Environmental and Genetic Risk Factors in Developmental Dysplasia of the Hip for Early Detection of the Affected Population.

Diagnosis of developmental dysplasia of the hip (DDH) mostly relies on physical examination and ultrasound, and both methods are operator-dependent. Late detection can lead to complications in young adults. Current evidence supports the involvement of environmental and genetic factors, such as single nucleotide variants (SNVs). Incorporating genetic factors into diagnostic methods would be useful for implementing early detection and management of affected individuals. Our aim was to analyze environmental factors and SNVs in DDH patients. We included 287 DDH cases and 284 controls. Logistic regression demonstrated an association for sex (OR 9.85, 95% CI 5.55-17.46, p = 0.0001), family history (OR 2.4, 95% CI 1.2-4.5, p = 0.006), fetal presentation (OR 3.19, 95% CI 1.55-6.54, p = 0.002), and oligohydramnios (OR 2.74, 95%CI 1.12-6.70, p = 0.026). A model predicting the risk of DDH including these variables showed sensitivity, specificity, PPV, and NPV of 0.91, 0.53, 0.74, and 0.80 respectively. The SNV rs1800470 in TGFB1 showed an association when adjusted for covariables, OR 0.49 (95% CI 0.27-0.90), p = 0.02. When rs1800470 was included in the equation, sensitivity, specificity, PPV and NPV were 0.90, 0.61, 0.84, and 0.73, respectively. Incorporating no-operator dependent variables and SNVs in detection methods could be useful for establishing uniform clinical guidelines and optimizing health resources.

COMT and SCN9A gene variants do not contribute to chronic low back pain in Mexican-Mestizo patients.

BACKGROUND: Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT and SCN9A with CLBP and their interaction, in a Mexican-Mestizo population. METHODS: A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. RESULTS: Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 of COMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. CONCLUSION: COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes.

Background: Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods: We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases (n = 30) were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls (n = 30) were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results: Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared (p = 0.0035). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect (OR = 0.04 [0.001-0.36]; p = 0.04). Conclusions: Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

Epigenetic Evaluation of the TBX20 Gene and Environmental Risk Factors in Mexican Paediatric Patients with Congenital Septal Defects.

The TBX20 gene has a key role during cardiogenesis, and it has been related to epigenetic mechanisms in congenital heart disease (CHD). The purpose of this study was to assess the association between DNA methylation status and congenital septal defects. The DNA methylation of seven CpG sites in the TBX20 gene promoter was analyzed through pyrosequencing as a quantitative method in 48 patients with congenital septal defects and 104 individuals with patent ductus arteriosus (PDA). The average methylation was higher in patients than in PDA (p < 0.001). High methylation levels were associated with a higher risk of congenital septal defects (OR = 4.59, 95% CI = 1.57-13.44, p = 0.005). The ROC curve analysis indicated that methylation of the TBX20 gene could be considered a risk marker for congenital septal defects (AUC = 0.682; 95% CI = 0.58-0.77; p < 0.001). The analysis of environmental risk factors in patients with septal defects and PDA showed an association between the consumption of vitamins (OR = 0.10; 95% CI = 0.01-0.98; p = 0.048) and maternal infections (OR = 3.10; 95% CI = 1.26-7.60; p = 0.013). These results suggest that differences in DNA methylation of the TBX20 gene can be associated with septal defects.

The High Clinical Burden of Erosive Hand Osteoarthritis is Associated with Clinical Findings, Pain, and Radiographic Severity.

