Patricia Castro-Santos

Significant association of the KIR2DL3/HLA-C1 genotype with susceptibility to Crohn's disease.

We aimed to analyze the possible association of KIR/HLA-C genotypes with the susceptibility to Crohns disease (CD) in a Spanish population. A total of 125 patients with CD and 339 healthy controls were selected for this study. KIR and HLA-C typing were developed by sequence-specific oligonucleotide probing. We found that the centromeric A/A genotype and HLA-C1 combination was significantly increased in CD patients (P<10(-3)). The KIR2DL3/2DL3 genotype was significantly increased in CD patients (P<0.0005). Moreover, we also observed a highly significant increase of KIR2DL3-HLA-C1 homozygosis in CD patients (P<0.0005). Our results confirm the relevance of the KIR2DL2/KIR2DL3 genes and their interaction with HLA-C to CD. We show that the contribution of the KIR genes to CD susceptibility extends beyond the association with individual KIRs, with an imbalance between activating and inhibitory KIR genes seeming to influence the susceptibility to CD.

Genetic study confirms association of HLA-DPA1∗01:03 subtype with ankylosing spondylitis in HLA-B27-positive populations

The association of human leukocyte antigen (HLA)-B27 with ankylosing spondylitis (AS) has been known for over 38 years. However, it is not the only gene associated with AS. The aim of this study was to confirm the association of HLA markers around HLA-DPA1/DPB1 region with AS in HLA-B27 positive populations. Five SNPs (rs422544, rs6914849, rs92777535, rs3128968 and rs2295119) from the HLA-DPA1/DPB1 region were genotyped in 340 individuals HLA-B27-positive from Portugal (137 AS patients and 203 healthy controls). Characterizations of HLA-DPA1/DPB1 alleles were also performed. rs422544 revealed a significant association with AS (P<0.05) and sliding windows (SW) analysis showed association of some groups of adjacent SNPs within HLA-DPA1/DPB1 region with AS (P<0.05). We also found association of the HLA-DPA1(∗)01:03 allele with AS (P<0.05). This is the first study that confirms the association of HLA markers and haplotypes around HLA-DPA1 and HLA-DPB1 with AS.

ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population:

Large genome-wide analysis studies (GWAS) and meta-analyses have dramatically increased our knowledge of the genetic risk factors of inflammatory bowel disease (IBD), identifying at least 163 loci. The endoplasmic reticulum aminopeptidase-2 (ERAP2) gene has been reported as a potential candidate gene for IBD. GWAS have also shown the potential associations between ERAP single nucleotide polymorphisms (SNP) loci and susceptibility to several autoimmune diseases, and ERAP1 and ERAP2 polymorphisms are related to HLA class I-associated diseases, including ankylosing spondylitis and Behçet’s disease. Interestingly, these associations were confined to individuals carrying HLA class I-risk alleles. The aim of this study was to investigate the association of ERAP1 and ERAP2 SNPs with IBD in a Spanish population, analysing their possible interaction with specific HLA-C alleles to IBD susceptibility. A total of 367 individuals were divided into 216 IBD cases and 151 controls. SNP genotyping was performed using TaqMan® genotyping assays, whereas HLA-C typing was analysed by sequence-specific oligonucleotide probing. Herein, we report an association of the ERAP1 SNP rs30187 with the HLA-C*07 allele. The existence of shared inflammatory pathways in immunologically related diseases together with the understanding of ERAP1 function may offer clues to novel treatment strategies.

Genética, HLA-B27 y espondilitis anquilosante: 40 años

Ankylosing spondylitis (AS) is a prototypical inflammatory disease of the locomotor system affecting axial skeleton. It is part of the general group of spondyloarthopathies (SpA). Its strong association with histocompatibility antigen HLA-B27 is known since 1973. However, HLA-B27 contribution to AS genetic risk is approximately 16%. Therefore, other genes are necessarily involved in the pathogenesis of the disease. Genomic development and the possibility of making genome wide screening have contributed enormously to the study of the disease. In this paper, we describe the actual knowledge about AS genetic risk, which has contributed to understand the influence of HLA-B27 on the etiology and pathogenesis of the disease. We also intend to foresee how these findings will result in an improvement of patients’ quality of life

Genetics of rheumatoid arthritis: a new boost is needed in Latin American populations.

