ABSTRACT
Psoriasis is a chronic, autoimmune skin disease. In psoriasis, PON1 activity is diminished and peroxidation biomarkers are elevated. The most studied PON1 polymorphisms are rs662 (A > G) and rs854560 (A > T), which have been associated with the antioxidant activity of PON1, risk of cardiovascular diseases and psoriasis development. The aim of this study, was to determine the association of rs662 (A > G) and rs854560 (A > T) PON1 polymorphisms with psoriasis susceptibility in Western Mexico population. In this case-control study, we included 104 psoriasis patients and 124 control subjects. The genotyping of polymorphisms rs662 (A > G) and rs854560 (A > T) of PON1 was carried out by PCR-RFLPs. The lipid profiles were quantified by enzymatic colorimetric method, and PON1 activity was determined by spectrophotometry. The lipid profile levels, except HDL-C and atherogenic index, were higher in patients vs. controls. Patients presented lower paraoxonase and arylesterase activity. The G allele of rs662 (A > G) is associated with risk for psoriasis, while the T allele of rs854560 (A > T) is associated with low susceptibility to psoriasis. The AG haplotype was more frequent within the patient group (p < 0.05). The AA and AG genotypes of rs662 (A > G) and TT and AA genotypes of rs854560 (A > T) are associated with lower PONase and ARE activity in patients vs. controls. Patients with the G allele of rs662 (G > A) and T alleles of rs854560 (A > T) show significant differences in the lipid levels in comparison to controls. These results suggest that carriers of G allele of rs662 (A > G) present a greater susceptibility to psoriasis.
Subject(s)
Aryldialkylphosphatase/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Psoriasis/genetics , Adult , Aged , Alleles , Biomarkers , Female , Genotype , Haplotypes/genetics , Humans , Lipid Peroxidation/genetics , Male , Mexico/epidemiology , Middle Aged , Polymorphism, Single Nucleotide/genetics , Psoriasis/epidemiology , Psoriasis/pathologyABSTRACT
PTPN22 represents an important non-HLA gene that has been strongly associated with rheumatoid arthritis (RA) pathogenesis. Several studies have reported a specific genetic variant for PTPN22 (+788 G>A; rs33996649) that might be associated with decreased RA risk in Caucasian population; nevertheless, its specific role in western Mexican population has not been yet described. A case-control study with 443 RA patients and 317 control subjects (CS) was conducted. The genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique and the PTPN22 mRNA expression was determined by SYBR Green-based real-time quantitative-PCR assay. No association between the PTPN22 +788 G>A polymorphism and RA susceptibility in western Mexican population was found when comparing genotype and allelic frequencies between RA patients and CS (G/G vs. G/A: OR 0.55, p = 0.14, 95% CI 0.22-1.32; G vs. A: OR 0.56, p = 0.14, 95% CI 0.23-1.36). The PTPN22 mRNA expression increased 4.6-fold more in RA patients than in CS, and RA patients, carriers of PTPN22 +788 G/A genotype, expressed 15.6-fold more than RA patients carrying the homozygous G/G genotype. Overall, these results showed that the PTPN22 +788 G>A polymorphism is not associated with RA susceptibility in western Mexican population, whereas the presence of G/A genotype is associated with increased PTPN22 mRNA expression in RA patients.
Subject(s)
Arthritis, Rheumatoid/genetics , Genetic Markers , Genetic Predisposition to Disease , Polymorphism, Restriction Fragment Length , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Adult , Aged , Case-Control Studies , Female , Humans , Male , Mexico , Middle Aged , RNA, Messenger/genetics , Real-Time Polymerase Chain ReactionABSTRACT
Lactate dehydrogenase (LDH) is key for anaerobic glycolysis. LDH is induced by the hypoxia inducible factor -1 (HIF-1). HIF-1 induces genes involved in glucose metabolism and regulates cellular oxygen homeostasis. HIF-1 is formed by a regulatory α-subunit (HIF-1α) and a constitutive ß-subunit (HIF-1ß). The white spot syndrome virus (WSSV) induces anaerobic glycolysis in shrimp hemocytes, associated with lactate accumulation. Although infection and lactate production are associated, the LDH role in WSSV-infected shrimp has not been examined. In this work, the effects of HIF-1 silencing on the expression of two LDH subunits (LDHvan-1 and LDHvan-2) in shrimp infected with the WSSV were studied. HIF-1α transcripts increased in gills, hepatopancreas, and muscle after WSSV infection, while HIF-1ß remained constitutively expressed. The expression for both LDH subunits increased in each tissue evaluated during the WSSV infection, translating into increased enzyme activity. Glucose concentration increased in each tissue evaluated, while lactate increased in gills and hepatopancreas, but not in muscle. Silencing of HIF-1α blocked the increase of LDH expression and enzyme activity, along with glucose (all tissues) and lactate (gills and hepatopancreas) concentrations produced by WSSV infection. These results demonstrate that HIF-1 up regulates the expression of LDH subunits during WSSV infection, and that this induction contributes to substrate metabolism in energetically active tissues of infected shrimp.
