Background Disease expression and outcome vary greatly in SLE. As well as affecting susceptibility, noncoding gene polymorphisms have been reported to influence disease expression, for example indices of severity. FOXO3A is a transcription factor which induces the anti-inflammatory proteins TGF-beta and GILZ. A gain-of-function FOXO3A promoter single-nucleotide polymorphism (SNP), rs12212067, is associated with anti-inflammatory effects in vitro, and improved outcomes in colitis and RA (Lee et al, Cell, 2013).

Objectives The association of FOXOoxo3a polymorphisms with disease expression in SLE is unknown. We sought to determine the clinical associations of this SNP in SLE.

Methods SLE patients (ACR criteria) attending a single centre were recruited for a pilot study. Patients seen between 2007-2012 had disease activity (SLEDAI-2k) recorded at each visit. SLICC-SDI criteria (recorded annually) were used to define end-organ damage. Genomic DNA was isolated from whole blood and genotyped with the Immunochip (Illumina) (SNP) microarray.

Results 137 SLE patients (84% female, median age 42 years, disease duration 5 years) were studied. Organ damage (SDI) was highly correlated with disease duration (P<0.0001), and with time-adjusted mean SLEDAI (AMS) (P<0.0001) and glucocorticoid exposure (P<0.0001). The distribution of rs12212067 genotypes observed was TT (78.8%) TG (17.5%) and GG (3.7%).

The major finding was that rs12212067-G homozygosity was protective against organ damage in the SLICC-SDI domains of renal disease (P=0.001), vascular events (P=0.0002), and glucocorticoid-related damage (P<0.001), compared to rs12212067-T/T and G/T genotypes. rs12212067-G/T heterozygotes were also protected against vascular events. There was no difference between rs12212067 genotypes in total SLICC-SDI, glucocorticoid exposure, AMS, or other demographic, clinical or serological variables.

Conclusions These data suggest that a gain-of-function FOXO3A promoter SNP exerts a protective effect against end-organ damage in SLE. Confirmation of these findings in a larger study is required, along with investigation of the molecular mechanisms of this effect, for example via regulation of GILZ.

References

1. Lee, J. C., Espéli, M., Anderson, C. A., Linterman, M. A., Pocock, J. M., Williams, N. J., et al. (2013). Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway. Cell, 155(1), 57–69.

Acknowledgements LAC funded by NIH grant number P60 AR053308

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.3993