Rheumatoid arthritis (RA) is an autoimmune inflammatory rheumatic disease which affects several organs and tissue, predominantly the synovial joints. Like many other autoimmune diseases, RA is a complex disease, where genetic variants, environmental factors and random events interact to trigger pathological pathways. Genetic implication in RA is evident, and recent advances have expanded our knowledge about the genetic factors that contribute to RA. An exponential increment in the number of genes associated with the disease has been described, mainly through gene wide screen studies (GWAS) involving international consortia with large patient cohorts. However, there are a few studies on Latin American populations. This article describes what is known about the RA genetics, the future that is emerging, and how this will develop a more personalized approach for the treatment of the disease. Latin American RA patients cannot be excluded from this final aim, and a higher collaboration with the international consortia may be needed for a better knowledge of the genetic profile of patients from this origin.

Histological Changes Implicated in Metastasis

El desarrollo de malignidad esta asociado con la adquisicion de la capacidad de invadir otros tejidos. Varios procesos diferentes han sido asociados con la aparicion de metastasis. Concretamente, la transicion epitelio mesenquima (TEM), un mecanismo asociado con embriogenesis y reparacion de heridas pero tambien con adquisicion de movilidad, es uno de ellos. En la TEM, una celula epitelial pierde sus caracteristicas epiteliales, sus uniones con las celulas vecinas y con la lamina basal y adquiere movilidad y caracteristicas mesenquematicas. Tambien han sido asociados factores del microambiente del tumor. La presencia del tumor produce una respuesta en el tejido que lo rodea descrito como estroma reactivo. Sus caracteristicas son similares a las del estroma de las heridas en proceso de curacion: un incremento del numero de fibroblastos y un aumento de la densidad de capilares. La gran diferencia es la cronicidad del proceso tumoral. De gran relevancia es el papel de los macrofagos activados que muestran un fenotipo caracteristico. Finalmente, los fibroblastos asociados a cancer (FAC) son un tipo de celulas encontradas en tumores, que se desarrollan a partir del tejido local o quiza de la medula osea. Los FAC, de modo caracteristico muestran una morfologia diferente y secretan una gran cantidad de metaloproteasas permitiendo a la celula tumoral avanzar a traves del tejido. Ademas, los FAC ejercen un efecto directo sobre la supervivencia de las celulas epiteliales. Los tres procesos estan interrelacionados y la metastasis es causada probablemente por el efecto de todos ellos y probablemente por otros factores adicionales.

Genomics and epigenomics in rheumatic diseases: what do they provide in terms of diagnosis and disease management?

Most rheumatic diseases are complex or multifactorial entities with pathogeneses that interact with both multiple genetic factors and a high number of diverse environmental factors. Knowledge of the human genome sequence and its diversity among populations has provided a crucial step forward in our understanding of genetic diseases, identifying many genetic loci or genes associated with diverse phenotypes. In general, susceptibility to autoimmunity is associated with multiple risk factors, but the mechanism of the environmental component influence is poorly understood. Studies in twins have demonstrated that genetics do not explain the totality of the pathogenesis of rheumatic diseases. One method of modulating gene expression through environmental effects is via epigenetic modifications. These techniques open a new field for identifying useful new biomarkers and therapeutic targets. In this context, the development of “-omics” techniques is an opportunity to progress in our knowledge of complex diseases, impacting the discovery of new potential biomarkers suitable for their introduction into clinical practice. In this review, we focus on the recent advances in the fields of genomics and epigenomics in rheumatic diseases and their potential to be useful for the diagnosis, follow-up, and treatment of these diseases. The ultimate aim of genomic studies in any human disease is to understand its pathogenesis, thereby enabling the prediction of the evolution of the disease to establish new treatments and address the development of personalized therapies.