Varying reports exist on the clinical impact of erosive hand osteoarthritis (EHOA) in terms of pain and articular function. Few studies have assessed the association of a patient's clinical features with the presence of more severe radiographic disease. The aim was to evaluate clinical and radiographic characteristics in EHOA comparing with non-erosive (NEHOA); to examine pain and functional impairment between EHOA and NEHOA; and correlate functional impairment with clinical findings, pain, and radiographic severity. METHODS: 62 patients with EHOA and 57 with NEHO were included. Pain was assessed through Visual Analogue Scale (VAS) and Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain. Functioning was evaluated with the Health Assessment Questionnaire (HAQ) concerning hand function and AUSCAN. Radiographs were scored with the Kallman scale and subchondral erosions with the Verbruggen-Veys method. Student t-tests were used for comparing quantitative data, chi-squared tests for categorical variables, and Pearson or Spearman tests for assessing correlation. RESULTS: Patients with EHOA reported significantly higher levels of pain on the VAS and AUSCAN (p<0.01). In EHOA, VAS positively correlated with the HAQ and AUSCAN scales (rho=0.68 and 0.77). In NEHOA, Visual Analogue Scale (VAS) positively and strongly correlated with HAQ and AUSCAN (rho=0.84 and 0.89). Nodes, Kallman score and erosions showed a positive but weak correlation with HAQ and AUSCAN in both groups. CONCLUSION: Both EHOA and NEHOA participants had functional impairment, but the erosive subtype had higher clinical burden and increased joint damage. This higher clinical burden is attributed mainly to pain.

DNA Methylation Levels of the TBX5 Gene Promoter Are Associated with Congenital Septal Defects in Mexican Paediatric Patients.

The TBX5 gene regulates morphological changes during heart development, and it has been associated with epigenetic abnormalities observed in congenital heart defects (CHD). The aim of this research was to evaluate the association between DNA methylation levels of the TBX5 gene promoter and congenital septal defects. DNA methylation levels of six CpG sites in the TBX5 gene promoter were evaluated using pyrosequencing analysis in 35 patients with congenital septal defects and 48 controls. Average methylation levels were higher in individuals with congenital septal defects than in the controls (p < 0.004). In five CpG sites, we also found higher methylation levels in patients than in the controls (p < 0.05). High methylation levels were associated with congenital septal defects (OR = 3.91; 95% CI = 1.02-14.8; p = 0.045). The analysis of Receiver Operating Characteristic (ROC) showed that the methylation levels of the TBX5 gene could be used as a risk marker for congenital septal defects (AUC = 0.68, 95% CI = 0.56-0.80; p = 0.004). Finally, an analysis of environmental factors indicated that maternal infections increased the risk (OR = 2.90; 95% CI = 1.01-8.33; p = 0.048) of congenital septal defects. Our data suggest that a high DNA methylation of the TBX5 gene could be associated with congenital septal defects.

Epistasis Between Two Gene Variants of Leptin and Vascular Endothelial Growth Factor Genes in the Development of Primary Knee Osteoarthritis.

BACKGROUND: The association of leptin (LEP) and vascular endothelial growth factor A (VEGFA) genes with the susceptibility to knee osteoarthritis (OA) has been analyzed; however, the epistasis between them has not been investigated. OBJECTIVE: The objective of the study was to analyze the association of LEP and VEGFA variants and their interaction with primary knee OA in a Mexican Mestizo population. METHODS: A case-control study was developed. Cases were ≥40 years, BMI ≤27 kg/m2, with primary knee OA and radiologic Grade ≥2. Controls were participants with no knee OA and a radiologic Grade < 2. The rs2167270 of LEP and rs2010963 of VEGFA were genotyped. Genotypic association was tested under codominant, dominant, and recessive models. Uni- and multi-variate analyses were developed through non-conditional logistic regression. The multifactor dimensionality reduction algorithm was developed to detect epistasis. RESULTS: Participants comprised 103 cases and 179 controls. Allelic and genotypic distributions did not show differences between the groups. Notwithstanding, a statistically significant interaction was observed between the LEP and VEGFA genes (p = 0.02) with a testing accuracy of 0.5199 and cross-validation consistency of 10/10. This interaction model confers an increased risk to knee OA (OR [95% CI] = 1.8 [1.1-2.9]). CONCLUSION: Interaction between LEP and VEGFA is related with genetic susceptibility to developing primary knee OA.

Contribution of APOA5, APOC3, CETP, ABCA1 and SIK3 genetic variants to hypertriglyceridemia development in Mexican HIV-patients receiving antiretroviral therapy.

