Background/Purpose: Biomarkers to recognize patients with a more intensive therapy necessity in rheumatoid arthritis are essential and scarce. VIP has shown immunoregulatory properties both in vivo and ex vivo in human and murine cells. We recently reported that low VIP serum levels are associated to a worse clinical course in patients with early arthritis. We aim to validate the association of genetic variants of VIP to its serum levels in a new cohort of early arthritis patients and to associate those variants with treatment requirements.

Methods: Princesa Early Arthritis Register Longitudinal (PEARL) study includes patients with early arthritis (EA). Demographic, clinical, laboratory, therapeutic, radiological data and biological samples are systematically collected along follow-up (baseline, 6, 12, 24 and 60 months). We carried out the study in two phases with two different sets of patients from the PEARL register after a preliminary screening, as follows: Screening VIP serum levels were measured by Enzyme-Immunolinked-Assay (EIA, Martinez et al. 2014) in a set of EA patients. From that set, 11 patients with high and 9 patients with low VIP serum levels were selected for sequencing of VIP gen. Amplification and sequencing was performed using BigDyeDirect sequencing kit (Applied Biosystems) and were analyzed by capillary electrophoresis on a 3500xL genetic Analyzer (Applied Biosystems). 16 single nucleotide polymorphisms (SNPs) were selected due to its differential distribution in patients with extreme VIP levels. Discovery and Validation Phases Genetic variants selected by sequencing were genotyped in 93 EA patients for the discovery phase of the study and 131 EA patients for the validation phase, using pre-designed SNP Genotyping Assays (Applied Biosystems). In both sets of patients VIP serum levels were measured by EIA. We used the backward-stepwise selection to fit several multivariate models by generalized estimating equations for repeated measures after previous bivariate analysis to determine the adjusting variables. Statistical analysis was performed using Stata 12 for Windows (StataCorp PL, College Station, TX, USA).

Results: We found that patients with CC genotype of the SNP rs688136 had higher serum VIP levels either in the discovery and validation populations, as well as in the meta-analysis of both sets (p=0.033, p=0.007 and p=0.004, respectively). This effect was impaired by the presence of minor alleles of rs35643203 and/or rs12201140, which had a clear trend towards the association with low serum VIP levels (p=0.118 and p=0.049 respectively). We also observed a significant correlation between the combination of the different alleles of those SNPs and the treatment intensity. Patients with CC genotype of rs688136 and no minor alleles of the two other polymorphisms required less treatment than those who had the CC genotype but at least one of the minor alleles (p=0.022).

Conclusion: In two populations of patients of the PEARL study a combination of genetic variants of VIP associated with VIP serum levels are also associated with the requirements of treatment of those patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-variants-of-the-vasoactive-intestinal-peptide-vip-gen-in-association-with-rheumatoid-arthritis-treatment-requirements/