Crohn’s Disease-associated variant in laccase domain containing 1 (LACC1) modulates T cell gene expression, metabolism and T cell function

Yingcong Li, Gabriel Ascui, Martina Dicker, Thomas Riffelmacher, Vivek Chandra, Benjamin Schmiedel, Ting-Fang Chou, Pandurangan Vijayanand () and Mitchell Kronenberg ()
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Yingcong Li: La Jolla Institute for Immunology
Gabriel Ascui: La Jolla Institute for Immunology
Martina Dicker: La Jolla Institute for Immunology
Thomas Riffelmacher: La Jolla Institute for Immunology
Vivek Chandra: La Jolla Institute for Immunology
Benjamin Schmiedel: La Jolla Institute for Immunology
Ting-Fang Chou: La Jolla Institute for Immunology
Pandurangan Vijayanand: La Jolla Institute for Immunology
Mitchell Kronenberg: La Jolla Institute for Immunology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Genome wide association studies (GWAS) identify many risks for Crohn’s disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.

Date: 2025
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DOI: 10.1038/s41467-025-57744-3

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