Subject(s)
Gene Expression Regulation/immunology , Hypoxia-Inducible Factor 1/genetics , Immunity, Innate/genetics , L-Lactate Dehydrogenase/genetics , L-Lactate Dehydrogenase/immunology , Penaeidae/genetics , Penaeidae/immunology , Amino Acid Sequence , Animals , Arthropod Proteins/chemistry , Arthropod Proteins/genetics , Arthropod Proteins/immunology , Base Sequence , Gene Expression Profiling , Hypoxia-Inducible Factor 1/metabolism , L-Lactate Dehydrogenase/chemistry , Phylogeny , Sequence Alignment , White spot syndrome virus 1/physiologyABSTRACT
OBJECTIVES: To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression. RESULTS: Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54-7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29-5.40, p = 0.01). CONCLUSION: Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.
ABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/genetics , Interleukin-10/genetics , Adult , Aged , Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Case-Control Studies , Female , Gene Frequency , Haplotypes , Humans , Interleukin-10/blood , Male , Middle AgedABSTRACT
Acute coronary syndrome (ACS) is considered one of the main causes of death worldwide. Contradictory findings concerning the impact of the angiotensin-converting enzyme (ACE) gene on cardiovascular diseases have been reported. Previous conclusions point out that the variability in results depends on ethnicity and genetic polymorphisms to determine the association of rs4340 polymorphisms of the ACE gene and ACE circulating levels in ACS. Genotyping of rs4340 polymorphisms was performed in a total of 600 individuals from Western Mexico divided into two groups: the ACS and the control group (CG). The polymorphisms were identified by polymerase chain reaction. Serum ACE concentration was determined by enzyme-linked immunosorbent assay. D/D carriers had higher ACE levels than I/I carriers (3.6 vs 2.8 ng/mL, P < 0.0021) in the CG. The D/D genotype of the rs4340 polymorphism is associated with higher ACE concentration levels; however, the polymorphism was not associated with ACS.
Subject(s)
Acute Coronary Syndrome/genetics , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide , Acute Coronary Syndrome/blood , Aged , Case-Control Studies , Female , Genotype , Heterozygote , Humans , Male , Mexico , Middle Aged , Peptidyl-Dipeptidase A/bloodABSTRACT
OBJECTIVE: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). RESULTS: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). CONCLUSIONS: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients.
Subject(s)
B-Cell Activating Factor/blood , B-Lymphocyte Subsets/metabolism , Lupus Erythematosus, Systemic/physiopathology , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Adolescent , Adult , Aged , B-Cell Activation Factor Receptor/genetics , B-Cell Maturation Antigen/genetics , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Immune Tolerance , Lupus Erythematosus, Systemic/immunology , Middle Aged , Severity of Illness Index , Transmembrane Activator and CAML Interactor Protein/genetics , Young AdultABSTRACT
Allele frequencies and statistical parameters of forensic efficiency for 30 deletion-insertion polymorphisms (DIPs) were estimated in six Mexican populations. For this purpose, 421 unrelated individuals were analyzed with the Investigator DIPplex kit. The Hardy-Weinberg and linkage equilibrium was demonstrated for this 30-plex system in all six populations. We estimated the combined power of discrimination (PD ≥ 99.999999%) and combined power of exclusion (PE ≥ 98.632705%) for this genetic system. A low but significant genetic structure was demonstrated among these six populations by pairwise comparisons and AMOVA (F ST ≥ 0.7054; p ≤ 0.0007), which allows clustering populations in agreement with geographical criteria: Northwest, Center, and Southeast.
