ABSTRACT
The Behçet's disease (BD)-associated human leukocyte antigen (HLA) allele, HLA-B*51 (B*51), encodes a ligand for a pair of allelic killer immunoglobulin-like receptors (KIR) present on cytotoxic cells-KIR3DL1, which inhibits their cytotoxicity, and KIR3DS1, which activates their cytotoxic activity. We tested whether KIR-regulated mechanisms contribute to BD by testing for association of KIR3DL1/KIR3DS1 genotypes with disease in 1799 BD patients and 1710 healthy controls from Turkey, as well as in different subsets of individuals with HLA-type-defined ligands for the KIR3D receptors. HLA types were imputed from single nucleotide polymorphism genotypes determined with the Immunochip. The presence of inhibitory KIR3DL1 or activating KIR3DS1 alleles did not differ significantly between cases and controls (KIR3DL1: 92.9% vs 93.4%, Pdominant=0.55; KIR3DS1: 42.7% vs 41.0%, Pdominant=0.29). The KIR3DL1/KIR3DS1 alleles were also present at similar frequencies among cases and controls bearing HLA-B with a Bw4 motif; HLA-B with a Bw4 motif with isoleucine at position 80; and HLA-B*51. Our results suggest that pathogenic mechanisms associated with HLA-B*51 do not primarily involve differential interactions with KIR3DL1 and KIR3DS1 receptors. However, due to the complexity of this locus (that is, sequence variation and copy number variation), we cannot exclude a role for other types of KIR variation in the pathogenesis of BD.
Subject(s)
Behcet Syndrome/genetics , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Receptors, KIR3DS1/genetics , Genotype , HLA Antigens/genetics , HumansSubject(s)
Behcet Syndrome/genetics , Exons , Granzymes/genetics , Polymorphism, Single Nucleotide , Adult , Case-Control Studies , Female , HLA-B Antigens/genetics , HLA-B51 Antigen , Humans , MaleABSTRACT
OBJECTIVES: To investigate the role of shared epitope (SE) alleles in the short-term clinical response to leflunomide for the treatment of active RA. METHODS: In an open-label, multi-centre study of 16-weeks duration, 93 patients (82% female) fulfilling ARA 1987 RA criteria were treated with leflunomide (100 mg loading dose for 3 days, then 20 mg/day as the maintenance dose). The primary efficacy criterion was the response status according to the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score-28 (DAS28) activity measure. SE determinations have been undertaken by polymerase chain reaction and sequence-specific oligonucleotide genotyping methods. RESULTS: The mean (s.d.) Disease Activity Score-28 (DAS28) was 5.1 (1.3) before the treatment, which was significantly decreased after 16 weeks [3.0 (1.1), P < 0.001]. According to the EULAR response criteria, 55 patients (59.1%) were classified as good responders. SE was positive in 51 (54.8%) of the patients, with 13 (13.9%) having SE homozygosity or carrying any two SE alleles. Among SE-positive patients, 68.6% (35/51) were good responders, compared with 47.6% (20/42) in SE negatives (P = 0.04). No difference was present according to SE hetero- or homozygosity (68.4 vs 69.2%). RF was also present significantly more frequently in the SE-positive group compared with negatives (78.4 vs 57.1%, P = 0.03). However, no significant difference was observed in the prevalence of RF positivity in patients with a good clinical response (72.7 vs 63.2%, P = 0.32). CONCLUSIONS: The results suggest that HLA-DRB1 SE presence may favourably affect the outcome of leflunomide monotherapy in an unselected group of RA patients with an active disease and naive to leflunomide.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , HLA-DR Antigens/genetics , Isoxazoles/administration & dosage , Adult , Alleles , Arthritis, Rheumatoid/immunology , Biomarkers/analysis , Dose-Response Relationship, Drug , Drug Administration Schedule , Epitopes , Female , Follow-Up Studies , HLA-DR Antigens/analysis , HLA-DRB1 Chains , Humans , Leflunomide , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Risk Assessment , Severity of Illness Index , Treatment OutcomeABSTRACT
OBJECTIVE: Contribution of HLA-B51 to the genetic susceptibility for Behçet's disease is well documented and recent studies suggest involvement of other genes. Tumour necrosis factor (TNF) genes are located in the vicinity of the HLA-B locus. Polymorphisms in the promoter region of TNF-alpha gene has been found to be associated with altered TNF secretion, and it may have a prominent role in the increased inflammatory responses of Behçet's disease. METHODS: The study group consisted of 99 Behçet's disease patients and 96 healthy matched controls. All patients fulfilled the International Study Group criteria for Behçet's disease. The TNF-alpha -308 and -376 promoter alleles were assigned by the digestion of each amplified PCR product with NcoI and TasI enzymes, respectively. RESULTS: No significant difference was observed in the distribution of TNF-alpha promoter region polymorphisms between patients with Behçet's disease and controls. There was no association between the presence of uncommon -308A and -376A alleles and the manifestations or severity of Behçet's disease either. The TNF-alpha -308A allele and HLA-B*50 was found to be associated in this series of Turkish patients and controls. CONCLUSION: The role of TNF-alpha promoter region -308 and -376 polymorphisms in the pathogenesis of Behçet's disease is not supported by this data. The overexpression of TNF-alpha in Behçet's disease may be caused by other polymorphisms in the TNF gene or by post-transcriptional mechanisms.
