Autoimmune Tolerance & T-Cell Regulation

Intronic variant in RABEP1 associated with fasting glucose modulation under psychotropic drug treatment; G allele carriers show lower glucose levels, potentially reflecting altered endosomal trafficking of metabolic receptors

Intronic regulatory variant near the PDCD1 (PD-1) immune checkpoint locus that disrupts a RUNX1 transcription factor binding site, altering PD-1 expression and conferring susceptibility to systemic lupus erythematosus and multiple sclerosis

Intronic regulatory variant in TSHR intron 1; the T allele disrupts thymic expression of the TSH receptor, allowing autoreactive T cells to escape tolerance and increasing susceptibility to Graves' disease — the most common autoimmune cause of hyperthyroidism

Intronic regulatory variant in TSHR intron 1 that is the primary PLZF repressor-binding site in the open chromatin region controlling thymic TSHR expression; the T allele allows stronger PLZF binding, reduces intrathymic TSHR levels, impairs central immune tolerance to thyroid antigens, and confers susceptibility to Graves' disease

Intronic PTPN22 variant independently associated with psoriasis and ankylosing spondylitis, operating through a distinct mechanism from the established R620W risk allele

An intronic variant in TYK2 intron 7 that promotes exon 8 inclusion in the mature TYK2 transcript, enhancing TYK2 receptor-binding capacity and conferring protection against SLE in Caucasian populations; acts through the same exon 8 splicing mechanism as the co-associated rs2304256 (V362F) variant

A missense variant in the TYK2 pseudokinase (JH2) domain that partially impairs TYK2 catalytic regulation, reducing IL-12-stimulated STAT4 signaling and conferring independent protection against rheumatoid arthritis, psoriasis, SLE, and type 1 diabetes

Intronic variant in IL2RA intron 1 that creates an estrogen-responsive enhancer element — the risk C allele allows estrogen receptor alpha binding and increases IL2RA transcription, altering T-regulatory cell function and autoimmune disease susceptibility

Intronic PTPN22 haplotype tag variant that refines autoimmune risk stratification beyond R620W and associates independently with Hashimoto's thyroiditis in Asian populations

Intronic PTPN22 variant in a transcription factor-binding site, associated with type 1 diabetes in Asian populations where the R620W coding variant is absent

Upstream promoter variant (~1147 bp 5' of CTLA4) tagging an autoimmune-associated haplotype block that influences T-cell checkpoint gene expression and susceptibility to lupus, Graves' ophthalmopathy, RA, and ANCA-associated vasculitis

Regulatory variant at the chromosome 13q12 locus that tags a region upstream of USP12, a deubiquitinase controlling CD4+ T cell activation and NF-κB signaling via BCL10 stabilization; the C risk allele increases susceptibility to ulcerative colitis and predicts risk of disease relapse in carriers

Intronic regulatory variant in TSHR intron 1; the A allele reduces thymic expression of the TSH receptor, impairing central tolerance to thyroid antigens and increasing susceptibility to Graves' disease — the most common autoimmune cause of hyperthyroidism

Intronic variant affecting IL-2 receptor alpha chain expression and soluble IL-2RA shedding — impairs T-regulatory cell signaling and increases autoimmune disease susceptibility

Regulatory variant at the SLC26A3 locus associated with ulcerative colitis susceptibility — SLC26A3 encodes the DRA chloride/bicarbonate antiporter essential for intestinal epithelial barrier function and mucosal immune homeostasis

Intronic IL2RA variant that modulates soluble IL-2RA shedding and Treg signaling; independently associated with psoriasis susceptibility and contributes to the IL2RA locus autoimmune risk signal

Intronic variant in TSHR intron 1; the C allele increases susceptibility to Graves' disease by altering thyroid-stimulating hormone receptor expression in the thymus, impairing central immune tolerance to TSHR — but notably shows no association with Graves' ophthalmopathy, suggesting variant-specific effects within this regulatory locus

A common missense and splicing variant in TYK2 that promotes exon 8 inclusion and mildly enhances TYK2 expression, conferring protection against multiple autoimmune diseases including SLE, rheumatoid arthritis, type 1 diabetes, and psoriasis

Missense variant in the CTLA-4 leader peptide that reduces surface expression of this immune checkpoint receptor, increasing T cell activity and autoimmune disease risk

Upstream regulatory variant in the CTLA4 MH30 region associated with latent autoimmune diabetes in adults (LADA); the G allele reduces soluble CTLA-4 expression and is linked to the disease-risk haplotype

Deep-intronic variant in the CD226 (DNAM-1) co-stimulatory receptor gene associated with rheumatoid arthritis, multiple sclerosis, and altered neutrophil and white blood cell counts, likely acting as a regulatory variant that modulates CD226 expression in immune cells

The strongest non-HLA autoimmune risk allele, affecting T-cell and B-cell signaling threshold

Promoter variant in PTPN22 that alters gene expression and modulates autoimmune susceptibility, particularly in Asian populations where it acts independently of the R620W coding variant

Immune checkpoint regulatory variant in the 3'UTR affecting T-cell activation and autoimmune disease susceptibility

Intronic IL2RA variant independently associated with rheumatoid arthritis risk and part of the IL-2 receptor locus haplotype architecture modulating Treg-driven immune tolerance

Protective loss-of-function variant in the PTPN22 catalytic domain that reduces phosphatase activity and lowers risk of SLE, RA, and ulcerative colitis

A rare missense variant in the TYK2 pseudokinase (JH2) domain that partially reduces TYK2 catalytic activity by disrupting intradomain regulatory contacts, conferring strong independent protection against rheumatoid arthritis (OR 0.53) and other autoimmune diseases including SLE

Synonymous RSBN1 variant that tags a PTPN22 locus haplotype independently associated with early-onset psoriasis, psoriatic arthritis risk, and Graves' disease susceptibility. Curator note — gene field stays RSBN1 (LD-block proximity), but the functional signal is at the PTPN22 locus; do not double-count with rs2476601 (PTPN22 R620W) when both appear in the same panel as they tag overlapping autoimmune risk.

Regulatory variant in the IL2RA locus altering LEF1 transcription factor binding and soluble IL-2 receptor levels — the C allele increases type 1 diabetes susceptibility while the minor A allele raises Graves' disease risk

Intronic PTPN2 variant whose G allele reduces T-cell protein tyrosine phosphatase (TC-PTP) activity, amplifying JAK-STAT signaling and conferring susceptibility to psoriasis and related autoimmune conditions

Promoter variant that increases CTLA-4 transcription; T allele carriers show better response to abatacept in rheumatoid arthritis and may have modestly altered autoimmune susceptibility

Intronic PTPN2 variant that reduces expression of T-cell protein tyrosine phosphatase (TC-PTP), lowering the threshold for JAK/STAT-driven T-cell activation and increasing susceptibility to Crohn's disease, rheumatoid arthritis, and juvenile idiopathic arthritis

Intronic variant in the autophagy regulator CLEC16A that alters thymic T-cell selection and immune tolerance, influencing risk for type 1 diabetes and multiple sclerosis

Intronic RABEP1 variant associated with rheumatoid arthritis risk, acting through endosomal trafficking and autophagy pathways that regulate antigen processing in immune cells

Missense variant in the T-cell and NK-cell co-stimulatory receptor CD226 (DNAM-1) that raises the activation threshold of adaptive immunity and confers risk for multiple autoimmune diseases including type 1 diabetes, multiple sclerosis, SLE, and rheumatoid arthritis