Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism. METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways. RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination. CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

Genetic contribution to waist-to-hip ratio in Mexican children and adolescents based on 12 loci validated in European adults.

BACKGROUND/OBJECTIVES: The prevalence of abdominal obesity in Mexican children has risen dramatically in the past decade. Genome-wide association studies (GWAS) for waist-to-hip ratio (WHR) performed predominantly in European descent adult  populations have identified multiple single-nucleotide polymorphisms (SNPs) with larger effects in women. The contribution of these SNPs to WHR in non-European children is unknown. SUBJECTS/METHODS: Mexican children and adolescents (N = 1421, 5-17 years) were recruited in Mexico City. Twelve GWAS SNPs were genotyped using TaqMan Open Array and analyzed individually and as a gene score (GS). RESULTS: Mexican boys and girls displayed 2.81 ± 0.29 and 3.10 ± 0.31 WHR standard deviations higher than children and adolescents from the United States. WHR was positively associated with TG (ß = 0.733 ± 0.190, P = 1.1 × 10-4) and LDL-C (ß = 0.491 ± 0.203, P = 1.6 × 10-2), and negatively associated with HDL-C (ß = -0.652 ± 0.195, P = 8.0 × 10-4), independently of body mass index. The effect allele frequency (EAF) of 8 of 12 (67%) SNPs differed significantly (P < 4.17 × 10-3) in Mexican children and European adults, with no evidence of effect allele enrichment in both populations (4 depleted and 4 enriched; binomial test, P = 1). Ten out of 12 SNPs (83.3%) had effects that were directionally consistent with those reported in GWAS (P = 0.04). HOXC13 rs1443512 displayed the best fit when modeled recessively, and was significantly associated with WHR under a recessive mode of inheritance (ß = 0.140 ± 0.06, P = 2.3 × 10-2). Significant interactions with sex were also observed for HOXC13 rs1443512 and the GS on WHR (P = 2.2 × 10-2 and 1.2 × 10-2, respectively). HOXC13 rs1443512 (ß = 0.022 ± 0.012, P = 4.7 × 10-2) and the GS (ß = 0.007 ± 0.003, P = 7.0 × 10-3) were significantly associated with WHR in girls only. CONCLUSIONS: This study demonstrates that Mexican children are at high risk for abdominal obesity and detrimental lipid profiles. Our data support a partial transferability of sex-specific European GWAS WHR association signals in children and adolescents from the admixed Mexican population.

Dietary patterns in Mexican children and adolescents: Characterization and relation with socioeconomic and home environment factors.

BACKGROUND: Eating habits in children and adolescents are influenced by multiple determinants, which include socioeconomic and home environmental factors. OBJECTIVE: To characterize the dietary patterns in Mexican children and adolescents and to assess its association with socioeconomic and home environmental factors. METHODS: A cross-sectional study was conducted in 878 children and adolescents aged 5-15 years, unrelated, selected randomly from Morelos Sports Unit at north of Mexico City. Dietary, anthropometric, family, and socioeconomic information was obtained from each participant. Dietary patterns were identified through cluster analysis. The association between dietary patterns with socioeconomic and home environmental factors was assessed by a multivariate multinomial logistic regression model. RESULTS: Three major dietary patterns were identified: diverse dietary pattern (D), high fat dietary pattern (HF), and high sugar dietary pattern (HS). 87% of the participants followed the HF or HS dietary patterns (36% & 51%, respectively). Mother's occupation and the child's screen time was associated with a significant likelihood of following a HF and HS dietary patterns. CONCLUSION: A high percentage of children and adolescents reported following a HS or HF dietary pattern, which in turn were associated with socioeconomic and home environmental factors. These results suggests priority groups for prevention and control actions.

High relative abundance of firmicutes and increased TNF-α levels correlate with obesity in children.

OBJECTIVE: To investigate the correlation among pro- or anti-inflammatory cytokines and the two main gut microbiota phyla in obese children. MATERIALS AND METHODS: Anthropometric data were obtained from 890 children under 14 years old to determine the degree of obesity. Serum cytokine concentration was measured by ELISA. Relative abundance of gut microbiota in feces was evaluated by quantitative RealTime PCR assays. RESULTS: Anthropometric and biochemical parameters were statistically higher in overweigth/ obese children (OW/O) than in lean (NW), Increased TNF-α levels were found in obese children that also have a high relative abundance of Firmicutes. CONCLUSIONS: Obese children have a high relative abundance of Firmicutes that correlates with increased levels of TNF-α. This is the first study that shows a relation between Firmicute abundance and TNF-α serum concentration in obese children.