Subject(s)
Genetics, Population , INDEL Mutation , Polymerase Chain Reaction/instrumentation , Polymorphism, Genetic , DNA Fingerprinting , Gene Frequency , Humans , Linkage Disequilibrium , MexicoABSTRACT
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.
Subject(s)
Gene Frequency , Haplotypes/genetics , Interleukin-10/genetics , Polymorphism, Single Nucleotide/genetics , Alleles , Ethnicity/genetics , Humans , Linkage Disequilibrium/genetics , Mexico , Promoter Regions, Genetic/geneticsABSTRACT
Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the -383 in promoter region position. The TNFR1-383 AËC polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 AËC polymorphism and TNFR1 soluble (sTNFR1) levels and laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the AËC genotype were observed. In these patients, the SSDAI score was higher than in AËA genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 AËC polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in AËC genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 AËC polymorphism.
Subject(s)
Receptors, Tumor Necrosis Factor, Type I/genetics , Sjogren's Syndrome/genetics , Adult , Aged , Arthritis, Rheumatoid/genetics , C-Reactive Protein/genetics , Case-Control Studies , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Polymorphism, Genetic , Receptors, Tumor Necrosis Factor, Type I/metabolism , Rheumatoid Factor/geneticsABSTRACT
The CD40 pathway is involved in the development and pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). Two single nucleotide polymorphisms (SNPs) in the CD40 gene, rs1883832 and rs4810485, are associated with susceptibility to inflammatory and autoimmune diseases and are thought to alter CD40 expression at the mRNA and protein level. This study assessed for the first time the association of these SNPs with RA and CD40 mRNA levels in a western Mexican population. A total of 278 RA patients and 318 control subjects were included. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, and CD40 mRNA expression was determined by real-time quantitative PCR. No significant differences in genotype and allele frequencies were identified between the RA patients and controls. When stratified by genotype, these SNPs were not found to be associated with the presence of autoantibodies or the clinical activity of the disease. CD40 mRNA levels were elevated 1.5-fold in RA patients compared to control subjects; however, no clear tendencies were observed following stratification by genotype. These results suggest that the CD40 SNPs rs1883832 and rs4810485 are not RA susceptibility markers in the western Mexican population. Further studies are needed to clarify their roles in CD40 mRNA expression.
Subject(s)
Arthritis, Rheumatoid/genetics , CD40 Antigens/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Adult , Aged , Arthritis, Rheumatoid/pathology , CD40 Antigens/biosynthesis , Female , Gene Expression Regulation , Genotype , Humans , Male , Mexico , Middle Aged , Polymorphism, Single Nucleotide , RNA, Messenger/biosynthesis , RNA, Messenger/geneticsABSTRACT
Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.
Subject(s)
Polymorphism, Genetic , Promoter Regions, Genetic , Sjogren's Syndrome/genetics , fas Receptor/genetics , Adult , Alleles , Case-Control Studies , Female , Gene Expression , Gene Frequency , Genotype , Heterozygote , Humans , Male , Middle Aged , Models, Genetic , Sjogren's Syndrome/blood , Sjogren's Syndrome/pathology , Solubility , fas Receptor/bloodABSTRACT
Macrophage migration inhibitory factor (MIF) is an upstream pro-inflammatory cytokine that is associated with the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis (RA). Two polymorphisms in the upstream region exist in the MIF gene and are associated with RA susceptibility or severity in different populations. In this case-control study, we investigated whether MIF polymorphisms are associated with RA susceptibility or activity in a western Mexican population .The relationship of MIF levels with clinical features of disease also was assessed. Genotyping of the -794 CATT5-8 (rs5844572) and the -173 G>C (rs755622) polymorphisms was performed by PCR and PCR-RFLP respectively on 226 RA patients and 210 healthy subjects. Serum MIF levels were determined by ELISA. We found a significant association between the -794 CATT5-8 6,7 MIF genotype with RA. Moreover, we detected an association between the -794 CATT7 allele with early onset RA. The -794 CATT7 and -173(*)C alleles, which are in linkage disequilibrium, were associated with high disease activity on RA patients. A positive correlation between circulating MIF levels and C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, anti-citrullinated protein/peptides antibodies and TNFα was detected. MIF levels appear to be associated with disease progression rather than disease activity, which is distinct from the established relationship between disease activity and TNFα levels. In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease.
