Association between shared epitope and anti-citrullinated peptide antibodies in rheumatoid arthritis: A systematic review and meta-analysis

The group of major histocompatibility complex (MHC) alleles known as shared epitope (SE)is to date the strongest rheumatoid arthritis (RA) genetic risk factor. Many studies have shown that the measurement of anti-citrullinated peptides antibodies would be useful in the diagnosis and follow-up of RA. Our aim is to determine the magnitude of the association between the possession of SE alleles and serum positive titres of antibodies against citrullinated peptides. Our selection criteria included case–control or cohort studies, where data involving antibodies against citrullinated peptides and SE in RA patients were available. No date or language restrictions were imposed. Bibliographical databases MEDLINE, Cochrane Database of Systematic Reviews and EMBASE were searched for pertinent literature. Two reviewers independently identified relevant citations and extracted data. Data extraction was then checked by two different reviewers. Five published and one unpublished (own data) studies were included in the final metaanalysis. Overall, 2700 European descent RA patients were included in this meta-analysis. A significant association between SE and positive titres of serum antibodies against citrullinated peptides [OR(95% CI) = 3.19 (2.21–4.60)] was found. Positive titres for antibodies against citrullinated peptides are threefold more frequent in RA patients who carry SE alleles than in those patients lacking them (AU)

El grupo de alelos del complejo mayor de histocompatibilidad (MHC) conocidos como epí-topo compartido (EC) es a día de hoy el más fuerte los factores de riesgo genético a artritisreumatoide (AR). Diferentes estudios han puesto de manifiesto que la presencia de autoanticuerpos contra péptidos citrulinados sería útil en el diagnóstico y seguimiento de la artritisreumatoide. Nuestro objetivo es determinar la magnitud de la asociación entre la posesión de alelos del SE y la presencia de títulos positivos de anticuerpos contra péptidos citrulinados. Nuestros criterios de selección incluyeron estudios de cohortes y caso-control en los que hubiera datos disponibles acerca de los anticuerpos contra péptidos citrulinados y el epítopo compartido en artritis reumatoide. No se hicieron restricciones de fecha ni de idioma. Se realizaron búsquedas en las bases de datos bibliográficas MEDLINE, Cochrane Database of Systematic Reviews y EMBASE. Dos revisores identificaron de manera independiente lascitas relevantes y extrajeron los datos. La extracción de datos fue comprobada posteriormente por dos revisores diferentes de los anteriores. En el meta-análisis definitivo se incluyeron cinco estudios publicados y uno no publicado(datos propios). En total se incluyeron 2700 casos de RA de ascendencia europea en el metaanálisis. Se encontró una asociación significativa entre los títulos de anticuerpos positivos y el hecho de ser portador de alelos del epítopo compartido [OR(95% CI) = 3.19 (2.21–4.60)]. Los títulos positivos de anticuerpos contra péptidos citrulinados son tres veces más frecuentes en pacientes de AR portadores de alelos del EC que en los no portadores (AU)

Herpesvirus active replication in multiple sclerosis: a genetic control?

Although the etiology of multiple sclerosis (MS) is unknown, it is generally believed that genetic, immunologic, and environmental factors are involved. The objectives of this study were: 1. to analyze if a genetic control could explain why HHV-6 would be able to actively replicate in a subset of MS patients but not in controls; 2. to study if MS patients with HHV-6 active replication are clinically different from those without HHV-6 active replication. A total of 195 MS patients and 195 controls were analyzed for two SNPs at the MHC2TA locus and two SNPs at the CD46 locus. Furthermore, the MS cohort was analyzed by PCR for the detection of HHV-6 genomes in five serum samples collected every six months along two-year follow-up. We found that 59/195 (30.2%) MS patients had at least one HHV-6 positive serum sample. No statistical significant difference was found for the two genes when the comparison was made between MS patients and controls; however, a statistical significance was found for the two polymorphisms of MHC2TA when we compared MS patients with active replication and controls (p=0.0000004 for rs4774C and p=0.011 for rs3087456G). Furthermore, increased significant differences were found for MHC2TA and CD46 when we compared interferon beta responders and non-responders within MS patients. In conclusion, we describe a gene-environment interaction in MS patients between HHV-6 and MHC2TA and CD46 that should be further studied to clarify if that interaction could be a genetic control. The results show that MS patients without HHV-6 active replication are better responders to interferon beta treatment than those with HHV-6 active replication.

[Complex diseases genetics]. / Genética de las enfermedades complejas.

