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. Overall design: 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.