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

Yingcong Li,G. Ascui,Martina Dicker,Thomas Riffelmacher,Vivek Chandra,Benjamin J. Schmiedel,Ting-Fang Chou,P. Vijayanand,Mitchell Kronenberg

Published 2025 in Nature Communications

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. Prior studies implicate an allele near laccase domain containing 1 (LACC1) for risk of Crohn’s disease and decreased LACC1 expression in T cells. Using human genome analyzes and mouse genetic models, here the authors link specific LACC1 variants with the modulation of T cell gene expression, metabolism and function.

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