rs16840252 — CTLA4

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

See your personal result for CTLA4

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

CTLA4 −1147 — The Promoter Tag Variant

CTLA-4 is the immune system's master checkpoint — a protein on activated T cells that competes with the stimulatory receptor CD28 for binding to B7 ligands (CD80/CD86) on antigen-presenting cells. When CTLA-4 wins this competition it delivers an inhibitory signal that dampens T-cell activation, preventing excessive immune responses and self-reactivity. The rs16840252 variant sits approximately 1,147 bp upstream11 1,147 bp upstream
Referred to as the "−1147 C>T" promoter variant in the literature; position chr2:203,866,795 on GRCh38 of the CTLA4 transcription start site — well within the promoter and regulatory region of the gene. The T allele (minor allele, global frequency ~16%) tags a haplotype block that also includes the −318 C>T variant (rs5742909) and is in partial linkage disequilibrium with the more extensively studied +49A>G (rs231775) and CT60 (rs3087243) CTLA4 variants.

The Mechanism

Rs16840252 lies in the 5' upstream regulatory region of CTLA4, upstream of the core promoter elements. Variants in this region can alter transcription factor binding22 transcription factor binding
Promoter SNPs can create or destroy binding sites for transcription factors including NF-κB, SP1, AP-1, and RUNX1, which regulate CTLA4 expression in activated T cells and chromatin accessibility, influencing the level of CTLA-4 mRNA and ultimately the amount of inhibitory checkpoint protein on T-cell surfaces. Reporter gene assays in the region have confirmed that nearby CTLA4 promoter variants (rs733618 and rs4553808) reduce transcriptional activity, and rs16840252 tags haplotypes containing these functionally active elements.

The variant itself has a CADD score of 2.35 and GERP conservation score of −1.8533 CADD score of 2.35 and GERP conservation score of −1.85, indicating modest intrinsic functional impact as a standalone variant. Its biological significance is primarily as a haplotype tag — it marks combinations of nearby regulatory variants (the extended CTLA4 promoter haplotype) that collectively alter CTLA4 expression levels in autoreactive T cells.

The Evidence

Systemic Lupus Erythematosus: A Taiwanese case-control study44 Taiwanese case-control study
Chen DP, Lin WT, Yu KH, 2022, examining nine co-stimulatory molecule SNPs in SLE found rs16840252 strongly associated with SLE across multiple genotype comparisons (CC vs. CT vs. TT p<0.001; CC vs. CT p<0.001), making it one of the most significant CTLA4 signals in that cohort.

Rheumatoid Arthritis: A case-control study of 124 RA patients55 case-control study of 124 RA patients
Chen DP et al. 2023, also examining immune co-stimulatory molecule variants found rs16840252 associated with RA at p=0.007 (CC vs. CT vs. TT) and p=0.011 (CC vs. CT), placing it among the significant CTLA4 variants in immune-mediated arthritis.

Graves' Ophthalmopathy: A study examining CTLA4 haplotypes in Taiwanese GO patients found the rs733618C–rs16840252C haplotype66 rs733618C–rs16840252C haplotype
Chen DP et al. 2019, investigating CTLA4 promoter haplotypes in Graves' ophthalmopathy conferred OR = 2.375 (p = 0.043) for GO risk, while individual SNP analysis of rs16840252 alone showed a borderline trend (p = 0.052). This is characteristic of a haplotype-tagging variant — the effect is carried by the extended promoter block, not the C>T change in isolation.

ANCA-Associated Vasculitis: A Guangxi population case-control study77 Guangxi population case-control study
Bu K et al. 2025, 343 AAV cases and 343 controls identified rs16840252 as one of three CTLA4 SNPs significantly associated with AAV susceptibility, with specific haplotypes (ATT and GCC configurations) driving increased disease risk.

Null findings: rs16840252 showed no significant independent association with LADA in a 61-patient Estonian cohort, and no correlation with cytomegalovirus infection outcomes after renal transplantation (270 allograft recipients). This pattern reinforces that its effects are largely haplotype-dependent rather than intrinsic to the C>T change.

