biostudies-literatureKim TBristol-Myers Squibb Company | Bristol-Myers Squibb CanadaNCATS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Center for Research ResourcesU.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin DiseasesNHGRI NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | NIH | National Human Genome Research InstituteNIAMS NIH HHSArthritis National Research Foundation2150https://www.ebi.ac.uk/biostudies/studies/S-EPMC10923805biostudies-literatureUnknown15(1)Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4⁺ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 Nature communicationsNon-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.PMC10923805R01AR065538P30 AR070549AR078769P30AR069625R01 AR073201R01AI024717R01 AR077607R01 HG010730R01 AR075906R01AR063759R01 NS099068K08AR072791P30AR070253R01 AR073228R01AR073228R01 AR065538P30 AR069625IM101-835UL1TR002541R01AR077607R01 AR063759R01AR075906U01AI130830UL1 TR002541P30AR072577U01 AI130830T32 AR007530T32 AR007611P30 AR072577R01HG010730R01AR073201R01 AI024717P30 AR070253K08 AR072791R01NS099068R01 AR078769Hackert NChiu DJBaglaenko YWeirauch MTRao DARaychaudhuri SNigrovic PALaza-Briviesca RWestra HJDarbousset RSparks JAAguiar VRCKim TKoh BWang QMartinez-Bonet MChen XGutierrez-Arcelus MfalseNon-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4⁺ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 2024-01-01T00:00:00Z2024 Mar2026-07-15T14:02:14.312Z2024-11-09T19:15:22.647ZS-EPMC109238053845903210.1038/s41467-024-46457-8