Subject(s)
Arthritis, Rheumatoid/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Arthritis, Rheumatoid/blood , Case-Control Studies , Female , Gene Frequency/genetics , Haplotypes/genetics , Humans , Intramolecular Oxidoreductases/blood , Macrophage Migration-Inhibitory Factors/blood , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , Tumor Necrosis Factor-alpha/blood , Young AdultABSTRACT
Glucocorticoids are frequently used in rheumatoid arthritis (RA) in order to alleviate symptoms of joint inflammation, retard erosions and to treat extra-articular manifestations, although these drugs may increase the risk of bone mineral loss and osteoporotic fractures. To date, in Mexico there are no studies that identify the frequency of patients with RA with corticosteroids, receiving therapy for osteoporosis. Therefore, we evaluated the prevalence and factors related to the prescription of antiresorptives in 520 Mexican patients with RA. We used a multivariate model to identify variables associated with antiresorptives prescription. We identified that although 79% of patients were under treatment with glucocorticoids, only 13% received antiresorptive agents as preventive therapy for osteoporosis. The multivariate analysis identified that higher proportions of antiresorptive drugs prescriptions were associated with female patients (OR 11.40, 95% CI: 1.5-84.3, P = 0.02), an age of 40 years or more (OR 3.22, 95% CI: 1.3-8.3, P = 0.02) and to consume a lower number of cointerventions with other drugs (OR 1.09, 95% CI: 1.0-1.2, P = 0.03). Corticosteroid treatment was not associated with the prescription of antiresorptives (P = 0.31). In conclusion, a low proportion of Mexicans with RA receive antiresorptive therapy independently regardless of whether they consume or not chronically corticosteroids. Additional strategies should be evaluated to encourage the prevention and early treatment for osteoporosis in patients with RA.
Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Bone Density Conservation Agents/therapeutic use , Bone Resorption/prevention & control , Glucocorticoids/adverse effects , Osteoporosis/prevention & control , Adult , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/epidemiology , Comorbidity , Cross-Sectional Studies , Drug Therapy, Combination , Female , Humans , Male , Mexico/epidemiology , Middle Aged , Osteoporosis/complications , Osteoporosis/epidemiology , Prevalence , Sex FactorsABSTRACT
Nitric oxide (NO) is a molecule with multiple biological functions that is involved in various pathophysiological processes such as neurotransmission and blood vessel relaxation as well as the endocrine system, immune system, growth factors, and cancer. However, in the carcinogenesis process, it has a dual behavior; at low doses, NO regulates homeostatic functions, while at high concentrations, it promotes tissue damage or acts as an agent for immune defense against microorganisms. Thus, its participation in the carcinogenic process is controversial. Cancer is a multifactorial disease that presents complex behavior. A better understanding of the molecular mechanisms associated with the initiation, promotion, and progression of neoplastic processes is required. Some hypotheses have been proposed regarding the influence of NO in activating oncogenic pathways that trigger carcinogenic processes, because NO might regulate some signaling pathways thought to promote cancer development and more aggressive tumor growth. Additionally, NO inhibits apoptosis of tumor cells, together with the deregulation of proteins that are involved in tissue homeostasis, promoting spreading to other organs and initiating metastatic processes. This paper describes the signaling pathways that are associated with cancer, and how the concentration of NO can serve a beneficial or pathological function in the initiation and promotion of neoplastic events.
