rs4807015 — PTPRS PTPRS T2D risk variant

Intronic PTPRS variant that tags elevated type 2 diabetes risk in both sexes through increased receptor protein tyrosine phosphatase sigma activity, which dephosphorylates insulin-signalling substrates and attenuates both pancreatic insulin secretion and peripheral insulin sensitivity

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PTPRS rs4807015 — An Intronic Variant That Elevates Diabetes Risk in Both Sexes

The PTPRS gene encodes receptor protein tyrosine phosphatase sigma (RPTPσ)11 receptor protein tyrosine phosphatase sigma (RPTPσ)
A cell-surface enzyme that belongs to the LAR subfamily of receptor-type phosphatases. It has an extracellular ligand-binding domain and two intracellular catalytic domains, one active and one regulatory, located on chromosome 19p13.3. RPTPσ functions as a negative regulator of tyrosine-kinase-based signalling by removing phosphate groups from tyrosine residues on target proteins. Two of the most important targets in the context of glucose metabolism are the insulin receptor itself and insulin receptor substrate proteins (IRS-1 and IRS-2)22 insulin receptor substrate proteins (IRS-1 and IRS-2)
Adaptor proteins that relay the insulin receptor's signal into the cell's interior; when dephosphorylated by PTPs such as RPTPσ, the downstream signalling cascade is attenuated and insulin sensitivity is reduced.

rs4807015 is an intronic variant — it sits within an intron of PTPRS and does not change any amino acid in the protein. The PTPRS gene is transcribed from the minus strand of chromosome 19, so the genomic (plus-strand) reference allele is T, with C as the alternate allele. The C allele is the risk allele identified in the discovery cohort; it likely acts as a haplotype tag — travelling on the same chromosomal segment as one or more functional changes elsewhere in the gene that upregulate RPTPσ expression or activity.

The Mechanism

Two lines of experimental evidence connect elevated RPTPσ activity to impaired glucose homeostasis. First, in pancreatic beta cells33 beta cells
The insulin-secreting cells of the pancreatic islets of Langerhans; their capacity to release insulin in response to rising blood glucose is central to preventing type 2 diabetes, RPTPσ dephosphorylates proteins that mediate insulin granule exocytosis, reducing the efficiency of glucose-stimulated insulin secretion. The Goto-Kakizaki spontaneously diabetic rat model shows approximately 60% overexpression of PTP sigma in islets and liver compared with normoglycaemic controls; treating isolated GK islets with antisense oligonucleotides targeting PTP sigma restored glucose-induced insulin secretion to near-normal levels, establishing a direct causal link.

Second, mice lacking PTPRS entirely (RPTPσ knockout mice) display reduced fasting plasma glucose and insulin44 reduced fasting plasma glucose and insulin
Chagnon et al. 2006, Canadian Journal of Physiology and Pharmacology — RPTPσ-/- mice showed significantly lower fasting glucose and insulin and enhanced whole-body insulin sensitivity on insulin tolerance testing, consistent with the hypothesis that higher phosphatase activity constrains insulin action in vivo. More recently, pharmacological inhibition of PTPRS and related phosphatases in differentiated muscle cells was shown to increase cellular glucose uptake, pointing toward PTPRS as an actionable target in insulin-resistant tissues.

Epigenetic profiling of islets from pre-diabetic mouse models ranked PTPRS among the strongest predictors of future T2D (area under ROC curve 0.62–0.73), indicating that changes in PTPRS expression at the epigenetic level precede clinical disease onset — consistent with the gene being functionally upstream of the metabolic decline.