Androgen receptor CAG polymorphism and sporadic and early-onset prostate cancer among Mexican men.

A short CAG repeat length in the gene encoding for the androgen receptor (AR) has been associated with prostate cancer (PC) risk and aggressiveness. In Latino men, information on this association is scarce. Hence, the aim of this study was to evaluate this association in Mexican males. Using fragment analysis by capillary electrophoresis, we determined the number of CAG repeats-(CAG)n-in AR gene from 158 incident PC cases and 326 age-matched healthy controls (±5 years), residing in Mexico City, Mexico. According to Gleason scale and age at diagnosis, cases were classified as high (⩾7) and low grade (<7), as well as early onset (<60 years) or late onset PC (⩾60 years). At diagnosis, 78% of cases were classified as high-grade and 26.6% as early onset. Men with sporadic (no family history of PC) and early-onset PC presented shorter CAG repeat length than controls (18.6±2.2 vs 19.5±2.5; P=0.02). Lower number of CAG repeats (CAG)⩽19 were associated with a greater risk for early-onset PC (odds ratio: 2.31; 95% confidence interval: 1.14-4.69). CAG repeat length could increase the risk for sporadic and early-onset PC. The best cutoff point for identifying at-risk subjects was (CAG)19. However, further studies are necessary to replicate our findings in subjects with a family history of PC and also to evaluate the association between CAG repeats length and disease progression.

[Definitions for the diagnosis of metabolic syndrome in children]. / Definiciones para el diagnóstico de síndrome metabólico en población infantil.

OBJECTIVE: To present a monographic review of different definitions for the diagnosis of metabolic syndrome (MS) in children. DATA COLLECTION: Consult and literature review. SELECTION OF STUDIES: We included in the review articles in relation to the different definitions used for the diagnosis of MS worldwide. RESULTS: There are significant differences in both criteria for MS in children and adults. Some of these definitions include hyperglycemia after an oral glucose load, while others only consider fasting glycemia; other differences include obesity criteria with different cutoffs for waist circumference (CC) or body mass index (BMI); different values ​​for dyslipidemia criteria for triglycerides (TGC) and high density lipoprotein cholesterol (HDL-C); and different cutoffs for defining high blood pressure (HTA). The approach to each definition differs from the importance that each component or risk factor assumes. CONCLUSION: It is important to establish an appropriate definition for the diagnosis of MS in children, under the great controversies reported by authors and expert committees. This variability in the prevalence of MS populations from the use of different criteria makes it difficult to know the prevalence of MS for certain. Having a national consensus would serve to propose appropriate public health actions that could allow us to reduce the rates of morbidity and high costs for health institutions.

PPARγ and PPARGC1B polymorphisms modify the association between phthalate metabolites and breast cancer risk.

CONTEXT: Breast cancer (BC) risk has been differentially associated with urinary levels of some phthalate metabolites. OBJECTIVE: To investigate whether PPARγ and PPARGC1B polymorphisms modulate these associations. MATERIALS AND METHODS: 208 BC cases were age-matched with 220 population controls. Phthalate metabolites were determined by HPLC-MS. PPARγ Pro12Ala (rs1801281) and PPARGC1B Ala203Pro (rs7732671) and Val279Ile (rs17572019) were genotyped. RESULTS: The association between mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and BC risk was positively modified in PPARγ Pro12Ala C carriers. The association with mono-iso-butyl phthalate (MiBP) in PPARGC1B Ala203Pro G carriers was negatively modified. CONCLUSION: PPARγ and PPARGC1B polymorphisms modulate the association between phthalate exposure and BC risk.

The impact of short-chain fatty acid-producing bacteria of the gut microbiota in hyperuricemia and gout diagnosis.