Common diseases are not inherited in a mendelian way, but have got anyway a genetic component, as shown by their increased frequency in siblings. Differences in the genome of individuals are not bigger than 0.1%, but are the reason why the susceptibility to diseases, their prognosis and the response to treatments differ. There are approximately ten million variations in the human genome, most of them single nucleotide polymorphisms (SNP) but also insertions, duplications, deletions, inversions and translocations. Two big international projects finished at the beginning of this century (The Human Genome Project and the HapMap Project) have paved the way to the study of these variations. The rapid technological advances allow today the study of one million SNPs at one time and it is forecasted that is some years the whole human genome will be sequenced in a few hours. All this is making possible new discoveries of the genetic variations that confer susceptibility to diseases, the location of new therapeutic targets and the beginning of a new medicine: personalized medicine.

Autoantibodies against C-reactive protein: clinical associations in systemic lupus erythematosus and primary antiphospholipid syndrome.

OBJECTIVE: To investigate the prevalence of anti-C-reactive protein (CRP) autoantibodies in patients with systemic lupus erythematosus (SLE) and non-SLE patients with persistent antiphospholipid antibodies (aPL) and their association with clinical manifestations. METHODS: Sera of 137 patients with SLE, 127 with persistent aPL and 30 with idiopathic venous thromboembolic disease, were assayed for the presence of anti-CRP reactivity by ELISA. Associations of anti-CRP reactivity with clinical features, with other autoantibodies, and with serum concentrations of C3 and CRP were assessed. RESULTS: Antibodies against CRP were seen in 51% (n = 137) of patients with SLE and in 54% (n = 127) of patients with aPL. SLE patients with anti-CRP antibodies showed increased frequencies of anti-dsDNA and aPL antibodies compared to those without anti-CRP (52% vs 26% and 68% vs 31%, respectively). Mean serum C3 levels were lower in the subgroup of patients with SLE positive for anti-CRP antibodies (79 +/- 25 vs 92 +/- 25 mg/dl; p = 0.004 ) and mean serum CRP levels were significantly higher (13 +/- 17 vs 5 +/- 8 mg/l; p = 0.01 ). The frequency of nephritis was higher in SLE patients with anti-CRP antibodies, than in those without (27% vs 13%; p = 0.058). In patients with clinical and serological evidence of antiphospholipid syndrome (APS) the frequency of anti-CRP antibodies was significantly higher than in asymptomatic aPL carriers, in both SLE patients [85% (23 of 27) vs 59% (19 of 32); p = 0.021] and non-SLE patients [76% (38 of 50) vs 19% (9 of 47); p < 0.001]. Among patients with APS with or without SLE, 26 had arterial events, 31 had venous events, 6 had combined arterial and venous events, and 14 had fetal loss. Mean titers of IgG anti-CRP (29 +/- 21, 30 +/- 19, 60 +/- 37, and 26 +/- 12 AU/ml) and frequencies of anti-CRP antibodies (88%, 71%, 50%, and 71%) in these subgroups of patients were comparable. CONCLUSION: We confirmed the high prevalence of anti-CRP autoantibodies both in patients with SLE and in non-SLE and aPL-positive patients. We observed that the presence of these antibodies was associated with lupus nephritis and with clinical features of the APS in patients with lupus and non-lupus patients.

[Inflammatory bowel disease: genotype-fenotype relationship]. / Enfermedad inflamatoria intestinal: relación entre genotipo y fenotipo.

Inflammatory bowel diseases are complex diseases due to the combination of genetic and environmental factors. Many genes have a limited effect and none is necessary nor sufficient. It has been observed that many of these genes confer susceptibility to specific clinical forms of the disease. So, HLADRB1*0103 confer susceptibility to the pancolitis form of ulcerative colitis and also to Crohn's disease but only with colonic localization. IKBL gene confer susceptibility only to ulcerative colitis, also the pancolitis form and refractary to treatment. NOD2/CARD15 gene confer susceptibility only Crohn's disease with ileal localization with frequent stenosis.

Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease.

Celiac disease (CD) is characterized by a striking expansion of gamma delta T cells in the intestine. These cells interact with MICA, a cell surface protein encoded by a major histocompatibility complex gene. We investigated whether MICA gene polymorphism could contribute to susceptibility to CD. DNA typing for HLA-DR, DQA1, DQB1, TNF-308, TNFa, TNFb and a triplet repeat polymorphism in the transmembrane region of the MICA gene were carried out. We performed case-control stratified association studies and transmission disequilibrium tests. Our results indicate that although there is no primary association between MICA polymorphism and CD, there is, in addition to HLA-DQ, a second susceptibility locus on the 8.1 ancestral haplotype in strong linkage disequilibrium with MICA A5.1 allele.