The Evidence

The primary human evidence comes from a Swedish Caucasian cohort55 Swedish Caucasian cohort
Långberg et al. 2007, European Journal of Endocrinology — 497 subjects with normal glucose tolerance (NGT), 262 with impaired glucose tolerance (IGT), and 298 patients with T2D; all Swedish Caucasians; three PTPRS SNPs tested (n=1,057 total). Among three PTPRS variants tested, rs4807015 was associated with T2D with an odds ratio of 1.74 (p=0.029) across both sexes in logistic regression — the highest sex-combined effect size of the three variants in the study. This is one of the larger effect sizes reported for a common intronic variant in this category; for comparison, the well-replicated TCF7L2 rs7903146 T2D variant typically shows ORs of 1.35–1.45 in European cohorts. The limitation is that this association has not been formally replicated in independent large-scale GWAS data, and the discovery cohort of ~300 T2D cases has limited statistical power. The evidence level is accordingly classified as moderate.

Practical Actions

The C allele is nearly balanced with T in European populations (~48% vs 52%), meaning approximately one in four Europeans is CC homozygous. The actionable concern is that elevated RPTPσ activity attenuates insulin signalling in both beta cells and insulin-sensitive tissues. Interventions that reduce the secretory and metabolic burden — glycaemic load reduction, periodic cardiometabolic monitoring, and proactive fasting insulin testing — are most directly supported by the mechanistic model.

Interactions

PTPRS harbours two other variants associated with T2D in the same Swedish cohort: rs1143699 (synonymous, OR=1.57, strongest in men) and rs1978237 (intronic, OR=1.59, both sexes). All three may tag the same risk haplotype across the PTPRS locus, in which case their effects are not additive. Formal haplotype analysis has not been published. Users carrying risk alleles at multiple PTPRS variants may not face proportionally higher risk, but the co-occurrence strengthens the plausibility of a high-expression PTPRS haplotype.

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Risk Normal

Common genotype — no elevated diabetes risk from this variant

The TT genotype corresponds to the plus-strand reference allele at rs4807015 and represents the low-risk PTPRS haplotype background in the Swedish discovery cohort (Långberg et al. 2007, PMID 17893260). No excess T2D risk was observed in T allele homozygotes. PTPRS expression in insulin-relevant tissues is within the typical range for this genotype.

CT One Risk Allele Intermediate

One copy of the risk allele — modestly elevated diabetes risk

The CT heterozygous state corresponds to a single copy of the PTPRS risk haplotype. The discovery study (Långberg et al. 2007) did not separately report per-genotype ORs for heterozygotes vs. homozygotes; the OR of 1.74 was derived from a logistic regression model treating the risk allele in an additive or dominant framework. Under an additive model, one copy of C confers approximately half the log-odds increase of two copies. The biological expectation — that one risk haplotype produces an intermediate elevation of RPTPσ activity relative to zero or two copies — is consistent with codominant expression of the regulatory element tagged by this intronic variant.

CC High-Risk Homozygote High Risk

Two copies of the risk allele — substantially elevated T2D risk in both sexes

CC homozygosity at rs4807015 represents the highest-exposure state for the PTPRS risk haplotype. Unlike the sibling PTPRS variant rs1143699, which showed its strongest effect in men only, rs4807015 was associated with T2D risk in both sexes (Långberg et al. 2007, PMID 17893260), making it the more clinically actionable of the two variants regardless of sex.

The mechanistic model is supported by two independent experimental lines. Ostenson et al. 2002 (PMID 11866457) showed that ~60% overexpression of PTP sigma in GK rat islets directly impairs glucose-induced insulin secretion, and antisense knockdown restores it. Chagnon et al. 2006 (PMID 16998539) showed that PTPRS knockout mice have reduced fasting glucose and insulin with improved whole-body insulin sensitivity, confirming that loss of RPTPσ function improves metabolic outcomes. The genetic evidence (OR=1.74) is consistent with a gain-of-function or overexpression scenario tagged by the C allele haplotype.

Epigenetic data from pre-diabetic mouse islets (Ouni et al. 2020, PMID 32816961) ranked PTPRS among the top predictors of future T2D (AUC 0.73), suggesting that PTPRS upregulation is an early event in T2D progression — not merely a downstream consequence. This supports proactive rather than reactive monitoring.

The discovery cohort is a single Swedish Caucasian sample of approximately 300 T2D cases and 497 controls; large-scale GWAS replication for this specific variant is lacking, constraining the evidence to moderate.