within a regulatory element of PPP2R2B preventing CCCTC-binding factor binding. This phenotype could be induced in healthy T cells by exposure to TNF-α. Our results reveal a gene whose expression is affected by an acquired defect, through an epigenetic mechanism, in the setting of systemic autoimmunity. Because failure to remove activated T cells through CWID could contribute to autoimmune pathology, this mechanism illustrates a vicious cycle through which autoimmune inflammation contributes to its own perpetuation.

Tetralogy of Fallot (ToF) is one of the most common and severe congenital heart defects (CHD). Recently, unbalanced structural genomic variants or copy number variations (CNVs) were proposed to be involved in the etiology of many complex diseases, including CHDs. The aim of this study was to investigate the frequency of CNVs in a region with a high density of CNVs, 22q11.2, and other regions with CHD-related genes in a sample of 52 Mexican mestizo patients with isolated ToF and negative fluorescence in situ hybridization staining for 22q11. CNVs were studied using two multiplex ligation-dependent probe amplification (MLPA) kits, SALSA P250-B1® (DiGeorge gene region) and SALSA MLPA P311-A1® CHD-related gene regions (GATA4, NKX2-5, TBX5, BMP4, and CRELD1). The MLPA assay detected a de novo CNV deletion of the probes located in exons 2 and 7 of the TBX1 gene in one of the 52 patients studied; this result was confirmed by real-time quantitative polymerase chain reaction. This deletion was not present in the patient's parents and 104 chromosomes from healthy control subjects. Our results clearly suggest a possible etiologic association between the TBX1 deletion and the ToF in our patient.

Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder.Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly.Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA.A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene.We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome.

Female predominance is a common characteristic for autoimmune diseases attributed to the combined effect of hormonal influence and genetic factors. Since X chromosome has immunologically important genes, the age related X chromosome loss could contribute to the development of autoimmunity. X chromosome monosomy (XCM) has been associated with primary biliary cirrhosis (PBC) and systemic sclerosis. Herein, using fluorescence in situ hybridization (FISH) with specific centromeric probes, we report the rate of XCM in interphase nuclei in women with Reynolds syndrome (RS), an overlapping condition of PBC and systemic sclerosis (SSc). Frequency of nuclei with XCM was 12.1% (CI 95%, 8.5-17.1) in RS, 10% (7.1-13.9) in PBC, 9.2% (6.0-13.9) in SSc and 6.4% (5.1-8) in age-matched healthy controls. We found a significantly higher XCM frequency in RS PBC and SSc groups of patients when compared with controls, p0.01, p0.05 and p0.05 respectively. XCM was highest in the RS group but not statistically different from PBC and SSc patients. Fetal-maternal microchimerism prevalence evaluated by Q-PCR for SRY sequences varies among groups, although no statistical differences were observed. Besides the above, we found an apparently important additive effect (89.1%) of PBC and SSc on the prevalence of XCM cells in RS patients. Another interesting finding was that the prevalence of XCM cells seems not to be dependent on the time of evolution of the AID studied. Moreover, the shorter time of evolution and the higher prevalence of XCM interphase nuclei observed in RS patients sustain our hypothesis of the additive effect abovementioned.

Primary immunodeficiencies as well as autoimmune diseases have been associated to X chromosome abnormalities. Furthermore, the functional biology of the X chromosome is unique because genes located in this chromosome can undergo inactivation, and subsequently transcriptional silencing. Non-random X chromosome inactivation has been hypothesized to be involved in the development of autoimmunity. Recently X chromosome monosomy has also been proposed as a common etiologic mechanism for some autoimmune diseases. Herein, we review some of these findings above mentioned.

Summary Background Androgenetic alopecia (AGA) or common baldness is the most prevalent form of hair loss in males. Familial predisposition has been recognized, and heritability estimated in monozygotic twins suggests an important genetic predisposition. Several studies indicate that the numbers of CAG/GGC repeats in exon 1 of the androgen receptor gene (AR) maybe associated with AGA susceptibility. Aims To investigate a possible correlation between AR CAG/GGC haplotypes and the presence or not of alopecia in sibships with two or more brothers among them at least one of them has AGA. Patients/Methods Thirty-two trios including an alopecic man, one brother alopecic or not, and their mother were enrolled. Sanger sequencing of the exon 1 of the AR gene was conducted to ascertain the number of CAG/GGC repeats in each individual. Heterozygous mother for the CAG/GGC haplotypes was an inclusion criterion to analyze the segregation haplotype patterns in the family. Concordance for the number of repeats and AGA among brothers was evaluated using kappa coefficient and the probability of association in the presence of genetic linkage between CAG and GGC repeats and AGA estimated by means of the family-based association test (FBAT). Results The median for the CAG and GGC repeats in the AR is similar to that reported in other populations. The CAG/GGC haplotypes were less polymorphic than that reported in other studies, especially due to the GGC number of repeats found. Kappa coefficient resulted in a concordance of 37.3% (IC 95%, 5.0–69.0%) for the AGA phenotype and identical CAG/GGC haplotypes. There was no evidence of linkage disequilibrium. Conclusion Our results do not confirm a possible correlation or linkage disequilibrium between the CAG/GGC haplotypes of the AR gene and androgenetic alopecia in Mexican brothers.

INTRODUCTION 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. METHODS 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. RESULTS 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). CONCLUSIONS 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. IMPLICATIONS 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.