TLR4 polymorphism and haplotype are associated with obesity and lipid profile in young population: a pilot study.

BACKGROUND: The single nucleotide polymorphisms in the TLR4 gene can decrease or increase the response to lipopolysaccharide, increasing the susceptibility to inflammatory diseases, affecting the expression or receptor function by inducing a low-grade chronic inflammatory response. PURPOSE: The objective of this study was to evaluate the association of SNPs - 2570 A > G (rs2737190), - 2081 G > A (rs10983755), 896 A > G (rs 4986790), and 1196 C > T (rs4986791) of the TLR4 gene with obesity and metabolic alterations in the young population. RESULTS: In this study, it was found that the carriers of the heterozygous genotype of the SNPs - 2081 G > A, 896 A > G, and 1196 C > T confer a higher risk of developing obesity (OR = 3.73, p = 0.018; OR = 5.66, p = 0.014, and OR = 8.95, p = 0.014, respectively). Also, with the lipid profile, the SNP - 2081 G > A was associated with total cholesterol (TC) ≥ 200 mg/dL (OR = 3.91, p = 0.020) and Kannel index > 3% (OR = 4.00, p = 0.008). The SNP 896 A > G was associated with LDL-c ≥ 100 mg/dL (OR = 3.64, p = 0.040) and Kannel index > 3% (OR = 4.33, p = 0.016), and the SNP 1196 C > T was associated with TC ≥ 200 mg/dL (OR = 4.37, p = 0.048), Castelli index > 4.5/> 5% (OR = 5.33, p = 0.016), and Kannel index > 3% (OR = 16.00, p = 0.001). Finally, the AGGT haplotype was associated with Castelli index > 4.5/> 5% (OR = 5.40, p = 0.015) and Kannel index > 3% (OR = 10.46, p < 0.001), and the AAAC haplotype was associated with obesity (OR = 3.56, p = 0.020), TC ≥ 200 mg/dL (OR = 4.04, p = 0.007), LDL-c ≥ 100 mg/dL (OR = 2.98, p = 0.030) and Kannel index > 3% (OR = 4.20, p = 0.002). CONCLUSION: The heterozygous genotype of the SNPs - 2081 G > A, 896 A > G and 1196 C > T of the TLR4 gene was associated with altered lipid profile and development of obesity in young university students of Guerrero State, Mexico.

Aberrant expression of interleukin-10 in rheumatoid arthritis: Relationship with IL10 haplotypes and autoantibodies.

Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA.

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.

Analysis of IL10 haplotypes in primary Sjögren's syndrome patients from Western Mexico: Relationship with mRNA expression, IL-10 soluble levels, and autoantibodies.

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. Interleukin-10 (IL-10) plays a role in autoimmune diseases by promoting B-cell activation and autoantibodies production. IL10-1082A>G, -819C>T, -592C>A polymorphisms and their haplotypes have been associated with IL-10 production. The aim of this study was to associate IL10 haplotypes with mRNA expression and soluble IL-10 levels with susceptibility to pSS in 111 Mexican patients and 111 healthy subjects (HS). Primary Sjögren's syndrome patients showed high levels of sIL-10 (p=0.0001 vs HS) correlating with anti-Ro and anti-La antibodies (p<0.05). In addition, IL10 mRNA expression in pSS was higher than HS (0.8 vs 0.1, p=0.1537). However, no difference was observed in sIL-10 levels between haplotypes. Patients carriers of GCC haplotype showed higher mRNA expression than ACC+ATA (1.4 vs 0.6, p=0.2424) and high foci number (p=0.04 vs ACC). Our results suggest a strong relationship of IL10 with pSS which is demonstrated by the increased mRNA expression and also high sIL-10 levels positively correlated with autoantibodies. Besides that, the GCC haplotype carriers expressed high mRNA. However, IL10 haplotypes were not associated with sIL-10 in pSS from Western Mexico which suggest that diverse biological factors may regulate the IL10 expression in pSS.

Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-α in systemic lupus erythematosus.

Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF-α serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms was performed by PCR and PCR-RFLP, respectively in 186 SLE patients and 200 healthy subjects. MIF and TNF-α serum levels were determined by ELISA. A significant increase of MIF and TNF-α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the -794 CATT7 and -173(∗)C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population.