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

Chun Su, Matthew E. Johnson, Annabel Torres, Rajan M. Thomas, Elisabetta Manduchi, Prabhat Sharma, Parul Mehra, Carole Le Coz, Michelle E. Leonard, Sumei Lu, Kenyaita M. Hodge, Alessandra Chesi, James Pippin, Neil Romberg, Struan F. A. Grant and Andrew D. Wells ()
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Chun Su: The Children’s Hospital of Philadelphia
Matthew E. Johnson: The Children’s Hospital of Philadelphia
Annabel Torres: The Children’s Hospital of Philadelphia
Rajan M. Thomas: The Children’s Hospital of Philadelphia
Elisabetta Manduchi: The Children’s Hospital of Philadelphia
Prabhat Sharma: The Children’s Hospital of Philadelphia
Parul Mehra: The Children’s Hospital of Philadelphia
Carole Le Coz: The Children’s Hospital of Philadelphia
Michelle E. Leonard: The Children’s Hospital of Philadelphia
Sumei Lu: The Children’s Hospital of Philadelphia
Kenyaita M. Hodge: The Children’s Hospital of Philadelphia
Alessandra Chesi: The Children’s Hospital of Philadelphia
James Pippin: The Children’s Hospital of Philadelphia
Neil Romberg: The Children’s Hospital of Philadelphia
Struan F. A. Grant: The Children’s Hospital of Philadelphia
Andrew D. Wells: The Children’s Hospital of Philadelphia

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17089-5

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