Crohn's Disease-associated Variant in Laccase Domain Containing 1 (LACC1) Modulates T Cell Gene Expression, Metabolism and T Cell Function

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Mar 16

PMID 40089498

Authors

Yingcong Li

Gabriel Ascui

Martina Dicker

Thomas Riffelmacher

Vivek Chandra

Benjamin Schmiedel

Ting-Fang Chou

Pandurangan Vijayanand

Mitchell Kronenberg

Affiliations

Soon will be listed here.

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.

References

Franke A, McGovern D, Barrett J, Wang K, Radford-Smith G, Ahmad T . Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010; 42(12):1118-25. PMC: 3299551. DOI: 10.1038/ng.717. View

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

de Lange K, Moutsianas L, Lee J, Lamb C, Luo Y, Kennedy N . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017; 49(2):256-261. PMC: 5289481. DOI: 10.1038/ng.3760. View

Cader M, Boroviak K, Zhang Q, Assadi G, Kempster S, Sewell G . C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol. 2016; 17(9):1046-56. PMC: 6581540. DOI: 10.1038/ni.3532. View

Umeno J, Asano K, Matsushita T, Matsumoto T, Kiyohara Y, Iida M . Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis. Inflamm Bowel Dis. 2011; 17(12):2407-15. DOI: 10.1002/ibd.21651. View

Barrett J, Hansoul S, Nicolae D, Cho J, Duerr R, Rioux J . Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008; 40(8):955-62. PMC: 2574810. DOI: 10.1038/ng.175. View

Assadi G, Saleh R, Hadizadeh F, Vesterlund L, Bonfiglio F, Halfvarson J . LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis. Genes Immun. 2016; 17(4):261-4. DOI: 10.1038/gene.2016.17. View

Patel N, El Mouzan M, Al-Mayouf S, Adly N, Mohamed J, Al Mofarreh M . Study of Mendelian forms of Crohn's disease in Saudi Arabia reveals novel risk loci and alleles. Gut. 2014; 63(11):1831-2. DOI: 10.1136/gutjnl-2014-307859. View

10.

Wakil S, Monies D, Abouelhoda M, Al-Tassan N, Al-Dusery H, Naim E . Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2014; 67(1):288-95. DOI: 10.1002/art.38877. View

11.

Rabionet R, Remesal A, Mensa-Vilaro A, Murias S, Alcobendas R, Gonzalez-Roca E . Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. Sci Rep. 2019; 9(1):4579. PMC: 6418186. DOI: 10.1038/s41598-019-40874-2. View

12.

Karacan I, Ugurlu S, Sahin S, Everest E, Kasapcopur O, Tolun A . Gene Defects in Familial Form of Juvenile Arthritis. J Rheumatol. 2018; 45(5):726-728. DOI: 10.3899/jrheum.170834. View

13.

Kallinich T, Thorwarth A, von Stuckrad S, Rosen-Wolff A, Luksch H, Hundsdoerfer P . Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course. Pediatr Rheumatol Online J. 2016; 14(1):63. PMC: 5122026. DOI: 10.1186/s12969-016-0124-2. View

14.

Liu H, Irwanto A, Fu X, Yu G, Yu Y, Sun Y . Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet. 2015; 47(3):267-71. DOI: 10.1038/ng.3212. View

15.

Takeuchi M, Mizuki N, Meguro A, Ombrello M, Kirino Y, Satorius C . Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet. 2017; 49(3):438-443. PMC: 5369770. DOI: 10.1038/ng.3786. View

16.

Schmiedel B, Singh D, Madrigal A, Valdovino-Gonzalez A, White B, Zapardiel-Gonzalo J . Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell. 2018; 175(6):1701-1715.e16. PMC: 6289654. DOI: 10.1016/j.cell.2018.10.022. View

17.

Cader M, de Almeida Rodrigues R, West J, Sewell G, Md-Ibrahim M, Reikine S . FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle. Cell. 2020; 180(2):278-295.e23. PMC: 6978800. DOI: 10.1016/j.cell.2019.12.017. View

18.

Wei Z, Oh J, Flavell R, Crawford J . LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature. 2022; 609(7926):348-353. PMC: 9813773. DOI: 10.1038/s41586-022-05111-3. View

19.

Lahiri A, Hedl M, Yan J, Abraham C . Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nat Commun. 2017; 8():15614. PMC: 5472760. DOI: 10.1038/ncomms15614. View

20.

Huang C, Hedl M, Ranjan K, Abraham C . LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes. Cell Rep. 2019; 29(13):4525-4539.e4. PMC: 7372507. DOI: 10.1016/j.celrep.2019.11.105. View