OBJECTIVE: To investigate the impact of single nucleotide polymorphisms (SNPs) from APOA5, APOC3, CETP, ATP binding cassette transporter A1 and SIK3 genes in the development of hypertriglyceridemia in HIV patients under antiretroviral therapy. MATERIAL AND METHODS: A case-control study was developed. Leukocytic genomic DNA was extracted and genotyping for SNPs rs662799, rs964184, rs5128, rs2854116, rs2854117, rs3764261, rs4149310, rs4149267 and rs139961185 was performed by real time-PCR using TaqMan allelic discrimination assays, in Mexican mestizo patients with HIV infection, with hypertriglyceridemia (>1.7 mmol/L) under antiretroviral therapy. Genetic variants were also investigated in a control group of normolipidemic HIV patients (≤ 1.7 mmol/L). Haplotypes and gene interactions were analyzed. RESULTS: A total of 602 HIV patients were genotyped (316 cases and 286 controls). Age and antiretroviral regimen based on protease inhibitors were associated with hypertriglyceridemia (P = 0.0001 and P = 0.0002. respectively). SNP rs964184 GG genotype in APOA5 gene exhibited the highest association with hypertriglyceridemia risk (OR, 3.2, 95% CI, 1.7-5.8, P = 0.0001); followed by SNP rs139961185 in SIK3 gene (OR = 2.3; (95% CI, 1.1-4.8; P = 0.03 for AA vs. AG genotype; and APOC3 rs5128 GG genotype, (OR, 2.2; 95% CI, 1.1-4.9; P = 0.04) under codominant models. These associations were maintained in the adjusted analysis by age and protease inhibitors based antiretroviral regimens. CONCLUSIONS: This study reveals an association between rs964184 in APOA5; rs5128 in APOC3 and rs139961185 in SIK3 and high triglyceride concentrations in Mexican HIV-patients receiving protease inhibitors. These genetic factors may influence the adverse effects related to antiretroviral therapy.

Effect of whole-body vibration training on transcutaneous oxygen levels of the foot in patients with type 2 diabetes: A randomized controlled trial.

Whole body vibration (WBV) has been suggested as improving skin and blood flow. This study aimed to determine the effect of exposure to WBV on levels of partial transcutaneous oxygen pressure (TcPO2) in the foot of patients with type 2 diabetes (T2D) within the metabolic control goals. A block randomized, open, two-arm, parallel and controlled clinical trial was conducted. Participants recruited from the Center of Comprehensive Care for the Patient with Diabetes were assessed at the National Institute of Rehabilitation, Mexico City. Control group underwent multidisciplinary care for T2D; experimental group, in addition to the comprehensive diabetes care, was exposed to WBV through an exercise program, attending three times a week for a period of 3 months. TcPO2 was measured in the feet of the participants at baseline and after 12 weeks. A sample of 50 volunteers with recently-diagnosed T2D and similar baseline characteristics (demographic, cardiovascular risk, presence of diabetic polyneuropathy, and indicators of glycemic control and TcPO2) was recruited. The experimental group (n = 27) showed a mean value of 47.7 ± 6.1 mmHg in TcPO2, significantly higher (p = 0.028) than the 44.3 ± 7.5 mmHg of control group (n = 23), at the end of intervention. In conclusion, exposure to WBV promoted an increase and a significant 3 mmHg difference in the foot TcPO2 levels between those subjects with T2D that underwent the 12-week exercise program and those not exposed to the treatment.

Genetic analysis of muscular dystrophies: our experience in Mexico.

Muscular dystrophies are a group of well-defined genetic disorders characterized by the variable distribution of muscle wasting and progressive weakness. The diagnosis and treatment of these diseases remain challenging due to genetic heterogeneity and clinical overlapping. Herein, we describe our 10 years' experience with the diagnosis and management of muscular dystrophy patients. In total, 169 patients were screened for pathogenic variants in eleven genes linked to frequent muscular dystrophies using MLPA and NGS sequencing panels. Most frequent muscular dystrophies found in the Mexican population were dystrophinopathies, dysferlinopathies and calpainopathies. Novel variants were found in genes: DMD, CAPN3, DYSF, and FKRP. For Duchenne muscular dystrophy, improvements in early diagnosis and prolonged ambulation were achieved, on the contrary, for limb-girdle muscular dystrophies and congenital muscular dystrophies, uncomplimentary follow-up and lack of detection strategies were observed. For most common muscular dystrophies, improvements in diagnosis and management have been achieved in the last 10 years, due to a collaborative effort done nationwide.

