rs10924104 in the expression enhancer motif of CD58 confers susceptibility to human autoimmune diseases.

Autor: Hitomi Y; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. yhitomi@ri.ncgm.go.jp., Ueno K; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan., Aiba Y; Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan., Nishida N; Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan., Kawai Y; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan., Kawashima M; Database Center for Life Science, Research Organization of Information and Systems, Kashiwa, Japan., Khor SS; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.; Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore., Takada S; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan., Iwabuchi C; Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan., Nagasaki M; Division of Biomedical Information Analysis, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan., Tokunaga K; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan., Nakamura M; Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan.; Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.; Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2024 Jan; Vol. 143 (1), pp. 19-33. Date of Electronic Publication: 2023 Nov 23.
DOI: 10.1007/s00439-023-02617-2
Abstrakt: CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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