Subject(s)
Neoplasms , Nitric Oxide , Humans , Nitric Oxide/metabolism , Neoplasms/pathology , Signal Transduction , Carcinogenesis , ApoptosisABSTRACT
Mestizos currently represent most of the Mexican population (>90%); they are defined as individuals born in the country having a Spanish-derived last name, with family antecedents of Mexican ancestors back at least to the third generation. Mestizos are result of 500 years of admixture mainly among Spaniards, Amerindians, and African slaves. Consequently, a complex genetic pattern has been generated throughout the country that has been scarcely studied from the paternal point of view. This fact is important, taking into account that gene flow toward the New World comprised largely males. We analyzed the population structure and paternal admixture of present-day Mexican-Mestizo populations based on Y-STRs. We genotyped at least 12 Y-STRs in DNA samples of 986 males from five states: Aguascalientes (n = 293); Jalisco (n = 185); Guanajuato (n = 168); Chiapas (n = 170); and Yucatán (n = 170). AmpFlSTR Y-filer and Powerplex-Y(R) kits were used. Inclusion of North and Central Y-STR databases in the analyses allowed obtaining a Y-STR variability landscape from Mexico. Results confirmed the population differentiation gradient previously noted in Mestizos with SNPs and autosomal STRs throughout the Mexican territory: European ancestry increments to the Northwest and, correspondingly, Amerindian ancestry increments to the Center and Southeast. In addition, SAMOVA test and Autocorrelation Index for DNA Analysis autocorrelogram plot suggested preferential gene flow of males with neighboring populations in agreement with the isolation-by-distance model. Results are important for disease-risk studies (principally male-related) and for human identification purposes, because Y-STR databases are not available on the majority of Mexican-Mestizo populations.
Subject(s)
Black People/genetics , Chromosomes, Human, Y/genetics , Fathers , Genetics, Population , Indians, South American/genetics , White People/genetics , Gene Flow , Gene Frequency , Haplotypes , Humans , Male , MexicoABSTRACT
BACKGROUND: CODIS-STRs in Native Mexican groups have rarely been analysed for human identification and anthropological purposes. AIM: To analyse the genetic relationships and population structure among three Native Mexican groups from Mesoamerica. SUBJECTS AND METHODS: 531 unrelated Native individuals from Mexico were PCR-typed for 15 and 9 autosomal STRs (Identifiler™ and Profiler™ kits, respectively), including five population samples: Purépechas (Mountain, Valley and Lake), Triquis and Yucatec Mayas. Previously published STR data were included in the analyses. RESULTS: Allele frequencies and statistical parameters of forensic importance were estimated by population. The majority of Native groups were not differentiated pairwise, excepting Triquis and Purépechas, which was attributable to their relative geographic and cultural isolation. Although Mayas, Triquis and Purépechas-Mountain presented the highest number of private alleles, suggesting recurrent gene flow, the elevated differentiation of Triquis indicates a different origin of this gene flow. Interestingly, Huastecos and Mayas were not differentiated, which is in agreement with the archaeological hypothesis that Huastecos represent an ancestral Maya group. Interpopulation variability was greater in Natives than in Mestizos, both significant. CONCLUSION: Although results suggest that European admixture has increased the similarity between Native Mexican groups, the differentiation and inconsistent clustering by language or geography stresses the importance of serial founder effect and/or genetic drift in showing their present genetic relationships.
Subject(s)
Ethnicity/genetics , Indians, North American/genetics , Microsatellite Repeats , Demography , Forensic Genetics , Gene Amplification , Gene Flow , Gene Frequency , Genetic Drift , Genetic Markers , Genetic Variation , Genotype , Geography , Haplotypes , Humans , Mexico , Molecular Diagnostic Techniques , Polymerase Chain Reaction , White People/geneticsABSTRACT
The goals of our study were to determine the possible association of interleukin (IL)-31 with Th17 cytokine profile in serum and to quantify retinoic acid-related orphan receptor C (RORC) mRNA expression in psoriatic arthritis (PsA) patients. This cross-sectional study was conducted in 50 patients with PsA and 30 control subjects (CS) matched by age and gender. The cytokine serum levels were quantified by magnetic bead-based assay using the Bio-Plex MAGPIX system, and RORC mRNA expression was determined by quantitative polymerase chain reaction (qPCR). As a result, significant differences in IL-31 were observed between study groups (77.23 pg/mL in PsA vs 64.4 pg/mL in CS, P < 0.001) and Th17 cytokine profile serum levels (IL-17A: 6.36 pg/mL in PsA vs 2.97 pg/mL in CS, P = 0.02; IL-17F: 44.15 pg/mL in PsA vs 23.36 pg/mL in PsA, P = 0.01; IL-17E: 3.03 pg/mL in PsA vs 0.82 pg/mL in CS, P < 0.001; IL-21: 36.45 pg/mL in PsA vs 12.44 pg/mL in CS, P = 0.02); however, significant differences were not observed for IL-23 (31.2 pg/mL in PsA vs 53.26 pg/mL in CS, P = 0.58). Furthermore, positive correlations between IL-31 and Th17 cytokine profile serum levels were found (IL-17A: rs = 0.64, P < 0.001; IL-17F: rs = 0.73, P < 0.001; IL-17E: rs = 0.70, P < 0.001; IL-21: rs = 0.54, P = 0.002; IL-23: rs = 0.5, P < 0.01). Regarding RORC gene expression, the PsA group showed an increase of 6.85-fold compared to the CS group. We did not find any association between the serum levels of cytokines and RORC gene expression. In conclusion, in PsA, there are increased serum levels of IL-31, IL-17A, IL-17F, IL-17E, and IL-21, but not IL-23. Moreover, there was a positive correlation of IL-31 with the Th17 cytokine profile and a high RORC gene expression. Altogether, these findings suggest a proinflammatory contribution of IL-31 in close association with the Th17 cytokine profile in PsA.