INTRODUCTION/OBJECTIVES: Persistent hyperuricemia is a key factor in gout; however, only 13.5% of hyperuricemic individuals manifest the disease. The gut microbiota could be one of the many factors underlying this phenomenon. We aimed to assess the difference in taxonomic and predicted functional profiles of the gut microbiota between asymptomatic hyperuricemia (AH) individuals and gout patients. METHODS: The V3-V4 region of the 16S rRNA gene of the gut microbiota of AH individuals, gout patients, and controls was sequenced. Bioinformatic analyses were carried out with QIIME2 and phyloseq to determine the difference in the relative abundance of bacterial genera among the study groups. Tax4fun2 was used to predict the functional profile of the gut microbiota. RESULTS: AH individuals presented a higher abundance of butyrate- and propionate-producing bacteria than gout patients; however, the latter had more bacteria capable of producing acetate. The abundance of Prevotella genus bacteria was not significantly different between the patients but was higher than that in controls. This result was corroborated by the functional profile, in which AH individuals had less pyruvate oxidase abundance than gout patients and less abundance of an enzyme that regulates glutamate synthetase activation than controls. CONCLUSION: We observed a distinctive taxonomic profile in AH individuals characterized by a higher abundance of short-chain fatty acid-producing bacteria in comparison to those observed in gout patients. Furthermore, we provide scientific evidence that indicates that the gut microbiota of AH individuals could provide anti-inflammatory mediators, which prevent the appearance of gout flares. Key Points • AH and gout patients both have a higher abundance of Prevotella genus bacteria than controls. • AH individuals' gut microbiota had more butyrate- and propionate-producing bacteria than gout patients. • The gut microbiome of AH individuals provides anti-inflammatory mediators that could prevent gout flares.

IL28B polymorphisms predict the response to chronic hepatitis C virus infection treatment in a Mexican population.

INTRODUCTION: The treatment of hepatitis C virus (HCV) genotype 1 with ribavirin (RBV) and pegylated-interferon alpha (peg-IFNα) provides a low-level sustained virological response (SVR). Single nucleotide polymorphisms (SNPs) in the interleukin 28B (IL28B) gene have been identified as SVR predictors. Our aim was to establish an association between three IL28B SNPs (rs8099917, rs12979860, and rs8103142) and the peg-IFNα/RBV treatment response in a Mexican population cohort with chronic HCV. MATERIAL AND METHODS: A cohort study was performed with 83 chronic HCV patients at the Fundación Clínica Médica Sur in Mexico City. All patients were treated with peg-IFNα and RBV. The data were analyzed by logistic regression, with adjustments for age, gender, and viral genotype, to determine any associations between the SNPs and the treatment response. RESULTS: In the study group of 83 HCV patients, the main genotype was genotype 1 (70%, n = 58) and the overall SVR was 32.53% (n = 27). In the HCV-1 group, SVR was 27%, whereas SVR was 44% in the HCV-2 group. We found an association between rs12979860 CC and SVR in a codominant model (OR = 4.83, 95% CI = 1.12-20.8, P = 0.033). There was no statistically significant association between SVR and rs8099917 or rs8103142. rs12979860 polymorphisms of CC, CT, and TT, were present in 24%, 41%, and 35% of patients, respectively. CONCLUSION: A Mexican HCV-1-infected population treated with peg-IFNα and RVB had a low SVR rate, which was associated with the SNP rs12979860 (CC). SVR was not associated with the SNPs rs8099917 or rs8103142.

[Genetic epidemiology research designs]. / Diseños de investigación en epidemiología genética.

This article describes the features of the epidemiologic research designs most commonly used in genetic association studies. Case-control studies are efficient in evaluating associations between candidate genes and disease. Cohort studies, in contrast, yield a greater degree of causality but are not efficient for the initial exploration to identify gene-disease associations. Cross-sectional studies are less expensive, require less time, and are useful for estimating the prevalence of diseases, risk factors, and genetic variants. Family-based studies have been successful in finding alleles that confer greater risk for developing Mendelian inheritance disorders.

Severe Quantitative Scale of Acanthosis Nigricans in Neck is Associated with Abdominal Obesity, HOMA-IR, and Hyperlipidemia in Obese Children from Mexico City: A Cross-Sectional Study.

Background: Acanthosis nigricans (AN) is a clinical sign that commonly occurs in obesity; however, its specificity and sensitivity have been controversial. It is unknown if AN severity degree can be a useful marker for cardiometabolic disorders screening. We suggest that the stratified analysis of AN severity degree in neck by Burke's scale could be a useful tool in the screening of cardiometabolic alterations in obese children. Objective: The aim of this study was the association of AN severity degree in neck by Burke's scale with anthropometric, biochemical, and inflammatory parameters in obese school-age children from Mexico City. Methods: A cross-sectional study was conducted, including 95 obese school-age children stratified by AN severity degree in neck by Burke's scale. Anthropometric and fasting biochemical measurements were determined. Variables were compared by x 2 test for frequencies and one-way ANOVA with Bonferroni posttest for continuous variables. Linear regression analysis adjusted by gender, BMI, and age was performed to evaluate the association between AN severity degree and cardiometabolic alterations. Statistical significance was set at p < 0.05. Results: As AN severity degree in neck by Burke's scale increased, diastolic blood pressure (p=0.001) and triglycerides (p=0.02) significantly increased and adiponectin significantly decreased (p=0.02). Positive associations between grade 3 AN and waist circumference, HOMA-IR, triglycerides, total cholesterol, and LDL cholesterol were observed. Conclusion: Our findings could be used to identify an easier clinical tool to prevent obesity progression and its complications in pediatrics. There are no similar studies.