The High Clinical Burden of Erosive Hand Osteoarthritis is Associated with Clinical Findings, Pain, and Radiographic Severity.

Varying reports exist on the clinical impact of erosive hand osteoarthritis (EHOA) in terms of pain and articular function. Few studies have assessed the association of a patient's clinical features with the presence of more severe radiographic disease. The aim was to evaluate clinical and radiographic characteristics in EHOA comparing with non-erosive (NEHOA); to examine pain and functional impairment between EHOA and NEHOA; and correlate functional impairment with clinical findings, pain, and radiographic severity. METHODS: 62 patients with EHOA and 57 with NEHO were included. Pain was assessed through Visual Analogue Scale (VAS) and Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain. Functioning was evaluated with the Health Assessment Questionnaire (HAQ) concerning hand function and AUSCAN. Radiographs were scored with the Kallman scale and subchondral erosions with the Verbruggen-Veys method. Student t-tests were used for comparing quantitative data, chi-squared tests for categorical variables, and Pearson or Spearman tests for assessing correlation. RESULTS: Patients with EHOA reported significantly higher levels of pain on the VAS and AUSCAN (p<0.01). In EHOA, VAS positively correlated with the HAQ and AUSCAN scales (rho=0.68 and 0.77). In NEHOA, Visual Analogue Scale (VAS) positively and strongly correlated with HAQ and AUSCAN (rho=0.84 and 0.89). Nodes, Kallman score and erosions showed a positive but weak correlation with HAQ and AUSCAN in both groups. CONCLUSION: Both EHOA and NEHOA participants had functional impairment, but the erosive subtype had higher clinical burden and increased joint damage. This higher clinical burden is attributed mainly to pain.

Are functional variants of the microRNA-146a gene associated with primary knee OA? Evidence in Mexican mestizo population.

MicroRNA-146a (miR-146a) is an inflammatory response regulator whose expression is deregulated in osteoarthritis (OA); variations in the miR-146a gene could affect OA risk. This study aimed to analyze the association between two functional variants of the miR-146a gene and primary knee OA in Mexican mestizo population. Methods and Results. A case-control study was conducted with cases defined as individuals aged ≥ 40 years with primary knee OA grade ≥ 2, according to the Kellgren-Lawrence system. Controls were volunteers with no primary knee OA with radiographic grade < 2. TaqMan allelic discrimination assays genotyped the rs2910164 and rs57095329. Allelic and genotypic frequencies, as well as the Hardy-Weinberg equilibrium (HWE), were calculated. The genetic association was tested under codominant, dominant, and recessive models. Non-conditional logistic regressions were carried out to estimate the association magnitude. We included 310 cases and 379 controls. Despite rs2910164 being in HWE, there was no association under codominant, dominant, and recessive models. In women with OA grade 2, the codominant model found a trend between the CC genotype and increased risk [OR (95% CI) 1.6 (0.7-3.5)]; the same trend was found in OA grade 4 in the codominant and recessive models [1.8 (0.6-5.4) and 2.0 (0.7-5.9)]. Conversely, in men with OA grade 4, the CC genotype tended to be associated with a lower risk in the codominant and recessive models [0.6 (0.1-6.0) and 0.5 (0.1-5.1)]. Conclusion. Our results show that miR-146a gene variants are not significantly associated with primary knee OA in Mexican mestizos.

Genetic Variants and Haplotypes in OPG Gene Are Associated with Premature Coronary Artery Disease and Traditional Cardiovascular Risk Factors in Mexican Population: The GEA Study.

