Description

Single cell expression quantitative trait loci (eQTL) analysis of established SLE-risk loci in Lupus Patient Monocytes

Yogita Ghodke-Puranik¹, Zhongbo Jin¹, Wei Fan^1, Mark A. Jensen¹, Jessica M. Dorschner¹, Danielle M. Vsetecka¹, Shreyasee Amin², Ashima Makol², Floranne Ernste², Thomas Osborn², Kevin Moder², Vaidehi Chowdhary², and Timothy B. Niewold¹

¹Department of Immunology and Division of Rheumatology, Mayo Clinic, MN; ²Division of Rheumatology, Mayo Clinic, MN

Background/Purpose: Most confirmed SLE-risk loci are found near or in genes with immune function, yet how these loci influence diverse immune cell subsets remains unknown.We performed single cell eQTL analysis in SLE monocytes to determine the impact of SLE-risk loci in single human monocytes.

Methods: Purified classical (CL) and non-classical (NCL) monocytes from SLE patients were analyzed for expression of 90 genes using Fluidigm C1 System, and the same patients were genotyped for 7 SLE-risk SNPs to enable eQTL analysis.Each monocyte subset was analyzed separately using non-parametric analyses.

Results:We observed a large number of significant eQTL associations that surpassed the 5% FDR.The SLE-associated SNPs demonstrated more eQTLs in NCLs as compared to CLs (p=2.5x10^-8).For a given SNP, the eQTL associated transcripts differed between monocyte subsets (p<0.001 for all 7 SNPs for discordance).For NCLs, TNFAIP3, IRF5, IRF7, PTPN22, and SPP1 shared a significant proportion of eQTL associations.For CLs, TNFAIP3 shared many eQTLs with SPP1 and ITGAM, while SPP1 and ITGAM showed limited overlap.Thus, SLE-associated risk loci exert coordinated effects on gene expression within individual human monocytes, and the risk loci interact in different ways in different cell types.

Conclusion: Our study revealed striking differences, using single cell gene expression, in the occurrence and interaction of SLE risk associated eQTLs within different but closely related cell types.This suggests pleiotropic effects from each locus across various immune cell types, and a high degree of complexity when considering how these loci impact the immune system.