Javier Fernández-Torres

The HIF1A rs2057482 polymorphism is associated with risk of developing premature coronary artery disease and with some metabolic and cardiovascular risk factors. The Genetics of Atherosclerotic Disease (GEA) Mexican Study.

The aim of the present study was to establish the role of HIF1A gene polymorphisms in the risk of developing premature coronary artery disease (CAD) in a well-characterized clinical cohort. Three polymorphisms in HIF1A (rs11549465, rs11549467, rs2057482) gene were genotyped in 949 patients with premature CAD, and 676 healthy controls (with negative calcium score by computed tomography). Under a dominant model adjusted for age, visceral to subcutaneous adipose tissue (VAT/SAT) ratio, hypertension, type 2 diabetes mellitus (T2DM), HDL-C levels, hypercholesterolemia and hypertriglyceridemia, the rs2057482 T allele was associated with decreased risk of premature CAD when compared to healthy controls (OR = 0.616, P(dom) = 0.020). The effect of the studied polymorphisms on various metabolic parameters and cardiovascular risk factors was explored. In this analysis, the rs2057482 T allele was associated with decreased risk of obesity, central obesity, hypertension, hypercholesterolemia, hypertriglyceridemia and increased risk of T2DM. Under a dominant model adjusted by age, the HIF1A rs2057482 T polymorphism was associated with high VAT/SAT ratio (P = 0.009) and HDL-C levels (P = 0.04) in healthy controls. The results suggest that HIF1A rs2057482 polymorphism is involved in the risk of developing CAD and is associated with some metabolic parameters and cardiovascular risk factors.

Ultrasound in psoriatic arthritis. Can it facilitate a best routine practice in the diagnosis and management of psoriatic arthritis

Important advances from both therapeutic and clinical assessment have recently been reported in psoriatic arthritis (PsA). Moreover, the constant challenge to provide a more comprehensive assessment of this heterogeneous disease results in a variety of clinical instruments that help the clinician for a global evaluation of both disease activity and responsiveness. The current European League Against Rheumatism (EULAR) recommendations on the use of imaging suggest the use of ultrasound (US) in chronic arthritis to increase the diagnostic accuracy and improvement of its management as compared to clinical examination alone. Although US findings are not firmly established in daily clinical practice, it demonstrated several positive aspects such as good sensitivity and specificity, acceptable reliability, and adequate sensitivity to change, especially in the peripheral PsA. Additionally, recent works introduced the role of US in the assessment of skin and nails opening interesting area of research. The aim of this paper is to describe the potential role of US in the assessment of PsA and to discuss the current evidence supporting its application in daily clinical practice.

The Overexpression of NALP3 Inflammasome in Knee Osteoarthritis Is Associated with Synovial Membrane Prolidase and NADPH Oxidase 2

Osteoarthritis is characterized by the presence of proinflammatory cytokines and reactive oxygen species. We aimed to clarify the role of prooxidant enzyme content at the synovial membrane level and how it correlates with the inflammatory process in patients with knee osteoarthritis (KOA). In synovial membranes from KOA patients and control group, we analyzed the protein content of prooxidant enzymes such as Nox2, xanthine oxidase (XO), and prolidase as well as the proinflammatory NALP3. Results show that protein content of prolidase and Nox2 increased 4.8- and 8.4-fold, respectively, and XO showed an increasing trend, while the NALP3 inflammasome increased 5.4-fold with respect to control group. Levels of prolidase and XO had a positive correlation between the levels of NALP3 and Nox2. By principal component analysis the protein expression pattern by study groups was evaluated. Three clusters were identified; protein expression patterns were higher for clusters two (prolidase) and three (XO and Nox2) between KOA patients and controls. Data suggest that prooxidant enzymes increase in synovial membrane of KOA patients and may contribute to the inflammatory state and degradation of the articular cartilage.

The ancestry of the HLA-DRB1*15 allele predisposes the Mexican mestizo to the development of aplastic anemia.

UNLABELLED Aplastic anemia (AA) is a hematological disorder characterized by pancytopenia in peripheral blood and hypoplasia in the bone marrow; the majority of cases have no known etiology, but it is thought that genetic and environmental factors can be involved in its pathogenesis. From the genetic viewpoint, it has been reported a significant increase frequency of the human leukocyte antigen HLA-DRB1(∗)15 in patients with AA as compared to ethnically matched healthy controls, this is true in different populations worldwide, which would suggests that this allele participates in the immune regulation of the disease. OBJECTIVE To determine gene frequencies of HLA-DRB1 alleles in Mexican mestizo patients with AA. METHODS We analyzed and compared the HLA-DRB1 alleles in 36 Mexican mestizo patients (female gender, n=13; male gender, n=23) with AA to those present in 201 umbilical cord blood (UCB) samples as a control group, this was done by means of the polymerase chain reaction-single specific primer (PCR-SSP) technique. RESULTS Analysis of gene frequencies of HLA-DRB1(∗) alleles exhibits a significant increase of HLA-DRB1(∗)15 allele in the group of patients with AA as compared to those present in the control group (15.27% vs. 2.23%, respectively; p=1×10(-5); odds ratio [OR]=9.3; 95% confidence interval [95% CI]=3.2-27.8). CONCLUSIONS Our results showed a positive association of the DRB1(∗)15 allele in Mexican patients with aplastic anemia, which coincides with that reported internationally. In addition, we think that this allele was introduced to the Mexican population structure inherited from European ancestry.

