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Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that downregulates T-cell activation through competition with CD28 for B7 ligands. Loss-of-function or common polymorphisms in CTLA4 have been implicated in multiple autoimmune diseases, including systemic lupus erythematosus (SLE). The genetic evidence for CTLA4 in SLE spans candidate SNP studies, family-based screens, meta-analyses and GWAS approaches, with functional assays corroborating altered expression and T-cell signaling in risk allele carriers.
Multiple case-control and family-based studies have assessed CTLA4 polymorphisms in SLE. A meta-analysis of 26 reports involving 3 847 SLE patients and 5 278 controls confirmed association of the +49A/G allele with increased SLE risk (G vs. A: p=0.03, OR=1.47) and the –1722T/C variant with protection (p=0.02) ([PMID:36597619]). A high-density family-based screen in 532 UK SLE families identified two 3′-flanking variants (rs231726/rs231727) demonstrating transmission disequilibrium (p=0.0008) ([PMID:17000707]). More recently, rs17268364 in the CTLA4–ICOS intergenic region was associated with SLE in 4 356 Chinese cases versus 21 107 controls (p_meta=7.02×10⁻¹¹, OR=1.19) and shown to reduce CTLA4 expression in reporter assays and patient samples ([PMID:34736521]).
Segregation analysis of CTLA4 promoter variants in 54 multiplex Portuguese SLE families (76 affected, 166 relatives) revealed a heritable decrease in CD4⁺CD25⁺FOXP3⁺ regulatory T-cell frequency linked to CTLA4 and TGFB1 haplotypes, consistent with a trait segregating in SLE pedigrees ([PMID:19173720]).
The CTLA4 variant spectrum includes exon-1 +49A/G (rs231775), CT60A/G in the 3′UTR, promoter variants –1661A/G and –1722T/C, and intergenic rs17268364. Rare coding mutations, such as c.416A>G (p.Tyr139Cys), have been reported in CTLA4 haploinsufficiency syndromes with prominent autoimmune features ([PMID:29375547]).
Functional studies demonstrate that the rs17268364 risk allele binds EWSR1 and reduces CTLA4 promoter activity, leading to lower mRNA levels and heightened type I interferon signatures in lupus nephritis patients ([PMID:34736521]). The CT60G susceptibility allele alters TCR signaling thresholds in CD4⁺ T cells, raising activation responses in naive and memory subsets ([PMID:18000051]). In murine models, overexpression of the short 1/4 CTLA-4 splice isoform exacerbates MRL/lpr lupus and increases anti-dsDNA titers, while cytoplasmic Tyr201 mutations impair Treg suppressive function in vivo ([PMID:23203389]; [PMID:10799894]).
Conflicting evidence arises from a Thai case-control study of 151 SLE patients versus 153 controls, which found no significant association of +49A/G or CT60 variants with SLE (P>0.05) ([PMID:22053592]). These discrepancies underscore population heterogeneity and limited power in smaller cohorts.
Collectively, genetic and experimental data support a Strong clinical validity for the CTLA4–SLE association: thousands of probands across 26 studies, family-based segregation, GWAS confirmation and concordant functional assays. CTLA4 polymorphism testing can refine risk stratification in SLE and guide immunomodulatory strategies targeting the CTLA-4 axis.
Gene–Disease AssociationStrongAssociation in 3,847 probands across 26 studies, replicated in family-based and GWAS cohorts with concordant functional data Genetic EvidenceStrong3,847 probands; transmission disequilibrium in 532 families; GWAS in 4,356 cases Functional EvidenceModerateAllele-specific expression, signal transduction assays and murine models demonstrate pathogenic CTLA4 alterations |