FP234
CD28 gene variants associated with lupus nephritis in a Chinese population

INTRODUCTION: Lupus nephritis (LN) is one of the most prevalent and serious complications of systemic lupus erythematosus (SLE). CD28 is an important costimulatory molecule in T cell activation and B7-CD28 costimulatory pathway plays a role the pathogenesis of SLE. CD4+CD28- T cells, which showed autoreactive effect, were increased and positively associated with a higher SDI (SLICC/ACR damage index) and renal impairment. Therefore, the aim of the present study was to identify susceptibility variants in CD28 gene along with its functional significance.

METHODS: Genetic association analysis in LN patients adopted from previous reported GWAS data with the use of ImmunoChip arrays. To identify functional significance, we analyzed publicly available Encyclopedia of DNA Elements data on transcription factor binding sites, blood expression quantitative trait locus data, and cell type-specific differential expression from GEO database.

RESULTS: A total of 76 single-nucleotide polymorphisms in a region spanning 52 kb encompassing the CD28 gene were analyzed in 1000 individuals. Seven of them were significantly associated the susceptibility to LN (p＜0.05). rs12693993 was the top signal (p = 1.13 × 10-2, OR = 1.38, 95% CI 1.08-1.78) and was independent with other six snps with r-square＜0.1. Functional significance of the associated variants was further examined by the in-silico method and rs3181096 (p = 1.53 × 10-2, OR = 0.77, 95% CI 0.62-0.95) showed the strongest function (Regulome DB score 3a) in CD28. The rs3181096 risk C-allele exhibited reduced nuclear protein binding (HNF1_3), and reduced CD28 (p=0.052) transcription comparing with protective T-allele. The expression of CD28 in blood was associated with rs3181096 by cis-eQTL. In CD4+ T cells, the levels of CD28 expression was significantly lower in patients with SLE (p=0.014).

CONCLUSIONS: We observed a likely genetic association between CD28, a widely used marker for costimulation signal, and susceptibility to LN.