Our fine-mapping of 76 non-MHC loci associated with risk for rheumatoid arthritis (RA, 11,475 cases, 15,870 controls) has recently identified rs117701653, a non-coding single nucleotide polymorphism (SNP) in the <a href="https://www.ncbi.nlm.nih.gov/gene/1493">CTLA4</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/940">CD28</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/29851">ICOS</a> locus, as the variant most likely to modulate RA risk within this region, with the minor allele C showing disease protection compared to the major allele A. We found that this SNP exhibits allele-specific protein binding and transcriptional modulation, further supporting its regulatory nature. Here, we aimed to determine whether the functional non-coding variant rs117701653 modulates the expression of genes within the CD28/CTLA4/ICOS locus. To address this question, we employed low-input RNA sequencing using the Illumina SmartSeq2 platform on resting total CD4+ T cells from the blood of 24 healthy subjects (8 AA, 8 AC, 8 CC) recruited based on genotype from the Mass General Brigham biobank. We performed a targeted cis-eQTL mapping analysis for protein coding genes with transcription start sites (TSS) within a 1MB window of SNP rs117701653. These genes included <a href="https://www.ncbi.nlm.nih.gov/gene/55759">WDR12</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/65065">NBEAL1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/57404">CYP20A1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/10152">ABI2</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/65059">RAPH1</a>, CD28, CTLA4, ICOS, and <a href="https://www.ncbi.nlm.nih.gov/gene/117583">PARD3B</a>. Surprisingly, allelic variation at rs117701653 correlated strongly with expression of ICOS. This suggests that individuals carrying the protective allele C at rs117701653 express lower levels of ICOS, implicating ICOS as a plausible target gene influenced by this protective allele. The raw sequence data from the 24 healthy individuals are available through dbGAP. Gene expression matrices have been deposited to GEO accession <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235868">GSE235868</a>.

Non-Coding Autoimmune Risk Variant Defines Role for ICOS in T Peripheral Helper Cell Development

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