Maternal Fibroblast Growth Factor 21 Levels Decrease during Early Pregnancy in Normotensive Pregnant Women but Are Higher in Preeclamptic Women-A Longitudinal Study.

(1) Background: Fibroblast growth factor 21 (FGF-21) is an endocrine factor involved in glucose and lipid metabolism that exerts pleiotropic effects. The aim of this study was to investigate the serum FGF-21 profile in healthy and mild preeclamptic pregnant women at each trimester of pregnancy; (2) Methods: Serum FGF-21 levels were determined by ELISA in a nested case-control study within a longitudinal cohort study that included healthy (n = 54) and mild preeclamptic (n = 20) pregnant women, women at three months after delivery (n = 20) and eumenorrheic women during the menstrual cycle (n = 20); (3) Results: FGF-21 levels were significantly lower in the mid-luteal phase compared to the early follicular phase of the menstrual cycle in eumenorrheic women (p < 0.01). Maternal levels of FGF-21 were significantly lower in the first and second trimesters and peaked during the third trimester in healthy pregnant women (p < 0.01). Serum levels of FGF-21 in healthy pregnant were significantly lower in the first and second trimester of pregnancy compared with the follicular phase of the menstrual cycle and postpartum (p < 0.01). Serum FGF-21 levels were significantly higher in preeclamptic compared to healthy pregnant women during pregnancy (p < 0.01); (4) Conclusions: These results suggest that a peak of FGF-21 towards the end of pregnancy in healthy pregnancy and higher levels in preeclamptic women might play a critical role that contributes to protecting against the negatives effects of high concentrations of non-esterified fatty acids (NEFA) and hypertensive disorder. Furthermore, FGF-21 might play an important role in reproductive function in healthy eumenorrheic women during the menstrual cycle.

Laminin-1 (LM-111) in preeclampsia and systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies. SLE has been associated with placental pathology, a finding that is also the determinant in preeclampsia (PE). Genetic evidence and serologic reports suggest laminin-1 (LM-111) as an immunogenic molecule and its polymorphic gene as a candidate gene for both disorders. OBJECTIVE: To evaluate the association between LAMA1 (rs543355) and LAMC1 (rs20563) polymorphisms and the presence of SLE and PE as well as to determine serum levels of anti-LM-111 autoantibodies in the PE group. METHODS: Group A: 169 women with PE and 172 healthy pregnant women. Group B: 204 women with SLE and 204 healthy women. Anti-LM-111 for group A was measured by ELISA and the genotyping was done by using a PCR system. RESULTS: Group A: Levels of anti-LM-111 was similar in women with PE and the control group (p = 0.3). The allelic frequencies and genotypes did not show statistically significant differences for LAMA1 and LAMC1 polymorphisms. Group B: Significant differences between SLE patients and controls for rs543355 polymorphism were not observed. Nevertheless, LAMC1 rs20563 A-allele provided protection against the development of SLE (OR 0.73, 95%CI 0.55-0.96). CONCLUSIONS: Serum levels of anti-LM-111 at the third trimester of gestation do not seem to have any direct relationship with the presence of PE, and the SNPs evaluated are not associated with the risk of developing this disorder. LAMC1 polymorphism could be a protective factor for SLE.

Complejo de la esclerosis tuberosa, revisión de tema y presentación de caso / The tuberous sclerosis complex, review and case presentation

La esclerosis tuberosa fue descrita por primera vez en 1880 y corresponde a un trastorno autosómico dominante, en el que se ha identificado la mutación de dos genes responsables de la enfermedad. Desencadena una enfermedad sistémica que cursa con convulsiones y manifestaciones cutáneas, además de compromiso de riñón, pulmón y corazón. El compromiso del sistema nervioso central genera una gran morbilidad en los pacientes que la padecen, usualmente ante la presencia de tubérculos corticales, y el desarrollo a mediano plazo de las capacidades cognitivas depende su manejo temprano. El diagnóstico se establece por el cuadro clínico a partir de criterios mayores y menores establecidos, además del apoyo de estudios de imágenes y moleculares que permiten identificar las mutaciones de los genes TSC1 y TSC2. El manejo quirúrgico de las lesiones mejora la evolución clínica y el aspecto físico del paciente.

Relevancia funcional de los polimorfsmos del gen de la enzima óxido nítrico sintasa endotelial / Functional relevance of polymorphisms of endothelial nitric oxide synthase gene

El óxido nítrico (NO) juega un papel importante en la regulación de la homeostasis vascular. La producción endotelial de NO está regulada por la óxido nítrico sintasa endotelial (NOSe), por lo tanto variaciones genéticas en el gen NOS3 podrían infuir en la producción de NO. Tres polimorfsmos (Glu298Asp, intrón-4 y -786T>C) en el gen NOS3, han sido asociados de forma inconsistente con enfermedades cardiovasculares (ECV). Estas variantes genéticas se han asociado con disminución de RNAm, concentración séricas bajas de nitritos/nitratos y disminución de la reactividad endotelial. A pesar de la amplia investigación de estos polimorfsmos en ECV y de las aproximaciones para evaluar el papel funcional, no existe evidencia sufciente que permita esclarecer el papel causal y funcional de dichos polimorfsmos sobre la enfermedad. Se requiere de nuevas estrategias que permitan seleccionar polimorfsmos funcionales para determinar el riesgo atribuido al genotipo sobre la enfermedad. En la presente revisión se discute el posible efecto sobre la expresión de la actividad de la NOSe de esto tres polimorfsmos genéticos descritos como de alta relevancia clínica en enfermedades cardiovasculares.