Subject(s)
Arthritis, Psoriatic/metabolism , Arthritis, Psoriatic/pathology , Cytokines/metabolism , Inflammation/metabolism , Inflammation/pathology , Interleukins/metabolism , Th17 Cells/metabolism , Adult , Aged , Cross-Sectional Studies , Cytokines/blood , Female , Humans , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukins/genetics , Male , Middle Aged , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolismABSTRACT
Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the -675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the -675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The -675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81-3.87; p < .001) and 4G/4G (OR = 2.70; CI 1.62-4.51; p < .001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31-2.03; p < .001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84-3.84; p < .001). The 4G/5G genotype was associated with shorter disease duration (p = .039), as well as lower levels of haemoglobin (p = .001) and haematocrit (p = .009); the need for prednisone treatment (p = .001), higher BMI (p = .03), presence of type 2 DM (p = .015), clinical activity (Mex-SLEDAI = 57%; p = .047), Chronicity (SLICC-ACR = 0; p = .015) and CRP levels (p = .015) were associated with 5G/5G genotypes. In conclusion, the -675 4G/5G and 4G/4G PAI-1genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.
Subject(s)
Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Plasminogen Activator Inhibitor 1/genetics , Adolescent , Adult , Alleles , Amplified Fragment Length Polymorphism Analysis , Chronic Disease/drug therapy , Chronic Disease/epidemiology , Comorbidity , Cross-Sectional Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Dyslipidemias/epidemiology , Dyslipidemias/genetics , Female , Gene Frequency , Hematocrit , Hemoglobins/analysis , Heterozygote , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/epidemiology , Male , Mexico/epidemiology , Middle Aged , Obesity/epidemiology , Obesity/genetics , Polymorphism, Restriction Fragment Length , Prednisone/therapeutic use , Young AdultABSTRACT
B cell-activating factor (BAFF) is an essential cytokine in primary Sjögren's syndrome (pSS) physiopathology. It has been reported that pSS patients develop germinal center-like (GC-like) structures in their minor salivary glands (MSGs). BAFF, BAFF-R, TACI, and BCMA expression was analyzed in MSGs from 29 subjects (nonspecific chronic sialadenitis and focal lymphocytic sialadenitis with the presence [pSS-GC(+)] or absence [pSS-GC(-)] of GC-like structures). Twenty-four percent of patients showed ectopic GC-like structures and a high focus score [p < 0.001 vs pSS-GC(-)]. BAFF serum levels (sBAFF) were high in pSS patients (p = 0.025 vs healthy subjects). However, the pSS-GC(-) group showed higher sBAFF levels than pSS-GC(+) patients. BAFF and BAFF-R glandular expression levels were higher in pSS-GC(+) patients, without significant differences compared to pSS-GC(-) patients. Soluble levels of BAFF correlated with anti-La/SSB antibodies and disease duration. Our results showed that BAFF could contribute to focal lymphocytic infiltration. The role of BAFF-binding receptors in MSGs is proposed as a mechanism for the possible establishment of ectopic GC-like structures and disease progression in some patients. In conclusion, this study supports previous evidence that considers the active BAFF system role in the pathogenesis of pSS and the need for strong biomarkers in this disease.