Basic and clinical research have demonstrated that osteoprotegerin (OPG) plays an important role in the development and progression of cardiovascular diseases. The aim of this study was to evaluate the association of four polymorphic sites (rs2073618, rs3134069, rs3134070, and rs3102735) of OPG gene with premature coronary artery disease (pCAD), and with cardiometabolic parameters. The polymorphisms were genotyped using 5' exonuclease TaqMan genotyping assays with real-time PCR in 1098 individuals with pCAD and 1041 healthy controls. rs2073618 polymorphism was associated with a high risk of developing pCAD according to different inheritance models: additive (p = 0.001; odds ratio [OR] = 1.283), dominant (p = 0.006; OR = 1.383), recessive (p = 0.011; OR = 1.423), and codominant 2 (p = 0.001; OR = 1.646). The four polymorphisms were associated with different cardiovascular risk factors in individuals with pCAD and controls. Our results suggest that OPG rs2073618 polymorphism is associated with an increased risk of pCAD. In addition, two haplotypes were associated with pCAD, one increasing the risk (CACT) and another one as protective (GACC).

Phenotypic Spectrum of Myopathies with Recessive Anoctamin-5 Mutations.

BACKGROUND: Biallelic variants in Anoctamin 5 (ANO5) gene are causative of limb-girdle muscular dystrophy (LGMD) R12 anoctamin5-related, non-dysferlin Miyoshi-like distal myopathy (MMD3), and asymptomatic hyperCKemia. OBJECTIVE: To describe clinic, histologic, genetic and imaging features, of ANO5 mutated patients. METHODS: Five patients, four from France (P1, P2, P3 and P4) and one from Mexico (P5), from four families were included. P1 and P2, belonging to group 1, had normal muscle strength; Group 2, P3, P4 and P5, presented with muscular weakness. Muscle strength was measured by manual muscle testing, Medical Research Council (MRC) grades 1/5 to 5/5. Laboratory exams included serum CK levels, nerve conduction studies (NCS)/needle electromyography (EMG), pulmonary function tests, EKG and cardiac ultrasound. ANO5 molecular screening was performed with different approaches. RESULTS: Group 1 patients showed myalgias with hyperCKemia or isolated hyperCKemia. Group 2 patients presented with limb-girdle or proximo-distal muscular weakness. Serum CK levels ranged from 897 to 5000 UI/L. Muscle biopsy analysis in P4 and P5 showed subsarcolemmal mitochondrial aggregates. Electron microscopy confirmed mitochondrial proliferation and revealed discontinuity of the sarcolemmal membrane. Muscle MRI showed asymmetrical fibro-fatty substitution predominant in the lower limbs.P1 and P2 were compound heterozygous for c.191dupA (p.Asn64Lysfs*15) and c.1898 + G>A; P3 was homozygous for the c.692G>T. (p.Gly231Val); P4 harbored a novel biallelic homozygous exons 1-7 ANO5 gene deletion, and P5 was homozygous for a c.172 C > T (p.(Arg 58 Trp)) ANO5 pathogenic variant. CONCLUSIONS: Our cohort confirms the wide clinical variability and enlarge the genetic spectrum of ANO5-related myopathies.

Prevalence of clinical and radiological osteoarthritis in knee, hip, and hand in an urban adult population of Mexico City.

INTRODUCTION: Osteoarthritis (OA) is the most prevalent articular disease worldwide, and its prevalence is highly variable depending on the classification criteria, population studied, and/or affected joints considered. Reporting epidemiologic data about clinical and radiological OA prevalence in Mexico has not been done before. PATIENTS AND METHODS: A descriptive cross-sectional study was carried out with participants of Mexico City, and included both men and women above 40 years of age. All participants were evaluated with radiological and clinical criteria for OA. RESULTS: Two hundred and four individuals participated in the study: 80 men (39.2%) and 124 women (60.8%). The average age was 57.4±10.9 years. Using clinical criteria alone, 36 participants were found to have hand OA (17.6%; 95% CI, 13-23.4), 37 with hip OA (18.1%; 95% CI 13.4-24), and 40 with knee OA (19.6%; 95% CI 14.7-25.6). When radiological criteria were used, 51 individuals were reported as having hand OA (25%; 95% CI 19.5-31), 54 with hip OA (26.5%; 95% CI 20.8-32.9), and 52 with knee OA (25.5%; 95% CI 20-31.8). When clinical criteria were used and then corroborated with radiological criteria, the prevalence was 28 individuals with hand OA (13.7%; 95% CI 9.6-19), 31 with hip OA (15.1%; 95% CI 10.9-20.7), and 36 with knee OA 36 (17.6%; 95% CI 12.2-26.2). DISCUSSION: The prevalences found in this study are greater than those found in other studies in Mexico that only report clinical criteria.