HLA-B*40 Allele Plays a Role in the Development of Acute Leukemia in Mexican Population: A Case-Control Study

Among oncohematological diseases, acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are characterized by the uncontrolled production and accumulation of blasts that can lead to death. Although the physiopathology of these diseases is multifactorial, a genetic factor seems to be at play. Several studies worldwide have shown association of ALL and AML with several alleles of the major histocompatibility complex (MHC). Objective. To determine gene frequencies of HLA-B alleles in Mexicans (individuals with Native American genetic background admixed with European descent) with ALL and AML. Methods. We compared the HLA-B alleles in 213 patients with ALL and 85 patients with AML to those present in 731 umbilical cord blood (UCB) samples as a control group; this was done by means of the PCR-SSP technique. Results. We found an increased frequency of the HLA-B*40 allele in ALL patients as compared to the control group (14.5% versus 9.84%, P = 0.003, OR = 1.67); this was particularly evident in a subgroup of young (less than 18 years old) ALL patients (P = 0.002, OR = 1.76); likewise, a decreased frequency of HLA-B*40 allele in AML patients was observed as compared to the control group (4.70% versus 9.84%, P = 0.02, OR = 0.42). Conclusions. These results might suggest opposing effects of the HLA-B*40 in the genetic susceptibility to develop ALL or AML and offer the possibility to study further the molecular mechanisms of cell differentiation within the bone marrow lineage.

Gene–gene interactions of the Wnt/β-catenin signaling pathway in knee osteoarthritis

This study was designed to investigate whether genetic polymorphisms of the Wnt/β-catenin signaling pathway and its interactions are involved in the development of knee osteoarthritis (KOA). Patients with KOA (n = 131) and healthy individuals (n = 190) with different ancestry from two Mexican populations (Mexico City and Guadalajara City) were analyzed. Twenty-five SNPs from thirteen genes (WISP1, DKK1, SOST, FRZB, LRP1, LRP4, LRP5, LRP6, GSKB, ADAMTS5, GDF5, FMN2 and COL11A1) involved in the Wnt/β-catenin signaling pathway were genotyped. Genetic and allelic frequencies and gene–gene interactions were performed for this study. After adjusting for age, sex, BMI and admixture, significant associations were found for five SNPs in Mexico City: LRP6 rs12314259 (G/G genotype OR 0.22, P = 0.029; and G allele OR 0.48, P = 0.022), SOST rs851054 (C/T genotype OR 0.42, P = 0.027; and T allele OR 0.62, P = 0.026), FMN2 rs986690 (G/A genotype OR 0.42, P = 0.034; and A allele OR 0.50, P = 0.015), FRZB rs409238 (A/G genotype, OR 2.41, P = 0.022), and COL11A1 rs2615977 (A/C genotype OR 2.39, P = 0.024); no associations for Guadalajara City were found. With respect to gene–gene interactions, the pairwise interactions of WISP1–COL11A1, COL11A1–FRZB, FRZB–SOST and WISP1–FMN2 make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles in both populations. These results suggest that gene–gene interactions in the Wnt/β-catenin signaling pathway play a role in the etiology of KOA.

Emergent nanotherapies in microcrystal-induced arthritis

&NA; The anti‐inflammatory and immunomodulatory effects of nanoparticles in several chronic diseases have been extensively researched. The aim of this review is to examine how nanoparticles modulate the inflammatory pathways that characterize the most prevalent forms of microcrystal‐induced arthritis, including gout, pseudogout, and BCP‐induced arthritis. The nanoparticles of chitosan‐coated calcium phosphate, uricase, aceclofenac, and gold have been investigated in crystal‐inducedarthritis. The most important results of the studies outlined in this review show that nanoparticles can inhibit the expression and the release of some pro‐inflammatory mediators and proteolytic enzymes, and the activity of different transcriptional factors in vitro, as well as decrease the uric acid levels in several studies of in vitro and in vivo models of gout, which show interesting results in terms of decreasing the amount of crystals and tissue damage, respectively. In view of their multiple beneficial effects, nanoparticles can be considered a valuable therapy that contributes to the pharmacological treatment in crystalinduced arthritis. HighlightsNPs modulate the inflammatory pathways of crystal‐induced arthritis.NPs could inhibit the expression of several pro‐inflammatory mediators and proteolytic enzymes in crystal‐induced arthritis.NPs could induce activity of different transcriptional factors, as well as decrease uric acid levels.NPs alleviate inflammatory responses, decreasing the amount of crystals and tissue damage in gout and pseudogout.NPs can be considered a valuable therapy that contributes to the pharmacological treatment in crystal‐induced arthritis.