A replication study of the IRS1, CAPN10, TCF7L2, and PPARG gene polymorphisms associated with type 2 diabetes in two different populations of Mexico.

Type 2 diabetes (T2D) is a chronic degenerative disease that involves the participation of several genetic and environmental factors. The objective of the study was to determine the association of the IRS1 (rs1801278), CAPN10 (rs3792267), TCF7L2 (rs7903146 and rs12255372), and PPARG (rs1801282) gene polymorphisms with T2D, in two different Mexican populations. We conducted a case-control replication study in the state of Guerrero and in Mexico City, with 400 subjects from Guerrero and 1065 from Mexico City. Data were analyzed by logistic regression, adjusting by ancestry, age, gender, and BMI, to determine the association with T2D. Heterozygosity for the Gly972Arg variant of the IRS1 gene showed the strongest association for T2D in both analyzed samples (OR = 2.43, 95% CI 1.12-5.26 and 2.64, 95% CI 1.37-5.10, respectively). In addition, an association of two SNPs of the TCF7L2 gene with T2D was observed in both cities: rs7903146, (for Guerrero OR = 1.98 CI95% 1.02-3.89 and for Mexico OR = 1.94 CI95% 1.31-2.88) and rs12255372 (OR = 1.79 CI95% 1.08-2.97, OR = 1.78 CI95% 1.17-2.71 respectively). We suggest that our results provide strong evidence that variation in the IRS1 and TCF7L2 genes confers susceptibility to T2D in our studied populations.

Hepatitis C seroprevalence and correlation between viral load and viral genotype among primary care clients in Mexico.

OBJECTIVE: To measure hepatitis C virus (HCV) sero-prevalence, prevalence, hepatitis risk characteristics frequency, and genotype correlation with viral load among clients attending health care clinics. MATERIAL AND METHODS: Venous blood samples from l12 226 consecutive consenting adults were collected from January 2006 through December 2009. HCV antibodies were detected by immunoassay. HCV RNA was detected by qRT-PCR and viral genotype was performed by PCR and LIPA test. RESULTS: The HCV seroprevalence observed was l.5 % (C.I. 95% l.3-l.7), from seropositive individuals 60.9 % reported previous blood transfusion, 28.3% declared to have relatives with cirrhosis, 25.2% had tattoos or piercings, and 6.9% referred to have used drugs. Male gender and transfusion (p<0.001) were the most frequent hepatitis risk characteristics in the HCV seropositive group. Among seropositive subjects 48.3% presented HCV RNA.The most frequent genotype detected in all geographic areas of Mexico was l (subtype lA, 33%; subtype lB, 21.4%) followed by genotype 2 (subtype 2A, 8.50%). Subjects with genotype 1 had a significant correlation with the highest viral load. CONCLUSIONS: Our results show that nearly half of seropositive individuals are chronically infected. HCV infection has been shown in this study to be an emerging health problem in Mexico.

Infant feeding, appetite and satiety regulation, and adiposity during infancy: a study design and protocol of the 'MAS-Lactancia' birth cohort.

