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ABSTRACT: The heme oxigenase 1 (HO-1), a rate-limiting enzyme for heme degradation, is an important cytoprotective protein. Transcriptional activity of HO-1 coding gene (HMOX1) can be regulated by the presence of a dinucleotide repeat polymorphism (GT)n at its promoter region. Accordingly, length of (GT)n repeat has been associated with susceptibility to several diseases. We investigated whether the HMOX1 (GT)n polymorphism was associated with childhood-onset systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA) susceptibility.
We studied 207 and 333 unrelated Mexican patients with JRA and childhood-onset SLE, respectively. The control population consisted of 653 individuals ethnically matched with cases. The HMOX1 (GT)n polymorphism was genotype by PCR and fluorescence technology.
We found 27 different alleles, with the 22 and 29 repeats as the most common alleles. Distribution of short allele (n<25) and SS genotype was not statistically associated with JRA subjects. Interestingly, the frequency of both short allele and SS genotype was significantly associated with SLE susceptibility (OR=1.47, 95%CI [1.14-1.89], p=0.002; and OR=2.79, 95%CI [1.24-6.24], p=0.01, respectively).
The distribution pattern of HMOX1 (GT) alleles was different in the Mexican population than those reported elsewhere. Our results suggest that HMOX1 (GT)n polymorphism was associated with susceptibility to childhood-onset SLE but not with JRA in Mexican individuals.
Clinical and experimental rheumatology 02/2012; 30(2):297-301. · 2.15 Impact Factor
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ABSTRACT: In several populations CFTR mutations, as well as IVS8-Tn CFTR polymorphism, have been associated with congenital bilateral absence of the vas deferens (CBAVD) and idiopathic obstructive azoospermia diseases. However, the involvement of these mutations in infertility of Mexican males has not been elucidated.
We investigated whether CFTR mutations and IVS8-Tn(TG)m polymorphisms are associated with infertility in azoospermic Mexican patients.
Sixteen CBAVD and 33 idiopathic azoospermic cases were included. The CFTR gene was sequenced in all CBAVD cases. In the idiopathic azoospermic patients, the p.F508del, p.G542X, p.N1303K, p.S549N, p.I507del, and p.R117H mutations and those detected in our CBAVD cases were screened.
The p.F508del, p.G85E, p.D1152H, and p.W1089X mutations were found in 3 CBAVD patients (18.8%). None of the 9 CFTR mutations screened for in idiopathic azoospermic were found; however, we documented a high frequency of the Gln1463Gln polymorphism in comparison with healthy controls (20% vs 6%; p=0.0029).
These data showed that the CFTR mutations but not the IVS8-Tn polymorphism are involved in CBAVD etiology in a Mexican population. Nevertheless, other screening strategies should be used to rule out the implication of CFTR mutations in idiopathic azoospermic disease.
Genetic Testing and Molecular Biomarkers 11/2011; 16(4):292-6. · 1.11 Impact Factor
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ABSTRACT: Variations in gene copy number (CNV) have been recognised as a hereditable source of susceptibility in human complex diseases. Recent studies have shown that Tlr7 gene dosage has a significant contribution in the autoimmune-enhancing effect in mouse models of systemic lupus erythematosus (SLE). A study was therefore performed to investigate whether CNVs in TLR7 contribute to the genetic component of childhood-onset SLE.
A case-control association study was performed in 328 Mexican children with SLE and 403 healthy controls. Determination of CNVs of TLR7 was achieved by real-time PCR using the ΔΔCt method. Expression levels of TLR7 and interferon α (IFNα) were determined in 23 patients. In addition, a stratification analysis was performed to investigate the association of TLR7 gene copy number (CN) with lupus nephritis.
A significant increase was found in the relative TLR7 gene CN in females patients with SLE compared with female controls (p<0.0001). However, logistic regression analysis by gender showed a higher OR (OR 6.61, p=0.005) in male patients with >1 copy of TLR7 than in female patients with >2 copies (OR 3.07, p<0.0001). This association was not observed with lupus nephritis. TLR7 mRNA levels correlated significantly with TLR7 CN and with IFNα mRNA levels.
These results show that an increase in TLR7 CN is a risk factor for childhood-onset SLE and provide new evidence for a role for X-linked gene dosage in SLE susceptibility. There is also evidence to suggest that TLR7 may be involved in the pathogenesis of SLE through the induction of IFNα.
Annals of the rheumatic diseases 10/2010; 69(10):1861-5. · 8.11 Impact Factor
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Silvia Jiménez-Morales, Rafael Velázquez-Cruz,
Julián Ramírez-Bello,
Edmundo Bonilla-González,
Sandra Romero-Hidalgo,
Guillermo Escamilla-Guerrero,
Francisco Cuevas,
Francisco Espinosa-Rosales,
Nora Ernestina Martínez-Aguilar,
Javier Gómez-Vera,
Vicente Baca,
Lorena Orozco
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ABSTRACT: There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha (TNF-alpha) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF-alpha promoter region have been associated with disease susceptibility and severity. We investigated whether -308G/A and -238G/A TNF-alpha polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF-alpha polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF-alpha-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients (p = 0.002 and p = 0.0086), and 6.7% of SLE patients (p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the -308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF-alpha -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-alpha gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.