Hearing Aid Use and Auditory Verbal Therapy Improve Voice Quality of Deaf Children.

BACKGROUND: Adequate phonation is self-regulated by auditory feedback. Children with bilateral profound hearing loss (PHL) lack this feedback resulting in abnormal voice. Adequate hearing aid use and auditory-verbal therapy (AVT) may improve voice quality in deaf children. OBJECTIVE: To study whether hearing aid use and AVT approach improve acoustic parameters of voice of children with bilateral PHL. MATERIALS AND METHODS: Nineteen children with bilateral PHL were studied. Age range 2-5 years (X = 53.04 months; SD = 9.54). All children were fitted with hearing aids according to auditory testing and they underwent a 1-year auditory habilitation period using the AVT approach. Acoustic analysis of voice including F0, shimmer, and jitter was performed at the onset and at the end of the auditory habilitation period. Final acoustic data were compared to a matched control group of 19 children, age range 2-5 years (X = 52.85; SD = 9.74) with normal hearing. RESULTS: Mean fundamental frequency (F0) was significantly increased after AVT intervention. Shimmer and jitter significantly (P < 0.05) improved after the intervention period. However, despite the improvements, mean F0 at the end of the intervention period was still significantly (P < 0.05) decreased as compared to controls. Also, mean shimmer and jitter at the end of the habilitation period were still significantly (P < 0.05) higher as compared to controls. CONCLUSIONS: The results of this preliminary study suggest that hearing aid use and auditory habilitation with AVT approach improved acoustic voice parameters of children with PHL. However, acoustic parameters persisted abnormal as compared to matched normal hearing controls. AVT approach and regular hearing aid use seem to be safe and reliable clinical tools for improving voice quality of children with PFL.

DNA methyltransferase genes polymorphisms are associated with primary knee osteoarthritis: a matched case-control study.

DNA methylation is an epigenetic mechanism involved in the development of primary osteoarthritis (OA). The association between DNA methyltransferases (DNMTs) genes polymorphisms and diseases in which DNA methylation plays a role in their pathogenesis has been described (e.g., cancer); however, its relationship with OA has not been investigated. The aim of this study was to analyze the association between DNMT1, DNMT3A, and DNMT3B polymorphisms with radiologic primary knee OA in Mexican mestizo population. A matched case-control study was conducted (ratio, 1:1). Cases included 244 subjects with definite radiographic knee OA (grade ≥ 2). Controls were matched by age and gender and were subjects with no definite radiographic knee OA/normal (grade < 2). The DNMTs polymorphisms were genotyped by TaqMan allelic discrimination assays. Conditional logistic regression was carried out, and the genetic association was tested under co-dominant, dominant, and recessive inheritance models. Haplotypes for DNMT1 polymorphisms were constructed and their associations were also tested. The CC genotypes of rs2228611 and rs2228612 of DNMT1 were associated with a lower risk for primary knee OA under a co-dominant and a recessive model [OR (95% CI) 0.4 (0.2-0.8)/0.5 (0.3-0.8) and 0.3 (0.1-0.8)/0.3 (0.1-0.7), respectively]. The CT haplotype of DNMT1 polymorphisms was associated with a lower risk [OR (95% CI) 0.71 (0.51-0.97)]. The CC genotype of rs2424913 of DNMT3B was associated with an increased risk under a co-dominant and a dominant model [OR (95% CI) 3.0 (1.1-8.0), and 1.6 (1.1-2.4), respectively]. Our results show that DNMTs polymorphisms are associated with primary knee OA.

