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Resumen Antecedentes y objetivo La mutacion BRAFT1799A se ha relacionado con caracteristicas tumorales de mas agresividad, recidiva tumoral y persistencia de carcinoma papilar de tiroides (CPT), aunque no todos los estudios apoyan esta asociacion. En este, se analiza la asociacion entre la presencia de la mutacion BRAFT1799A en el tumor primario de pacientes con CPT y las caracteristicas clinicopatologicas de riesgo, recidiva y persistencia tumoral. Pacientes, material y metodo Hemos seguido a 97 pacientes intervenidos de CPT durante una mediana de 64,1 meses. La mutacion BRAFT1799A se determino en acido desoxirribonucleico procedente de muestras de la tiroidectomia inicial mediante amplificacion por PCR del exon 15 del gen braf y analisis de los fragmentos de restriccion con la enzima TspRI. Los casos positivos fueron confirmados por secuenciacion. La asociacion estadistica entre la mutacion BRAFT1799A y las diferentes variables se estudio mediante los correspondientes tests de contraste de hipotesis mas regresion logistica. Resultados El 46,4% de los pacientes eran positivos para la mutacion BRAFT1799A. Tras analisis bivariante y multivariante, la mutacion BRAFT1799A solo se asociaba con edad superior a 60 anos (odds ratio [OR] = 5,5; intervalo de confianza [IC] del 95%, 1,4-21,9; p = 0,019) y tamano de 1 cm o superior (OR = 3,6; IC del 95%, 1,2-10,3; p = 0,016). No se asociaba con subtipos histologicos, metastasis, recidiva, necesidad de nuevos tratamientos ablativos con I131 o de otras intervenciones quirurgicas debidas a la aparicion de metastasis o persistencia de enfermedad al final del seguimiento. Conclusiones La mutacion BRAFT1799A esta asociada a edad superior a 60 anos y tamano tumoral de 1 cm o mayor, pero no con otras caracteristicas clinicopatologicas, recidiva tumoral o persistencia de enfermedad.

Background and objective The BRAF T1799A mutation is reported to be associated with aggressive, persistent, and recurrent tumor in patients with papillary thyroid carcinoma (PTC). The association of the BRAF T1799A mutation in the primary tumor with the clinicopathological characteristics of PTC was analyzed. Patients, materials, and methods Ninety-seven PTC patients were followed up for a median of 64.1 months. The BRAF T1799A mutation was analyzed in DNA from initial thyroidectomy biopsies by PCR amplification and restriction fragment length polymorphism using the TspRI enzyme. Positive results were confirmed by DNA sequencing. The statistical association of the BRAF T1799A mutation and clinicopathological characteristics was analyzed using the relevant hypothesis tests and logistic regression. Results The BRAF T1799A mutation was found in 46.4% of patients. Bivariate and multivariate analyses showed the mutation to be only associated with age over 60 years (odds ratio [OR] = 5.5; 95% confidence interval [CI], 1.4–21.9; p = 0.019) and to a tumor size of 1 cm or greater (OR = 3.6, 95% CI, 1.2–10.3; p = 0.016). The mutation was not associated with histological subtype, metastasis, recurrence, more aggressive treatments (131I ablation therapy or other surgery), or PTC persistence at the end of follow-up. Conclusions The BRAF T1799A mutation is associated with age over 60 and a tumor size of 1 cm or greater, but not with other clinicopathological characteristics, tumor recurrence, or PTC persistence.

iNOS or NOS2 is a molecule that plays a key role in the immunological control of a broad spectrum of infectious agents. Investigation is hampered by difficulty in estimating in vivo production of nitric oxide (NO), but genetic studies provide a potential means of examining the relation between NO production and disease outcome. To better characterize the host genetic factors determining the susceptibility to TB, we evaluated the influence of two polymorphisms in the NOS2A gene on the risk of developing pulmonary TB in a Northwestern Colombian population, which is a moderately-high endemic area. One hundred and fourteen patients with TB and negative for human immunodeficiency virus, plus 304 healthy controls were examined for NOS2A CCTTT and TAAA polymorphisms. A total of 160 healthy controls mentioned before, underwent tuberculin skin test (TST). Analysis disclosed significant differences between patients and controls with NOS2A CCTTT polymorphism (P=0.0001, Pc=0.001, OR=0.4, and 95%CI=0.3-0.7) independent of TST status. When the NOS2A alleles were stratified into short (8-11) and long (12-16) repeats, significant differences with short repeats were observed between TB patients and all controls (P=0.005, OR=0.63, 95%CI=0.46-0.86). No individual association with NOS2A TAAA was detected. These results indicate that a polymorphism in the NOS2A gene influences the susceptibility to TB and suggest a role for NOS2A in the pathogenesis of mycobacterial infection. © 2007 Elsevier Ltd. All rights reserved.

