CTLA4 Variants rs231775 and rs3087243: What They Mean for Immune Health

Oct 4

4 min read

CTLA4 is an immune checkpoint gene: it helps keep T-cell responses from becoming excessive. Two common CTLA4 variants, rs231775 and rs3087243, have been studied in connection with autoimmune conditions, especially autoimmune thyroid disease. They may contribute a small part of a complex genetic picture, but neither variant can diagnose or predict an autoimmune disease on its own.

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What Does CTLA4 Do?

When an immune cell encounters a possible threat, it needs both an activation signal and careful control. Antigen-presenting cells display molecules called CD80 and CD86. These can bind to CD28 on T cells and help stimulate an immune response. CTLA-4 uses the same CD80/CD86 partners to limit that stimulation. Regulatory T cells also use CTLA-4 as part of their work keeping immune responses in check. In experimental models, CTLA-4 can remove CD80 and CD86 from neighboring cells, reducing the costimulatory signal available to T cells [R].

This balancing role helps explain why researchers study CTLA4 in autoimmunity. If immune regulation varies, the likelihood of certain immune responses may also vary. But the effects of common variants are modest and context dependent; they do not mean that a person’s immune system is simply “strong” or “weak.”

CTLA4 rs231775: The +49A>G Variant

CTLA4 rs231775 is also called +49A>G. It is a common coding variant in exon 1 that changes amino acid 17 in the protein’s signal peptide: the A allele encodes threonine (Thr), while the G allele encodes alanine (Ala), written p.Thr17Ala. A signal peptide helps guide a newly made protein through the cell.

Laboratory studies have reported that this change can affect CTLA-4 processing or its appearance at the cell surface. One study observed reduced CTLA-4 upregulation after T-cell activation in cells from G/G donors [R]. These results offer a possible biological explanation for reported population-level associations, but they should not be treated as a direct measurement of immune function in an individual.

The p.Thr17Ala change is not the same as a rare pathogenic CTLA4 mutation. ClinVar’s expert panel classifies it as benign for CTLA4 haploinsufficiency, a rare monogenic immune-regulation disorder. That classification addresses that specific disorder; it does not rule out small statistical associations with common, complex diseases [R].

CTLA4 rs3087243: The CT60 Variant

CTLA4 rs3087243 is commonly called CT60 or +6230G>A. It is a noncoding variant in the 3′ region of CTLA4. Because it does not change the protein’s amino-acid sequence, researchers have investigated whether it tags regulatory differences, including changes in CTLA4 RNA processing and the balance between soluble and membrane-bound forms of CTLA-4.

An influential early study linked variation in the CTLA4 3′ region, including CT60, with autoimmune susceptibility and lower messenger RNA levels of a soluble CTLA-4 form [R]. Follow-up work did not consistently find a relationship between CT60 genotype and soluble CTLA-4 levels, so the mechanism remains unsettled [R, R].

The allele described as “risk-associated” can depend on the disease, population, and study. In several studies of autoimmune thyroid disease, the G allele was associated with greater susceptibility. An “alternate allele” label in a DNA report is a reference-genome designation; it does not automatically mean that allele is the risk-associated one.

What Do CTLA4 Variants Have to Do With Autoimmune Disease?

Researchers have studied CTLA4 variants in several autoimmune conditions, including Graves’ disease, Hashimoto’s thyroiditis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus [R, R, R]. The size and consistency of associations differ by condition and population. A result from one ancestry group or disease study should not be assumed to apply equally to everyone.

For example, a Han Chinese case-control study examined 289 adults and 265 children with Graves’ disease, 229 children with Hashimoto’s disease, and 1,058 controls. In that study, the rs231775 G allele was associated with Graves’ disease with an odds ratio (OR) of 1.50 in adults and 1.42 in children. For rs3087243, the G allele had an OR of 1.63 in adults and 1.58 in children. The two markers were strongly linked in that cohort, so their signals could not be considered fully independent [R].

How to Read a CTLA4 DNA Result

A raw DNA result for rs231775 or rs3087243 tells you which genotype was measured at that marker—for example, whether the tested file shows two copies of one allele or one copy of each. It does not measure CTLA-4 protein levels, T-cell activity, thyroid function, or whether you have an autoimmune condition.

When reviewing a result, keep these points in mind:

Check the variant identifier. rs231775 and rs3087243 are different markers with different locations and evidence.
Check allele orientation. Research papers may use a strand or allele convention that differs from a consumer DNA file. Follow the strand orientation specified by the reporting tool.
Treat association estimates as population research. Odds ratios from a case-control study are not personal risk percentages.
Consider the full clinical picture. Symptoms, family history, laboratory testing, and medical assessment matter far more than either common SNP alone.

A consumer DNA file may also have a missing or uncertain call at a marker. If a medically relevant result is suspected, a qualified clinician can advise whether clinical testing is appropriate.

Can GenesUnveiled Analyze CTLA4 rs231775 and rs3087243?

GenesUnveiled GeneExplorer includes CTLA4 rs231775 and rs3087243 among the markers readers can explore with a compatible raw DNA file. GeneExplorer is free to use. The result is an educational starting point for learning about immune regulation and genetic research—not a diagnosis, treatment recommendation, or substitute for medical testing.