ABSTRACT
The TRAILR1/TRAIL system is implicated in the induction of the extrinsic apoptotic pathway and constitutes an emerging target in cancer therapeutics. The objective of this study is to assess lymphoma risk associated with certain polymorphisms in TRAILR1 and TRAIL1 genes. DNA was extracted from 381 subjects (190 lymphoma cases and 191 matched controls) and genotyped for polymorphisms rs20576, rs2230229 and rs20575 in TRAILR1 and rs12488654 in TRAIL gene. In contrast to TRAILR1 polymorphisms, the genotype distribution of rs12488654 in TRAIL gene was different between cases and controls, A allele carriers (CA/AA) being much more common in the cases with different lymphoma types (follicular, 45 %; diffuse large B cell, 45.2 % and Hodgkin lymphomas, 40 %) than in controls (15.7 %) (odds ratio (OR), 3.5; CI, 2.15.9; p<0.001; OR, 3.5; CI, 1.67.9; p=0.001; OR, 2.9; CI, 1.17.5; p=0.027, respectively). This effect was consistently independent of the association with the TRAILR1 polymorphisms studied, as demonstrated by linkage disequilibrium and haplotype analyses. This study is the first one to report an association between a TRAIL polymorphism and lymphoma risk and suggests a possible role of TRAIL in B cell lymphomagenesis.
Subject(s)
Alleles , Genetic Predisposition to Disease , Lymphoma/genetics , Polymorphism, Genetic , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/genetics , Adult , Aged , Female , Humans , Lymphoma/metabolism , Male , Middle Aged , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , TNF-Related Apoptosis-Inducing Ligand/metabolismABSTRACT
OBJECTIVES: As the role of polymorphisms in death receptors (DRs) such as Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) and Tumor Necrosis Factor Receptor 1A (TNF-R1A) on the response to anti-TNF therapy remains unknown, we evaluated the association between TRAILR1 and TNFR1A gene polymorphisms (rs20575/C626G and rs767455/G36A) and the pharmacogenetics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with TNFα blockers. METHODS: One hundred and forty-five patients (90 RA and 55 PsA) treated with anti-TNFα therapy (RA: 75 infliximab, 8 etanercept, 7 adalimumab. PsA: 27 infliximab, 19 etanercept, 9 adalimumab) were genotyped for TRAILR1 and TNFR1A polymorphisms by allelic discrimination. The response to anti-TNFα was assessed by EULAR criteria. RESULTS: In RA, the TRAILR1 CC genotype was associated with a better response after 3 and 6 months of anti-TNFα treatment (CC: 91.7% vs. CG/GG: 62.2%; P=0.019, and CC: 82.6% vs. CG/GG: 56.1%; P=0.019, respectively). Similar results were observed in only infliximab-treated RA patients. With respect to the TNFR1A polymorphism, there was an association between the AA genotype and a poorer response at 3 months in RA patients (AA: 39.3% vs. AG/GG: 19.0%; P=0.04). In PsA, TRAILR1 CC genotype was only associated with EULAR response to infliximab at 6 months (CC: 71.4% vs CG/GG: 50%P=0.048). In contrast to RA, the TNFR1 polymorphism in PsA was associated with a better response at 3 months (AA 88% vs AG/GG 58.9%; P=0.04). CONCLUSIONS: This study provides the first evidence that a polymorphism in TRAILR1 influences the response to anti-TNFα therapy in RA and also suggests that TNFR1A polymorphism may have opposing effects on the response to anti-TNFα in RA and PsA.
