Rapid advances in genotyping technology, analytical methods, and the establishment of large cohorts for population genetic studies have resulted in a large new body of information about the genetic basis of human rheumatoid arthritis (RA). Improved understanding of the root pathogenesis of the disease holds the promise of improved diagnostic and prognostic tools based upon this information. In this review, we summarize the nature of new genetic findings in human RA, including susceptibility loci and gene-gene and gene-environment interactions, as well as genetic loci associated with sub-groups of patients and those associated with response to therapy. Possible uses of these data are discussed, such as prediction of disease risk as well as personalized therapy and prediction of therapeutic response and risk of adverse events. While these applications are largely not refined to the point of clinical utility in RA, it seems likely that multi-parameter datasets including genetic, clinical, and biomarker data will be employed in the future care of RA patients.3
Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF–treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.
Genetic overlap between PsA and RA was detected for the rs34536443 SNP of the TYK2 gene within a Greek population. An association of STAT4 (rs10181656) with PsA was confirmed whereas CD226 (rs763361) was associated with PsA but not with RA, in contrast to previous reports. The different findings of this study compared to previous ones highlights the importance of comparative studies that include various ethnic or racial populations.
Background The vascular endothelial growth factor receptor 2 (VEGFR2) gene polymorphisms have already been correlated with vascular diseases such as Coronary Heart Disease (CHD). In view of the premature atherosclerosis observed in systemic lupus erythematosus (SLE), we hypothesized that variation of VEGFR2 gene may influence endothelial function in patients with SLE. Objectives a) To construct a three-dimensional (3D) model of the VEGFR2 regions harboring the polymorphisms rs2305948 and rs1870377, localize them on this model and explore their putative role on the VEGFR2 function in SLE; and b) To determine whether these polymorphisms are associated with risk of SLE by influencing endothelial cells. Methods Three-dimensional (3D) homology modeling of the mutation V297I was based on the 3D structure of domains D2 and D3 of VEGFR2 in complex with VEGF-C, while mutation Q472H was investigated by homology modeling on the KIT ectodomain structure. The V297I (rs2305948) and Q472H (rs1870377) SNPs in VEGFR2 were genotyped with Taqman technology in 250 SLE patients and 241 healthy controls from a Greek population (Cretan). The replication sample set for the rs1870377 SNP consisted of 253, 184 and 77 patients with SLE of African-, European- and Hispanic-American origin, respectively, as well as geographically/ethnically-matched controls Results Modeling revealed that polymorphism V297I affects the efficiency of trans-autophosphorylation and cell signaling while Q472H affects homotypic contacts of membrane proximal Ig-like domains. These findings prompted us to examine whether these polymorphisms contribute to SLE risk or vascular damage. No significant difference was observed in the frequency of the minor allele A of rs1870377 when SLE patients were compared with controls either in the Greek population or in the 3 replication groups analyzed. The TT genotype was found to be associated with a higher number of circulating endothelial cells (CECs) in SLE patients. Half of the Greek SLE patients enrolled in the study, with clinical data, analyzed further but no association between genotype and clinical CVD was detected. Furthermore, no association was found between rs2305948 SNP and SLE when tested in the Greek population. Conclusions Although structural data suggest that both VEGFR2 SNPs may contribute to SLE pathogenesis by impairing cell signaling, none of the SNPs analyzed was associated with increased susceptibility to SLE. However, they still may be relevant to the vascular damage/atherosclerosis in SLE and other genetic variations in or near the VEGFR2 locus may play a role in the disease. Disclosure of Interest None Declared
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