rs3087243 — CTLA4 CT60

CTLA4 CT60 — The Immune Checkpoint Sentinel

CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) is a critical immune checkpoint molecule¹¹ molecule
CTLA-4 is expressed on activated T cells and functions as a negative regulator, preventing overactive immune responses that acts as a brake on the immune system. The CT60 variant (rs3087243), located in the 3' untranslated region of the CTLA4 gene²² of the CTLA4 gene
The 3'UTR region contains regulatory sequences that control mRNA stability and translation efficiency, is one of the most extensively studied autoimmune susceptibility variants. This single nucleotide change from A to G has profound implications for immune regulation and autoimmune disease risk.

The Mechanism

The CT60 variant sits in the 3'UTR of the CTLA4 mRNA, a region that doesn't code for protein but critically controls gene expression. The G allele is in strong linkage disequilibrium with an (AT)n dinucleotide repeat³³ with an (AT)n dinucleotide repeat
Longer (AT)n repeats are associated with the G allele and reduce CTLA4 mRNA stability in the same region. Research has shown that the length of this repeat inversely correlates with both CTLA4 mRNA and protein levels in autoreactive T-cell lines. When T cells carry longer (AT)n repeats linked to the G allele, they produce less CTLA-4 protein — the molecular brake on immune activation becomes weaker.

The 3'UTR sequence affects both mRNA stability and translational efficiency⁴⁴ The 3'UTR sequence affects both mRNA stability and translational efficiency
Studies using reporter gene assays demonstrated that the CTLA4 3'UTR can confer instability to mRNA and reduce protein expression in vitro. Additionally, the variant influences the ratio of full-length CTLA-4 (bound to cell membranes) to soluble CTLA-4 (circulating in blood), with the GG genotype associated with lower production of the soluble immunoregulatory form.

The Evidence

The association between rs3087243 and autoimmune disease is supported by extensive research across multiple conditions:

Graves' Disease and Autoimmune Thyroid Disease: A case-control study of 288 Graves' disease patients⁵⁵ case-control study of 288 Graves' disease patients
The G/G genotype frequency was 70.1% in cases vs 51.4% in controls found the GG genotype conferred an odds ratio of 2.22 (95% CI: 1.58-3.13) for disease. A comprehensive meta-analysis of 20 studies⁶⁶ comprehensive meta-analysis of 20 studies
Analysis included both Graves' disease and Hashimoto's thyroiditis across Asian and Caucasian populations confirmed that CT60 polymorphism confers susceptibility to autoimmune thyroid diseases, with the G allele consistently associated with increased risk across ethnicities.

Type 1 Diabetes: The variant's role in type 1 diabetes is particularly notable in individuals who also develop thyroid autoimmunity. In a study of 4,364 type 1 diabetic patients⁷⁷ study of 4,364 type 1 diabetic patients
10.6% had thyroid peroxidase autoantibodies (TPOAbs), those with TPOAbs showed a significantly stronger association with rs3087243 (OR = 1.49 for G allele) compared to TPOAbs-negative patients (OR = 1.16). This subgroup also had a 1.94:1 female-to-male ratio compared to 0.94:1 in those without thyroid autoimmunity.

Latent Autoimmune Diabetes in Adults (LADA): A meta-analysis of 820 LADA cases⁸⁸ meta-analysis of 820 LADA cases
Analysis included 4,824 controls across multiple ethnic groups identified significant associations with LADA, particularly in Caucasian populations under a recessive model, suggesting two copies of the risk allele substantially increase susceptibility.

Rheumatoid Arthritis: Interestingly, for RA the effect is reversed — the A allele (not G) is associated with risk. A large meta-analysis of 66 studies⁹⁹ large meta-analysis of 66 studies
Included 16,394 RA patients and 17,453 controls found that A allele carriers had approximately 13% reduced risk compared to G allele carriers, with AA genotype showing 20% reduced risk compared to GG. This paradoxical protective effect of the G allele in RA versus other autoimmune conditions highlights the complex, disease-specific roles of immune checkpoint regulation.

Practical Implications

If you carry one or two G alleles at rs3087243, your immune system's "off switch" may be less effective. This doesn't mean you'll develop autoimmune disease — most carriers never do — but it does mean your T cells are more prone to activation and potentially more likely to attack your own tissues under the right (or wrong) environmental triggers.

The clinical significance varies by which autoimmune conditions run in your family. If you have relatives with thyroid disease, type 1 diabetes, or other autoimmune conditions, the G allele may be particularly relevant to monitor. Women with the GG genotype who also have type 1 diabetes should be especially vigilant about thyroid function, as this combination strongly predisposes to autoimmune thyroid disease.

For those with established autoimmune conditions, understanding your CTLA4 genotype may eventually inform treatment decisions. CTLA-4 is the target of checkpoint inhibitor immunotherapies¹⁰¹⁰ CTLA-4 is the target of checkpoint inhibitor immunotherapies
Drugs like ipilimumab block CTLA-4 to enhance immune responses against cancer used in cancer treatment, and genetic variation at this locus may predict both therapeutic response and immune-related adverse events.

Interactions

CTLA4 rs3087243 interacts with other immune-regulatory variants to modulate autoimmune risk. The most notable interaction is with rs231775 (+49A/G)¹¹¹¹ rs231775 (+49A/G)
This exon 1 variant causes a threonine-to-alanine amino acid change affecting CTLA-4 glycosylation, also in the CTLA4 gene, which affects CTLA-4 protein folding and cell surface expression. Individuals carrying risk alleles at both positions show enhanced susceptibility to Graves' disease and type 1 diabetes compared to either variant alone.

The variant also shows epistatic interactions with PTPN22 rs2476601 (another T-cell regulatory gene variant) in determining autoimmune disease risk. Evidence suggests genetic interaction between HLA class II genotypes and rs3087243 in type 1 diabetes¹²¹² Evidence suggests genetic interaction between HLA class II genotypes and rs3087243 in type 1 diabetes
Combined effects were observed beyond simple additive models, indicating that autoimmune susceptibility emerges from complex networks of immune gene variants rather than single mutations.