INTRODUCTION: The prevalence of childhood obesity has risen dramatically in recent years. A proportion of this burden has been attributed to factors that occur during the first 1000 days of life such as genetic predisposition, breast feeding and complementary feeding. Although the mechanisms by which these factors affect weight and adiposity are less well understood, appetite and satiety regulation may be a key to understanding them. This cohort study aims to investigate the role of appetite and satiety regulation as a mediator in the association between infant feeding practices and genetic polymorphisms with children's growth, adiposity and metabolic risk factors. METHODS AND ANALYSIS: 'MAS-Lactancia' (the first word means 'more' and is also an acronym in Spanish for 'Appetite and Satiety Mechanisms', the second word is 'breastfeeding') is an open, ongoing, prospective birth cohort that began the enrolment in 2016 of mother-child pairs affiliated to the Mexican Social Security Institute and that live in the city of Cuernavaca, Mexico. Pregnant women between 16-week and 22-week gestation are followed during the second half of their pregnancies, at birth and throughout their infant's first 48 months of life (at 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months and 48 months) at the clinic and at-home visits that include questionnaires, anthropometric measurements and biospecimen collection. The main exposure variables are infant feeding (breast feeding and complementary feeding) and genetic polymorphisms (fat mass and obesity-associated, leptin and adiponectin genes). Outcome variables include infant's growth, adiposity and metabolic risk factors. We will conduct longitudinal models and path analyses to identify the potential mediating role of satiety and appetite indicators (leptin, adiponectin, insulin concentrations, appetite and satiety perception). ETHICS AND DISSEMINATION: The study protocol, data collection instruments, consent forms and procedures were approved by the institutional review boards of the National Institute of Public Health and the Mexican Social Security Institute in Mexico. Findings will be disseminated through conferences, peer-reviewed publications and meetings with stakeholders.

A polymorphism in the AT-hook motif of the transcriptional regulator AKNA is a risk factor for cervical cancer.

The AKNA gene is part of the 9q32 susceptibility locus for cervical cancer. A single-nucleotide polymorphism at codon 1119 of AKNA, yields a biologically relevant amino acid change (R1119Q) at the DNA binding AT-hook motif. Genotype frequencies in 97 allele pairs were: R/R = 0.597, R/Q = 0.278, Q/Q = 0.123. Q/Q homozygosity was present in 8.33% of healthy controls, 16.67% of patients with cervical intraepithelial neoplasia and 75% of cervical cancer patients. These differences are highly significant for the presence of Q/Q in cervical cancer (p = 0.01, odds ratio 3.66, 95% confidence interval 1.35-9.94). Therefore, AKNA appears to be an important genetic factor associated with the risk cervical cancer.

Bovine Interferon-Tau Activates Type I interferon-Associated Janus-signal Transducer in HPV16-positive Tumor Cell.

The mechanisms of signal transduction by interferon-tau (IFN-τ) are widely known during the gestation of ruminants. In trophoblast cells, IFN-τ involves the activation of the JAK-STAT pathway, and it can have effects on other cell types, such as tumor cells. Here we report that the HPV16-positive BMK-16/myc cell treated with ovine IFN-τ, results in the activation of the canonical JAK-STAT and non-canonical JAK-STAT pathway. The MAPK signaling pathway was activated, we detected the proteins MEK1, MEK2, Raf1, STAT3, STA4, STAT5 and STAT6. Moreover, IFN-τ induced the expression of MHC Class I, MX and IP10 in the tumor cells and this response may be associated with the viral replication and with the anti-proliferative and the immunoregulatory effects of IFN-τ.

Contribution of MSMB promoter region gene polymorphism to early-onset prostate cancer risk in Mexican males.

Sexually transmitted infections and its contribution to prostate cancer (PC) development have been relevant in different populations. MSMB gene polymorphism (rs10993994) has exhibited an association both with PC as well as the susceptibility to sexually transmitted infections. Hitherto, these conditions have been not studied in Mexico yet, neither if sexually transmitted infections could modify the MSMB and PC association. Herein, socio-demographic features, sexually transmitted infections records, the reproductive backgrounds, and the genetic characterisation were analysed in 322 incident PC cases and 628 population healthy controls from Mexico City. Whole PC, early-onset PC (PC at < 60 years old), late-onset PC (≥ 60 years old), and PC aggressiveness were used to evaluate the genetic variants contribution to PC risk using unconditional logistic regression models. Overall, none associations between the allelic variants of rs10993994 polymorphisms with whole and PC aggressiveness were found. Howbeit, the TT genotype carriers presented the highest susceptibility to develop early-onset PC (OR = 2.66; 95% CI = 1.41, 5.04; p = 0.03) than CC+CT carriers, both with codominant and recessive models. Although none association between whole PC and MSMB gene polymorphism was found, our results were reinforced by prior studies in European descendent populations, suggesting a contribution between rs10993994 and early-onset PC development.

High Relative Abundance of Lactobacillus reuteri and Fructose Intake are Associated with Adiposity and Cardiometabolic Risk Factors in Children from Mexico City.