Practical Implications

Carrying a T allele at rs16840252 signals membership in a CTLA4 promoter haplotype associated with modestly reduced checkpoint gene expression. Because CTLA-4 is a central regulator of T-cell tolerance, even subtle reductions in expression can lower the activation threshold for autoreactive T cells. The practical implications mirror those of other CTLA4 autoimmune-risk variants: heightened vigilance for early autoimmune symptoms, particularly thyroid disease (Graves', Hashimoto's), joint disease (RA), and systemic autoimmunity (SLE). The homozygous TT genotype is uncommon (~2.2% globally) but warrants the same proactive monitoring approach as other CTLA4 risk genotypes.

For those already diagnosed with RA or another T-cell-mediated autoimmune condition, the CTLA4 genotype context is clinically relevant when considering abatacept (Orencia)88 abatacept (Orencia)
A recombinant CTLA-4 fusion protein used as a biologic in RA; it compensates for reduced endogenous CTLA-4 by blocking T-cell costimulation directly, which works by supplementing the very checkpoint pathway that CTLA4 risk variants partially impair.

Interactions

Rs16840252 is in partial linkage disequilibrium with two extensively studied CTLA4 variants: the CT60 regulatory variant rs3087243 (3'UTR, affects mRNA stability) and the +49A>G coding variant rs231775 (affects CTLA-4 signal peptide processing and surface trafficking). Together these variants form a haplotype block spanning the CTLA4 gene. When rs16840252 T is co-inherited with rs231775 G and rs3087243 G, the combined haplotype substantially amplifies checkpoint impairment through complementary mechanisms — reduced promoter activity, reduced surface trafficking, and reduced mRNA stability acting simultaneously.

The CTLA4 locus also interacts epistatically with PTPN22 rs247660199 PTPN22 rs2476601
The R620W variant in PTPN22 impairs a different T-cell inhibitory signal (LYP phosphatase), compounding the effect of reduced CTLA-4 checkpoint function in determining seropositive autoimmune disease risk, particularly RA and type 1 diabetes.

Genotype Interpretations

What each possible genotype means for this variant.

CC Common Promoter Haplotype Normal

Two copies of the common allele; standard CTLA4 promoter activity and T-cell checkpoint function

You carry two copies of the common C allele at rs16840252. This genotype is not associated with the autoimmune-risk CTLA4 promoter haplotype. About 70% of people globally share this configuration. Your T cells are expected to produce CTLA-4 at baseline levels, maintaining normal immune checkpoint function and the standard threshold for self-tolerance. This is the reference configuration for this upstream regulatory position.

CT Promoter Haplotype Carrier Intermediate

One copy of the minor T allele, tagging a CTLA4 promoter haplotype associated with modestly increased autoimmune risk

As a single upstream tag variant, rs16840252 shows modest individual effect sizes in published studies. Its significance emerges in haplotype context: the T allele tags an extended CTLA4 promoter haplotype containing functionally active variants (including nearby rs733618) that reduce CTLA4 transcriptional activity. In Taiwanese cohorts, this haplotype conferred OR = 2.375 for Graves' ophthalmopathy; in SLE studies, the genotype comparison reached p<0.001. The effect in European populations may differ as most data come from East Asian cohorts where the haplotype block structure may vary. The T allele frequency is somewhat lower in South Asians (~7%) and East Asians (~11%) than in Europeans (~17%), suggesting the haplotype background differs by ancestry.

TT Homozygous Promoter Variant High Risk

Two copies of the minor T allele; greater CTLA4 promoter haplotype dosage and elevated autoimmune susceptibility across multiple conditions

The TT genotype is uncommon enough (~2%) that most published studies do not report separate TT-specific odds ratios — data are typically pooled as TT + CT versus CC, or analyzed with additive/dominant models. Available genotype-level results in SLE (p<0.001 across all comparisons including CC vs. CT vs. TT) and RA (p=0.007) are consistent with a dose- dependent effect where TT confers greater risk than CT. The haplotype data are the most clinically informative: the extended CTLA4 promoter haplotype tagged by the T allele has been associated with elevated risk across Graves' ophthalmopathy (OR≈2.4 for the C-C haplotype on the opposing allele), SLE, and AAV.

The TT genotype should be interpreted in context with your other CTLA4 variants (rs231775 and rs3087243). If you also carry G alleles at those positions, the combined haplotype spanning the CTLA4 locus represents the most impaired promoter-to-3'UTR checkpoint configuration, and monitoring should reflect the combined burden.