Nitric oxide (NO) plays an important role on vascular homeostasis regulation. NO endothelial production is regulated by endothelial nitric-oxide synthase (eNOS), reason for which genetic variations in NOS3 gene could infuence NO production. Three polymorphisms (Glu298Asp, intron-4, and -786T>C) in NOS3 gene have been inconsistently associated with cardiovascular diseases (CVD). These genetic variables have been linked to diminishment mRNA, nitrites/nitrate low serum levels, and low endothelial reactivity.Despite wide research on these polymorphisms in CVD and several approaches to evaluate their functional role, not enough evidence is available to clarify their functional and causal participation over the disease. New strategies are required to select functional polymorphisms and to determine genotype-attributable risk over disease. In this paper, we review and discuss the possible effect on NOSe activity expression of these genetic polymorphisms with high clinical relevance in CVD diseases.

The simultaneous presence of IL-1B and TNFA two-positions risk haplotypes enhances the susceptibility for celiac disease.

To assess the joint contribution of interleukin 1 beta (IL-1B) and tumor necrosis factor alpha (TNFalpha) to the genetic risk of developing celiac disease (CD), we analyzed four biallelic polymorphisms of TNFA and IL-1B genes in 228 patients and 244 healthy controls. The individual contribution of TNFA -308A and IL-1B -511C alleles was weak (OR 1.47 and 1.66, respectively) and was null for TNFA -238 A/G and IL-1B +3953 C/T single nucleotide polymorphisms (SNPs). Due to the potential linkage disequilibrium between TNFA, human leukocyte antigen (HLA) -DQA1 and HLA-DQB1 genes, only individuals carrying DQ2 antigen (DQ2-positive) were considered to perform haplotype analyses. Two-position risk haplotypes were first defined by the combined presence of -511C and +3953T alleles for IL-1B (OR 9.402) or -308A and -238A alleles for TNFA (OR 15.389). The TNFA/IL-1B combined haplotype-stratified association analysis showed that the simultaneous presence of TNFA risk and IL-1B non-risk haplotypes (OR 13.32) but not TNFA non-risk and IL-1B risk haplotypes (OR 0.71) is associated with CD. Interestingly, our data suggest that the coexistence of both risk haplotypes seems to work synergistically (OR 29.59), which enhances the risk of developing CD.

Physiological and pathological implications of laminins: from the gene to the protein.

The extracellular matrix plays an important role in modulating the behavior of cells with which it interacts. There are a number of families of extracellular matrix (ECM) proteins including collagens, proteoglycans and laminins (LM). LM are the major component of the basal lamina (BL). Here, we review the current knowledge on their structure, self-assembly, binding mechanisms, diverse tissue-expression patterns and its impact on pathology. Studies and hypothesis exploring the role of LM and their polymorphic genes on autoimmune diseases (AIDs) such as systemic lupus erythematosus and Sjögren's syndrome (SS) are also discussed.

Epigenética y epigenómica de la artritis rematoide / Epigenetics and epigenomics of rheumatoid arthritis

Resumen: Los mecanismos epigenéticos, como son las modificaciones del DNA y las histonas, dan como resultado un silenciamiento heredable de los genes, sin cambios en la secuencia codificante. A pesar que el estudio de las enfermedades humanas se ha centrado principalmente en mecanismos genéticos, una alteración en la red de eventos epigenéticos puede causar varias patologías, entre las cuales se encuentran el cáncer, síndromes de inestabilidad cromosómica y enfermedades autoinmunes (EAI). Estudios recientes en epigenética, que incluyen la mutilación del DNA y sus respectivas enzimas reguladoras, podrían contribuir a la comprensión de la fisiopatología de EAI como la artritis reumatoide (AR). En este artículo se revisa la importancia de la metilación del DNA en la AR, en especial la hipometilación. Existe un gran potencial en el desarrollo de ôterapia epigenético y varios inhibidores de las enzimas que controlan estos procesos, especificamente las DNA metiltransferasas y las deacetilasas de histonas, podrían ser una esperanza para el tratamiento de la AR.

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks may lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and autoimmune diseases. Recent studies on epigenetics, including DNA methylation and its regulatory enzymes, could contribute to the understanding of the rheumatoid arthritis (RA) pathogenesis. Herein, we review the DNA methylation and its importance in RA. Several studies have indicated the importance possible of DNA methylation, especially hypomethylation, in the etiology of RA. As a corollary, epigenetic therapy which includes several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone...

Non-HLA associations with autoimmune diseases.

Susceptibility to autoimmune diseases (AID) has been associated with multiple combinations of genes and environmental or stochastic factors. The strongest influence on susceptibility to autoimmunity is the major histocompatibility complex (MHC), in particular HLA; however, linkage analyses among multiple affected family members have established that non-MHC chromosomal susceptibility regions also influence the susceptibility towards AID. Besides HLA, three non-HLA genes have been convincingly associated with different AID: Citotoxic T lymphocyte-associated antigen 4 (CTLA4), Protein Tyrosine Phosphatase (PTPN22) and Tumor Necrosis Factor-alpha (TNF), indicating that autoimmune phenotypes could represent pleiotropic outcomes of non-specific diseases' genes that underline similar immunogenetic mechanisms. Identification of genes that generate susceptibility will enhance our understanding of the mechanisms that mediate these complex diseases and will allow us to predict and/or prevent them as well as to discover new therapeutic interventions.