rs1310182 — PTPN22 PTPN22 Intron Variant (c.2054-852T>C)

PTPN22 Intron Variant — A Population-Specific Gateway to Autoimmune Risk

The PTPN22 gene encodes lymphoid tyrosine phosphatase (LYP), a critical negative regulator of T-cell receptor (TCR) signaling. While the well-known R620W coding variant¹¹ R620W coding variant
rs2476601, the strongest non-HLA autoimmune risk allele in Europeans, changes arginine to tryptophan at the protein level is the dominant PTPN22 risk variant in Europeans and absent from Asian populations, rs1310182 represents a distinct intronic variant in a putative transcription factor binding site²² putative transcription factor binding site
Intronic variants overlapping transcription factor binding sites can alter PTPN22 expression levels without changing the protein sequence that modulates PTPN22 expression rather than protein function. This variant fills a mechanistic gap: explaining PTPN22-associated autoimmune risk in populations where R620W is essentially absent.

The Mechanism

Unlike R620W, which alters the phosphatase protein's interaction with CSK kinase, rs1310182 (HGVS: NM_015967.7:c.2054-852T>C) is located deep within an intron, 852 nucleotides before exon 16. Its location within a transcription factor binding site³³ transcription factor binding site
Intronic enhancers and transcription factor binding sites can regulate mRNA production and splicing; rs1310182 overlaps a region also shared with the AP4B1 antisense RNA 1 gene suggests the variant influences PTPN22 transcript levels or splicing rather than amino acid sequence. PTPN22 expression is tightly regulated⁴⁴ tightly regulated
PTPN22 is subject to NFAT-dependent transcriptional induction after TCR stimulation, with 2.1–3.6× more transcript in memory and regulatory T cells versus naive T cells; even modest changes in this regulation can shift the threshold at which T cells activate against self-antigens. The functional consequence — altered immune tolerance — mirrors what is seen with R620W, but through a different molecular route.

PTPN22 is expressed predominantly in lymphoid tissue and acts as a negative regulator of TCR signaling by dephosphorylating LCK, FYN, ZAP70, and ITAMs of the TCRζ/CD3 complex. Changes in PTPN22 expression level rather than function can disrupt the delicate balance between effective immune surveillance and inappropriate self-attack.

The Evidence

Population specificity is the defining characteristic of rs1310182. The R620W variant (rs2476601) is essentially absent from East Asian populations (~1% allele frequency), yet PTPN22 haplotypes still show associations with autoimmune disease in these populations. A Japanese haplotype study⁵⁵ Japanese haplotype study
rs1310182 C allele frequency differed significantly between T1D patients and controls; susceptibility haplotype containing rs1310182 risk allele was enriched in T1D patients while protective haplotype was absent demonstrated that rs1310182 is the primary PTPN22 signal for type 1 diabetes in Japanese patients. A separate Japanese study found rs1310182-containing haplotypes associated with autoimmune thyroid disease⁶⁶ rs1310182-containing haplotypes associated with autoimmune thyroid disease
PTPN22 haplotype distribution significantly differed in AITD patients; involvement of PTPN22 locus rather than rs2476601 in AITD development in Japanese (both Graves' disease and Hashimoto's thyroiditis) independently of the R620W locus.

In an Armenian population study⁷⁷ Armenian population study
96 T1D patients vs 100 controls of Armenian descent; T allele OR 4.82, 95% CI 2.38–9.76; TC heterozygotes OR 2.39, 95% CI 1.35–4.24; CC genotype negatively associated with T1D of 96 T1D patients and 100 controls, rs1310182 showed striking association with T1D. The TT homozygote (AA on plus strand) was the primary risk state while TC heterozygotes (AG on plus strand) were at intermediate risk. The CC genotype (GG on plus strand) was negatively associated with T1D in Armenians — protective in that population context. Additionally, the GG (plus-strand) genotype associated with higher HbA1c⁸⁸ GG (plus-strand) genotype associated with higher HbA1c
HbA1c positively correlated with GG genotype at diagnosis and 12 months post-diagnosis in Armenian T1D patients at T1D diagnosis suggests an influence on metabolic control severity once disease is established.

In Europeans, rs1310182 was associated with RA independent of rs2476601⁹⁹ rs1310182 was associated with RA independent of rs2476601
Two PTPN22 SNPs on a haplotype distinct from the R620W haplotype contribute to RA risk independently in Caucasian populations, implying independent functional contributions at the PTPN22 locus.

However, a 2025 updated meta-analysis¹⁰¹⁰ 2025 updated meta-analysis
842 T1D cases and 801 controls across 6 studies; no significant pooled association for rs1310182 in any genetic model tested of T1D associations found no statistically significant pooled association for rs1310182, driven partly by conflicting directionality across populations: the risk allele in Armenians (A/T coding) is the protective allele in Japanese (where G/C coding is the risk allele). This conflicting directionality across populations argues for population-stratified interpretation rather than a single universal risk model.

Practical Implications

The clinical utility of rs1310182 is most relevant for East Asian individuals, where it captures autoimmune risk that rs2476601 does not. For individuals carrying the G allele (the risk allele in East Asian populations), awareness of elevated T1D and autoimmune thyroid disease risk is warranted — especially when combined with other autoimmune risk factors or family history. The HbA1c association in T1D patients suggests that this variant may also relate to glycemic control once disease is established.

For individuals with European or Armenian ancestry, interpretation is more nuanced due to conflicting allele directions. In those populations, the rs2476601 (R620W) variant remains the primary PTPN22 risk signal.

Interactions

Rs1310182 exists on the same haplotype background as other PTPN22 variants including rs2488457 (-1123G>C promoter), rs2476601 (R620W), and rs3789604. In Asian populations where R620W is absent or rare, rs1310182 acts as the primary PTPN22 risk signal. In European populations, rs1310182 may contribute independent risk¹¹¹¹ independent risk
Two SNPs on rs3811021/rs3789605 haplotype associated with RA independent of R620W beyond what rs2476601 alone captures. Combined haplotype analysis of the PTPN22 locus provides better risk stratification than any single variant alone.

For East Asian individuals, the combination of rs1310182-G with risk haplotypes containing rs2488457-C (the functional promoter variant -1123G>C) likely represents the primary PTPN22 autoimmune haplotype in those populations. These two SNPs capture complementary aspects of PTPN22 regulatory variation.