Jácome Bruges Armas

Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations

Killer cell immunoglobulin-like receptors (KIRs) and humaAn leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles carrying Bw4-I80 in trans position in the Spanish population (30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7% in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other hand, 3DL1 was decreased in patients compared with B27 controls (p < 0.0001 in the Spanish population and p < 0.003 in Azoreans). The presence of this allele in combination with Bw4-I80 had a protective effect against the development of AS in the Spanish population (19.7% in AS, 35.2% in B27 controls; p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1 in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes may modulate the development of AS. The susceptibility to AS could be determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes.

Linkage disequilibrium between S65C HFE mutation and HLA A29-B44 haplotype in Terceira Island, Azores

Our objective was to investigate the frequency of HFE gene mutations and to study linkage disequilibrium (LD) between HLA-Class I alleles and these mutations in the population of Terceira Island, Azores, Portugal. A total of 218 unrelated individuals were investigated. Three HFE mutations--C282Y, H63D, and S65C--were identified by restriction endonuclease digestion of polymerase chain reaction (PCR)-amplified genomic DNA. HLA-Class I alleles were typed by PCR-single-strand polymorphism. Gene frequencies and LD were estimated using Arlequin V 1.1. Six genotypes were found in the population: WT/WT (58.3%), H63D/WT (31.2%), H63D/H63D (2.3%), H63D/C282Y (0.9%), S65C/WT (4.1%), and C282Y/WT (3.2%). No cases of C282Y or S65C homozygosity were identified. HLA haplotype A3-B7 was in LD with C282Y; HLA alleles A29, B44, and HLA haplotype A29-B44 were in LD with S65C mutation. HFE gene frequencies in this population are similar to those in other European populations; HFE S65C mutation was found in LD with the alleles A29, B44, and with A29-B44 HLA haplotype.

HLA and the Spondyloarthritis

Abstract The Spondyloarthritis are a group of diseases with a strong tendency for family agregation, which includes mainly Ankylosing Spondylitis (AS), Reiter‘s Syndrome / Reactive Arthritis (ReA), Enteropathic Spondylitis (Crohn‘s disease and Ulcerative Colitis), Psoriatic Arthropathy (PsA), and Undifferentiated Spondylitis (uSpA). The axial skeleton, mainly the sacroiliac joints, the peripheral joints – more frequently in the lower limbs, and the tendon insertions (enthesis), are particularly prone to an inflammatory process that may involve several targets at the same time or sequentially. Main symptoms depend on the stage of the disease or the SpA subset under examination, and their overlap is frequent. The most known subset of the SpA is Ankylosing Spondylitis, a chronic systemic inflammatory disease of the axial skeleton whose etiology is still unknown, affecting always the sacroiliac, and usually the apophyseal, costovertebral, and costotransverse joints of the spine. The symptoms begin in late adolescence or early adulthood, and chronic inflammatory back pain and stiffness are the most common and characteristic initial presenting complaints in adult-onset AS. The description in 1973 of a very strong association between HLA-B27, an immune response gene and AS permitted to consider this disease to have an autoimmune pathogenesis. The association of AS with HLA-B27 may be 95% to 99% according with the majority of authors but this proportion is inferior in Reiter‘s Syndrome and Psoriatic Arthritis.

A7.16 Lack of Replication of PTPRC Gene as a Predictor of Response to Anti-Tumour Necrosis Factor Therapy in Patients with Rheumatoid Arthritis

Background and Objectives A genome wide association study (GWAS) with Caucasian Northern European and North American rheumatoid arthritis (RA) patients and a replication study with English patients, pointed out for an association between PTPRC locus and response to anti-TNF drugs in RA. The Aim of our study was to evaluate whether this association is also verified in a population of Southern European (Portuguese) patients. Materials and Methods We evaluated 383 RA patients from the Portuguese Rheumatic Diseases Register, Reuma.pt, for association between anti-TNF treatment response assessed by an absolute change in DAS28 at six months as the primary outcome and Rs10919563 PTPRC locus. We also studied the same association using the proportion of EULAR good responders and non responders at six months as the secondary outcome. Additive models were used taking the homozygote for the two major alleles as the reference variable. Univariate and multivariate linear and logistic regression analyses were performed, adjusting for clinical variables that influenced treatment response. Results Taking the continuous primary outcome, univariate and multivariate linear regression adjusted for DAS28 and HAQ at baseline showed no association between change in DAS28 at 6 months and PTPRC locus (p-values of 0.72 and 0.69 respectively). Also univariate and multivariate logistic regression (good versus non-responders) did not depict any association with this SNP. Conclusions In this replication study with a cohort of RA. Portuguese patients, we did not observe an association between Rs10919563 PTPRC locus and response to anti-TNF treatment.

TRAF1/C5 locus is associated with response to anti-TNF in rheumatoid arthritis

Some of the rheumatoid arthritis (RA) risk allele variants were related to tumor necrosis factor (TNF) signaling pathways which raised the hypothesis that they might influence the response to anti-TNF drugs. The primary aim of our work was to investigate potential association between the HLA-DRB1 and RA risk alleles specifically selected for their relevance on RA biologic pathways with the response to anti-TNF treatment in a Southern European population using a nationwide register.

Combined approach for finding susceptibility genes in DISH/chondrocalcinosis families: whole-genome-wide linkage and IBS/IBD studies

Twelve families with exuberant and early-onset calcium pyrophosphate dehydrate chondrocalcinosis (CC) and diffuse idiopathic skeletal hyperostosis (DISH), hereafter designated DISH/CC, were identified in Terceira Island, the Azores, Portugal. Ninety-two (92) individuals from these families were selected for whole-genome-wide linkage analysis. An identity-by-descent (IBD) analysis was performed in 10 individuals from 5 of the investigated pedigrees. The chromosome area with the maximal logarithm of the odds score (1.32; P=0.007) was not identified using the IBD/identity-by-state (IBS) analysis; therefore, it was not investigated further. From the IBD/IBS analysis, two candidate genes, LEMD3 and RSPO4, were identified and sequenced. Nine genetic variants were identified in the RSPO4 gene; one regulatory variant (rs146447064) was significantly more frequent in control individuals than in DISH/CC patients (P=0.03). Four variants were identified in LEMD3, and the rs201930700 variant was further investigated using segregation analysis. None of the genetic variants in RSPO4 or LEMD3 segregated within the studied families. Therefore, although a major genetic effect was shown to determine DISH/CC occurrence within these families, the specific genetic variants involved were not identified.