Disease-associated variant in LACC1, a Crohn’s risk gene, acts in T cells to alter gene expression, metabolism and T cell function

Genome wide association studies (GWAS) identify a site near the metabolism gene laccase domain containing 1 (LACC1) as a risk for Crohn’s disease (CD). We previously found the Crohn’s disease risk allele near LACC1 correlates with decreased T lymphocyte LACC1 expression. Despite this, proof of this allelic effect, the mechanism by which gene expression is affected, and links to T cell function and inflammatory disease, remained unknown. Here we identified sites in a promoter region in a haploblock that influenced LACC1 gene expression. Direct association of disease-risk variants with lower LACC1 mRNA was confirmed by comparing transcripts from each allele in LACC1 heterozygous human CD4+ T cells. Using gene editing, we validated the role of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown showed altered metabolism, including a reduced oxygen consumption rate, and reduced regulatory T cell differentiation. Therefore, our study provides a mechanism for this disease GWAS hit by linking promoter region alterations to changes in T cell metabolism and function. To investigate how LACC1 deciciency influence the transcriptome of human Th0 and iTreg cells, we knocked down LACC1 by lentiviral shRNA in these CD4 cells. Then we performed bulk RNA-seq on empty vector (EV) and LACC1 knockdown (KD) transuced Th0 and iTreg cells, 4 or 5 human donors were used.