Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells

Nat Commun. 2020 Jul 3;11(1):3294. doi: 10.1038/s41467-020-17089-5.


Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • Cells, Cultured
  • Chromosome Mapping / methods
  • Gene Expression Profiling / methods
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods*
  • Humans
  • Jurkat Cells
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic / genetics*
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • RNA Interference
  • Receptors, CXCR5 / genetics
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*


  • Autoantibodies
  • BCL6 protein, human
  • CXCR5 protein, human
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5
  • HIPK1 protein, human
  • MINK1 protein, human
  • Protein Serine-Threonine Kinases