In Mexico, 3 of 10 children are overweight. Fructose intake and relative abundance (RA) of Lactobacillus reuteri (L. reuteri) in the intestinal microbiota are associated with obesity and diabetes in adults, but studies in children are limited. This study evaluates the association between fructose intake and L. reuteri RA with adiposity and cardiometabolic risk markers in Mexican children dietary information, microbiota profiles, adiposity indicators (Body Mass Index, BMI and Waste Circumference, WC), and cardiometabolic markers were analyzed in 1087 children aged 6-12 years. Linear regression and path analysis models were used. High-tertile fructose intake and L. reuteri RA were positively associated with BMI (ßTertil 3 vs. Tertil 1 = 0.24 (95% CI, 0.04; 0.44) and ßT3 vs. T1 = 0.52 (95% CI, 0.32; 0.72)) and WC (ßT3 vs. T1 = 2.40 (95% CI, 0.93; 3.83) and ßT3 vs. T1 = 3.40 (95% CI, 1.95; 4.90)), respectively. Also, these factors mediated by adiposity were positively correlated with high triglycerides and insulin concentrations and HOMA-IR (p ≤ 0.03) and negatively associated with HDL-C concentration (p < 0.01). High-tertile fructose intake and L. reuteri RA were directly associated with adiposity and indirectly associated though adiposity with metabolic disorders in children. In conclusion, fructose intake and L. reuteri RA were directly associated with adiposity and indirectly associated with metabolic disorders in children, mediated by adiposity.

Role of TLR9 in Oncogenic Virus-Produced Cancer.

Nucleic acid recognition by toll-like receptor 9 (TLR9) initiates signaling pathways that regulate the production of proinflammatory cytokines or type I interferons, as well as many other molecules required to initialize the immune response. The use of synthetic oligodeoxynucleotides (ODNs) has been crucial to emulate the recognition of DNA sequences by TLR9. Furthermore, ODN administration to mice has shown to confer protection against a wide range of viral, bacterial, and parasitic pathogens. In contrast, oncogenic DNA viruses like hepatitis B virus, Epstein-Barr virus, and human papilloma virus inhibit TLR9 expression, thus contributing to the establishment of chronic viral infections. In this review, we will focus on TLR9 signals initiated by ODN recognition, on the inhibition of TLR9 expression mediated by DNA oncogenic viruses, and on TLR9 expression as a relevant event in the progression to cancer, considering other functions of this receptor, aside from viral recognition.

TLR9 gene polymorphism -1486T/C (rs187084) is associated with uterine cervical neoplasm in Mexican female population.

PURPOSE: The aim of this work was to evaluate the association of single nucleotide polymorphisms in TLR9 (-1486 T/C [rs187084], -1237T/C [rs5743836] and G2848A [rs352140]) with HPV infection, squamous intraepithelial lesions, and uterine cervical neoplasm in a Mexican population. Additionally, the peripheral expression of TLR9 was evaluated to evaluate the differences in the TLR9 expression associated with every genotype in the locus -1486 of the TLR9 gene. The serum concentration of TLR9 was evaluated in a randomly selected subsample. METHODS: Genotyping was performed using predesigned 5' endonuc lease assays and the association of the polymorphisms with the diagnosis groups were assessed by performing multinomial regression models. The relative expression of TLR9 in peripheral blood mononuclear cells was evaluated by real-time polymerase chain reaction and the association of the level of TLR9 expression with the diagnosis was evaluated by performing multinomial regression models. The serum concentration of TLR9 was evaluated in a subsample of patients diagnosed with uterine cervical neoplasm by ELISA. RESULTS: The results showed that genotype TT in the -1486 locus of TLR9 was significantly associated with HPV infection (OR = 3.25, 95% CI 1.12-9.46), squamous intraepithelial cervical lesion (OR = 3.76, 95% CI 1.36-10.41), and uterine cervical neoplasm (OR = 5.30, 95% CI 1.81-15.55). Moreover, the highest level of TLR9 expression was significantly associated with a greater risk for developing squamous intraepithelial cervical lesion and uterine cervical neoplasm. The serum TLR9 concentration was higher in patients with uterine cervical cancer than in controls. CONCLUSION: Our findings indicate that genotype TT in the -1486 locus of the TLR9 gene could comprise a risk genotype for HPV infection, squamous intraepithelial cervical lesion, and uterine cervical neoplasm in Mexican female population. Further studies with larger samples are needed to evaluate if the peripheral expression of TLR9 could be used as a biomarker of uterine cervical neoplasm progression.