Background/Purpose: VIP has shown immunoregulatory properties in assays performed with human or murine cells. VIP has demonstrated a therapeutic effect in a murine model of collagen-induced arthritis. We recently reported that low VIP serum levels (sVIP) were associated to a worse clinical course in patients with early arthritis despite receiving a more intense treatment. Purpose: determine whether genetic variants of VIP lead to variations in sVIP

Methods: Princesa Early Arthritis Register Longitudinal (PEARL) study includes patients with early arthritis in which demographic, clinical, laboratory, therapeutic and radiological data are collected for 5 years follow-up (baseline, 6, 12, 24 and 60 months). Biological samples are obtained at each visit. sVIP had been measured in a previous study (Martinez et al. 2014). 11 patients with the highest and 9 patients with the lowest sVIP were selected for sequencing of VIP gene. Primers were designed to produce overlapping amplicons covering the promoter, exons and introns. We used BigDyeDirect sequencing Kit and performed capillary electrophoresis on a 3500xL Genetic Analyzer (Applied Biosystems [AB]). 16 single nucleotide polymorphisms (SNPs) were differentially expressed in patient groups with extreme sVIP. Rs3823082, rs35643203, rs71575932, rs7755568 and rs688136 were selected for validation (trend statistical significance [p<0.2] in population n=20). Results were validated in 457 patients (80% female, median age 54 [interquartile range 42-66], 60% RA, 40% undifferentiated arthritis) from PEARL study through RT-PCR and specific Taqman probes (AB). Fisher’s exact test was applied to determine the significance level in the distribution of genotypes between patients with low and high sVIP. Kruskal-Wallis test was used to assess potential differences in sVIP between SNPs genotypes. To determine the effect of SNPs on disease activity, cumulative DMARD treatment and radiological progression, we fitted 3 multivariate analysis using generalized estimating equations for repeated measures. Statistical analysis was performed using Stata 12.1 for Windows.

Results:In the whole population, the minor allele frequency was 23.2% for rs3823082, 6.5% for rs35643203, 7.5% for rs71575932, 6.8% for rs7755568 and 34% for rs688136. Patients with at least one minor allele for rs35643203, rs71575932 or rs7755568 (p=0.015; being these SNPs in linkage disequilibrium) and those carrying the TT genotype of rs3823082 (p=0.07) showed significantly lower sVIP, and these genotypes showed an additive effect (p=0.003). Patients homozygous for the minor allele of rs688136 showed a slight trend to higher sVIP (p=0.27). Patients carrying one minor allele for rs35643203 and being homozygous for the T allele of rs3823082 displayed higher DAS28 along the follow-up if they were ACPA negative (p=0.07), required more intensive DMARD treatment (p=0.028) and showed higher radiological progression (p=0.007). Patients with CC genotype of rs688136 showed a trend to lower disease activity (p=0.17)

Conclusion: In our PEARL population genetic variants of VIP associated with low serum levels of this peptide may be a biomarker of severe disease in EA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/vasoactive-intestinal-peptide-vip-genetic-variants-determine-vip-serum-levels-and-could-be-used-as-a-prognosis-biomarker/