Telomere length analysis on leukocytes derived from patients with Huntington Disease.

INTRODUCTION: Huntington´s disease (HD) is a neurodegenerative disorder characterized by neuropsychiatric, motor and cognitive manifestations. It is caused by expansion of the trinucleotide CAG on HTT. The molecular bases are not completely understood, DNA damage, such as double and single strand breaks and oxidative stress (OS) have been implicated. At telomeres, DNA breaks are less efficiently repaired. Double strand breaks evoke the break induced replication (BIR) mechanism. BIR, plus inefficient repair can produce telomere shortening and cellular senescence. Our aim was to investigate the correlation between leukocyte relative telomeric length (RTL) and HD. METHODS: 206 samples were analyzed, 71 patients with molecular diagnosis and symptomatology (HD), 29 individuals with positive molecular test but asymptomatic (PP) and 106 healthy individuals (NP). RESULTS: We found a significant difference in RTL between HD patients compared with both, PP and NP, independently of subjects' age. DISCUSSION: Here we present evidence supporting an association between telomere shortening and HD. Telomere shortening could be related to DNA damage caused by ROS and defective DNA repair mechanism. Both events have been probed to occur in the presence of a mutant Huntingtin. This study contributes with current evidence suggesting a potential role of telomere shortening as HD biomarker.

Genetic association analysis of Osteopontin and Matrix Gla Protein genes polymorphisms with primary knee osteoarthritis in Mexican population.

Primary osteoarthritis (OA) is a complex entity in which several loci related to different molecular pathways or classes of molecules are associated with its development as demonstrated through genetic association studies. Genes involved in bone formation and mineralization, such as osteopontin (OPN) and Matrix Gla protein (MGP), could also be related with OA. The aim of this study was to evaluate the association between the genetic variants of OPN and MGP with primary knee osteoarthritis in a Mexican population. A case-control study was conducted in 296 patients with primary knee osteoarthritis and in 354 control subjects. Study groups were assessed radiologically. The rs11730582 of OPN and rs1800802, rs1800801, and rs4236 of MGP were determined by TaqMan allele discrimination assays. The haplotypes of the polymorphisms of MGP were constructed. The association was tested through univariate and multivariate non-conditional logistic regression analyses. The polymorphisms of MGP complied with Hardy-Weinberg (HW) equilibrium. The polymorphisms of OPN and MGP were not significantly associated with primary knee osteoarthritis in the codominant, dominant, and recessive models (p > 0.05). Our study suggests that there are no associations between OPN and MGP polymorphisms with primary knee osteoarthritis in Mexican population.

Association between promoter hypermethylation of the DACT2 gene and tumor stages in breast cancer.

PURPOSE: Aberrant methylation of CpG islands in the promoter is a hallmark of cancer, leading to transcriptional silencing of tumor suppressor genes. The aim of this work was to evaluate the promoter methylation status of the DACT2 gene in breast cancer (BC) tissue and to analyze its possible effect on tumor type or grade. METHODS: CpG island from the DACT2 promoter in region -240 to -14 from transcriptional start site (TSS) were obtained. Through the use of sodium bisulfite DNA conversion analysis, followed by detection with MSP (methylation specific PCR), we analyzed 79 BC and 15 adjacent healthy samples. RESULTS: T he c ases a nalyzed w ere i n s tage I ( 2.5%), I I (38%), or III (59.5%). The most frequent tumor type was invasive ductal carcinoma (71.4%). Methylation analysis comparing tumor tissues with adjacent non-cancerous tissues showed statistical significance. Methylation was observed in 32.9% (26/79) of the samples; no methylation was found in adjacent healthy tissue. DACT2 methylation was associated with tumor stage I-II (p=0.03) and stage III (p=0.004). CONCLUSION: An association was found of DACT2 promoter methylation with advanced tumor stages. This gene has been suggested as a potential biomarker, however, more investigation is required to validate this function.