Human immunology 05/2009; 70(4):251-6. · 2.55 Impact Factor
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A-K Abelson,
A M Delgado-Vega,
S V Kozyrev,
E Sánchez, R Velázquez-Cruz,
N Eriksson,
J Wojcik,
M V P Linga Reddy,
G Lima,
S D'Alfonso, [......],
L Orozco,
T Witte,
N Ortego-Centeno,
H Abderrahim,
B A Pons-Estel,
C Gutiérrez,
A Suárez,
M F González-Escribano,
J Martin,
M E Alarcón-Riquelme
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ABSTRACT: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5.
30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR.
In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis.
These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.
Annals of the rheumatic diseases 12/2008; 68(11):1746-53. · 8.11 Impact Factor
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ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disorder of unknown etiology and unclear pathogenesis. Matrix metalloproteinase-1 (MMP-1) is strongly upregulated and may contribute to the abnormal remodeling that characterizes the disease. We conducted a case-control study of 130 IPF patients and 305 healthy controls to investigate associations between two polymorphisms of the MMP-1 gene promoter and IPF risk. First, using PCR-restriction fragment length polymorphism (PCR-RFLP) analysis we studied the 2G polymorphism at -1,607, shown previously to generate the core of an AP-1 binding site and correlate with high transcriptional activity and risk for IPF. The frequency of the 2G/2G genotype was higher in IPF than in controls (63 vs. 49%; P < 0.008; OR = 1.7; CI 1.15-2.79). Next, we studied a T/G SNP at position -755, which we identified by sequencing the MMP-1 promoter. Chromatin immunoprecipitation (ChIP) assay performed on IPF fibroblasts with either -755 genotype revealed an AP-1 binding site for TT(-755) and GT(-755) genotypes. The frequency of this SNP revealed no significant differences between IPF and healthy controls. However, when the study individuals were stratified by their smoking status, a significant increase in the T/T genotype frequency was observed in smoking cases compared with smoking controls (45 vs. 26%; P = 0.03; OR = 2.3; CI 1.15-4.97). These findings indicate that polymorphisms of the MMP-1 promoter may confer increased risk for IPF and reveal a putative gene-environment interaction between the -755 MMP-1 polymorphism and smoking in this disease.
Human Genetics 10/2008; 124(5):465-72. · 5.07 Impact Factor
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ABSTRACT: The IRF5 gene was found to be strongly associated with SLE. We identified two functional polymorphisms and recently an insertion/deletion together with a tag SNP defining the risk haplotype in individuals of European ancestry. We now analyzed sets of Mexican patients with SLE. Three polymorphisms in the IRF5 gene were genotyped in two sets of Mexican individuals with SLE and controls as well as in families including a set of pediatric SLE patients. A set of healthy Mexican Indians was also typed. Genetic association with SLE was found for all three polymorphisms. The genetic association was very strong in the case-control analysis in both sets (for SNP rs2070197, combined P = 1.26 x 10(-21)) and in families (combined P = 0.000004). Compared to healthy individuals with European ancestry, the frequency of the risk haplotype in healthy Mexican individuals was significantly higher and even higher in the healthy Mexican Indian group. Further, a much higher frequency of the risk haplotype and of individual homozygote for it was found among Mexican SLE patients. The significantly higher frequency of homozygote individuals for the risk haplotype among Mexican SLE patients could be the result of genetic admixture, and suggests the possibility that IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients.
Human Genetics 08/2007; 121(6):721-7. · 5.07 Impact Factor
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Rafael Velázquez-Cruz,
Lorena Orozco,
Francisco Espinosa-Rosales,
Roberto Carreño-Manjarrez,
Eunice Solís-Vallejo,
Norma D López-Lara,
Ivon K Ruiz-López,
Ana L Rodríguez-Lozano,
Jesús K Estrada-Gil,
Gerardo Jiménez-Sánchez,
Vicente Baca
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ABSTRACT: A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.
European Journal of HumanGenetics 04/2007; 15(3):336-41. · 4.40 Impact Factor
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ABSTRACT: El LES es el prototipo de las enfermedades autoinmunes en las que la respuesta inmune se dirige contra una gran variedad de antígenos propios, dando como resultado daño en múltiples órganos y sistemas. Esta entidad afecta principalmente al sexo femenino (> 90%) y en alrededor del 15% de los casos se manifiesta durante la infancia. El LES es una enfermedad compleja en la cual existen tanto factores genéticos (alelos de susceptibilidad o protección) como ambientales (infecciones, fármacos, estrés, etc.), que contribuyen a su desarrollo. La identificación de factores genéticos de riesgo para LES se ha obtenido a través de análisis de ligamiento en familias multicasos y estudios de asociación, ya sea bajo un diseño de casos y controles, ya sea basados en familias. Los resultados de estos análisis señalan varios genes cuyas variantes se asocian a susceptibilidad a LES y constituyen el primer paso para entender los mecanismos moleculares que definen a la enfermedad. Esta revisión tiene como objetivo describir los avances más recientes de la genómica del LES y mostrar los hallazgos obtenidos a través de la investigación genética de esta entidad en la población mexicana.
Gaceta medica de Mexico 148(4):371-80. · 0.22 Impact Factor
