HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region

Nicolas Vince (1) , Hongchuan Li (2) , Veron Ramsuran (2) , Vivek Naranbhai (3) , Fuh-Mei Duh (2) , Benjamin p. Fairfax (3) , Bahara Saleh (2) , Julian c. Knight (3) , Stephen k. Anderson (2) , Mary Carrington (2, 4)

1 ITUN - Institut de transplantation urologie-néphrologie
2 FNLCR - Frederick National Laboratory for Cancer Research
3 The Wellcome Trust Centre for Human Genetics [Oxford]
4 Ragon Institute of MGH, MIT and Harvard

Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 × 10−66). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1.8 × 10−20) and in two cohorts where HLA-C cell surface levels were determined directly by flow cytometry (n = 369 combined, p < 10−15). rs2395471 is located in an Oct1 transcription factor consensus binding site motif where the A allele is predicted to have higher affinity for Oct1 than the G allele. Mobility shift electrophoresis demonstrated that Oct1 binds to both alleles in vitro, but decreased HLA-C promoter activity was observed in a luciferase reporter assay for rs2395471_G relative to rs2395471_A on a fixed promoter background. The rs2395471 variant accounts for up to 36% of the explained variation of HLA-C level. These data strengthen our understanding of HLA-C transcriptional regulation and provide a basis for understanding the potential consequences of manipulating HLA-C levels therapeutically.

Domaines: Génétique humaine; Immunité adaptative

Nicolas Vince, Hongchuan Li, Veron Ramsuran, Vivek Naranbhai, Fuh-Mei Duh, et al.. HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region. American Journal of Human Genetics, 2016, 99 (6), pp.1353-1358. ⟨10.1016/j.ajhg.2016.09.023⟩. ⟨hal-02135177⟩