Interleukin 15 (IL-15) is a pleiotropic pro-inflammatory cytokine known to play a relevant role in rheumatoid arthritis (RA) pathogenesis. In this study we aimed to investigate for the first time the contribution of IL15 gene to RA susceptibility. We screened 13 single nucleotide polymorphisms (SNPs) localised within IL15 regulatory regions (promoter, 5' UTR region and 3' UTR region) in a total of 420 individuals, who were genotyped by direct sequencing of PCR products. In addition, an association study of these IL15 SNPs was conducted in three independent case-control cohorts of Spanish Caucasian origin, including a total of 645 RA patients and 656 healthy controls. The presence of the 13 selected IL15 SNPs in our population was confirmed and no new genetic variants were found. The distribution of the IL15 selected SNPs in RA patients and controls showed no statistically significant deviation in any of the populations studied. Additionally, we performed a haplotype analysis that revealed three IL15 haplotype blocks. None of the haplotype blocks was associated with RA susceptibility or severity in the three cohorts analysed. Our results suggest that the IL15 gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.

Transporter associated with antigen processing (TAP) molecules are involved in the processing of endogenous peptides that bind to major histocompatibility complex (MHC) class I molecules. The possible functional significance of TAP polymorphisms for antigenic peptide transport is an unresolved issue. Population genetics is a tool for investigating the evolutionary and functional significance of genetic polymorphisms. We studied 105 unrelated individuals from Eastern Andalusia in Southern Spain for TAP1 and TAP2 polymorphisms and to detect linkage disequilibrium between TAP1 and TAP2 and between TAP1/TAP2 and human lymphocyte antigen (HLA) DR, DP, and DQ genes. HLA-DR, -DQ, -DP, and TAP1 loci were genotyped with the polymerase chain reaction (PCR)-sequence-specific oligonucleotide method, and TAP2 genes were typed by using the amplification-refractory mutation system-PCR technique. The alleles TAP1*D (3.3%), TAP2*D (2.4%), and TAP2*E (2.9%) were present in the Eastern Andalusian population but not in the general Spanish population. No evidence of linkage disequilibrium was found between TAP1 and TAP2 or between the TAP genes and HLA-DR, -DP, and -DQ in the Eastern Andalusian population. These results are consistent with the absence of coevolution between TAP and MHC class II genes and the hypothesis of selective neutrality.

Loss of heterozygosity (LOH) of chromosome 6p21 is an important mechanism that generates HLA haplotype loss in various human tumors. This mechanism produces non-reversible HLA-deficient tumor cells that can escape T cell immune responses in peptide-vaccinated cancer patients. However, the exact frequency of this mechanism is still unknown, because contaminating stroma in solid tumor tissues masks the tumor DNA obtained from solid samples. A microdissection technique was applied to 4-8 microm sections of cryopreserved tumor tissues from a group of colorectal and laryngeal carcinomas. Fifteen patients were analyzed for the presence of LOH associated with the beta(2)-microglobulin gene in chromosome 15, and five patients for LOH associated with HLA genes in chromosome 6. In two cases, autologous metastasis tissue samples were also available. The patients were selected for showing an altered HLA class I tumor phenotype as determined by immunohistological techniques. DNA was obtained from this microdissected material and amplified in order to detect the presence or absence of nine previously selected microsatellite markers. HLA sequence based typing (SBT) was also applied to these microdissected DNA samples to define the HLA genotype. Microdissection greatly improved the definition of LOH, with nearly 100% signal reduction in one of the alleles. In addition, this procedure allowed us to detect beta(2)-microglobulin LOH in tumors that expressed some HLA molecules. Our data indicate that this procedure can be successfully applied to microdissected samples from solid tumors, thus enhancing the power and sensitivity of LOH detection.

Human preovulatory follicular fluids (FF) obtained in the course of stimulated cycles were analyzed for their possible immunologic functions. Different concentrations of FF (20%, 2%, 1%) inhibited the mitogenic response of normal human lymphocytes to concanavalin A (Con A). Lymphocytes were assessed for immunosuppressor activity after preincubation with FF. Lymphocyte mitogenic response to Con A was only suppressed by cells preincubated with FF at concentrations of 2% and 1% for at least 48 hours. No evidence of suppressor cell induction was seen following incubation of lymphocytes with 20% FF, nor was any significant relationship between FF immunosuppressor activity and the outcome of in vitro fertilization observed. We conclude that some factor(s) in FF may be capable of directly inhibiting lymphocyte response and inducing immunosuppressor cell activity in vitro.

Background & Aims: Recently, the interleukin 23 receptor (IL23R) gene encoding a subunit of the receptor of the inflammatory cytokine IL-23 has been identified as a novel genetic factor strongly associated with inflammatory bowel disease (IBD). We aimed to replicate the IBD association of IL23R genetic markers in an IBD independent Spanish cohort. Methods: Four hundred sixty IBD patients of Spanish white origin (238 CD and 222 UC) and 342 ethnically matched healthy controls comprised the study population. Eight single nucleotide polymorphisms (SNPs) spanning the IL23R gene and its downstream intergenic region were selected as genetic markers and genotyped by using Taqman 5′ allelic discrimination assay. Results: All genetic variants located within the IL23R gene were observed to confer a strong protective effect against IBD susceptibility in our population. The Arg381Gln (rs11209026) non-synonymous SNP was most significantly associated with IBD protection (odds ratio, 0.4; 95% confidence interval, 0.3-0.7). In addition to the single SNP analysis, we performed a haplotype analysis identifying 2 haplotypes significantly associated with IBD protection. Conclusions: In this study we replicate the association of IL23R genetic variants with IBD in a Spanish population. These findings, together with the previous results, suggest that the IL23R gene is one of the genetic factors implicated in the genetics of IBD in the general population. © 2007 AGA Institute.