Common gene variants interactions related to uric acid transport are associated with knee osteoarthritis susceptibility

ABSTRACT Background: The presence of genetic variants in uric acid (UA) transporters can be associated with hyperuricemia, and therefore with an increased risk of monosodium urate (MSU) crystal precipitation. The inflammatory process triggered by these crystals leads to cartilage damage, which, in turn, could promote knee osteoarthritis (KOA). Objective: To determine whether genetic polymorphisms of the UA transporters and their interactions are associated with KOA. Materials and Methods: Two hundred forty-three unrelated Mexican-mestizo individuals were recruited for this case-control study. Ninety-three of them were KOA patients but without gout, and one hundred and fifty healthy individuals with no symptoms or signs of KOA were recruited as controls. Forty-one single-nucleotide polymorphisms (SNPs) involved in the UA transporters were genotyped with OpenArray technology in a QuantStudio 12K flex-System with both cases and controls. Results: After adjusting by age, gender, BMI, and ancestry, significant associations were found for eight SNPs: rs1260326 (GCKR), rs780093 (GCKR), rs17050272 (INHBB), rs1471633 (PDZK1), rs12129861 (PDZK1), rs7193778 (IGF1R), rs17786744 (STC1), and rs1106766 (R3HDM2). With respect to gene–gene interactions, the pairwise interactions of rs112129861 (PDZK1) and rs7193778 (IGF1R); rs17050272 (INHBB) and rs1106766 (R3HDM2); rs1106766 (R3HDM2) and rs780093 (GCKR); rs1260326 (GCKR) and rs17786744 (STC1); and rs17786744 (STC1) and rs1106766 (R3HDM2) make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles on KOA development. Conclusions: Our preliminary results show that the common gene variants related to UA transport are associated with KOA in the Mexican population. Further studies must be carried out to corroborate it.

Fast Morphological Gallbladder Changes Triggered by aHypercholesterolemic Diet

INTRODUCTION AND AIM Obesity is a worldwide epidemic problem, described as a risk factor for hepatic diseases, such as non-alcoholic fatty liver disease and other pathologies related to development of cholesterol crystals and cholesterol gallbladder stones. It has been reported that cholesterol overload may cause hepatic damage; however, little is known about the effects of an acute hypercholesterolemic diet on the gallbladder. The aim of this manuscript was to evaluate the impact of a cholesterol-rich diet on the gallbladder. MATERIAL AND METHODS The study included ten eight-week-old C57BL6 male mice, which were divided into two study groups and fed different diets for 48 h: a hypercholesterolemic diet and a balanced Chow diet. After 48 h, the mice were analyzed by US with a Siemens Acuson Antares equipment. Mice were subsequently sacrificed to carry out a cholesterol analysis with a Refloton System (Roche), a crystal analysis with a Carl Zeiss microscope with polarized light, and a histological analysis with Hematoxylin-eosin staining. RESULTS The hypercholesterolemic diet induced an increase in gallbladder size and total cholesterol content in the bile, along with important histological changes. CONCLUSION Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.INTRODUCTION AND AIM Obesity is a worldwide epidemic problem, described as a risk factor for hepatic diseases, such as non-alcoholic fatty liver disease and other pathologies related to development of cholesterol crystals and cholesterol gallbladder stones. It has been reported that cholesterol overload may cause hepatic damage; however, little is known about the effects of an acute hypercholesterolemic diet on the gallbladder. The aim of this manuscript was to evaluate the impact of a cholesterol-rich diet on the gallbladder. MATERIAL AND METHODS The study included ten eight-week-old C57BL6 male mice, which were divided into two study groups and fed different diets for 48 h: a hypercholesterolemic diet and a balanced Chow diet. After 48 h, the mice were analyzed by US with a Siemens Acuson Antares equipment. Mice were subsequently sacrificed to carry out a cholesterol analysis with a Refloton System (Roche), a crystal analysis with a Carl Zeiss microscope with polarized light, and a histological analysis with Hematoxylin-eosin staining. RESULTS The hypercholesterolemic diet induced an increase in gallbladder size and total cholesterol content in the bile, along with important histological changes. CONCLUSION Cholesterol overloads not only trigger hepatic damage, but also affect the gallbladder significantly.

Papel da via de sinalização do HIF-1α na osteoartrite: revisão sistemática

Osteoarthritis (OA) is the most common form of arthritis and is frequently diagnosed and managed in primary care; it is characterized by loss of articular hyaline cartilage, which is a unique connective tissue that physiologically lacks blood vessels. Articular cartilage survives in a microenvironment devoid of oxygen, which is regulated by hypoxia inducible factor (HIF-1α). HIF-1α is considered the main transcriptional regulator of cellular and developmental response to hypoxia. To date, the relevance of HIF-1α in the assessment of cartilage has increased since its participation is essential in the homeostasis of this tissue. Taking into account the new emerging insights of HIF-1α in the scientific literature in the last years, we focused the present review on the potential role of HIF-1α signaling pathway in OA development, especially in how some genetic factors may influence the maintenance or breakdown of articular cartilage.