rs1143699 — PTPRS PTPRS C/T (rs1143699)

Synonymous PTPRS variant associated with increased type 2 diabetes risk in men with the homozygous risk genotype, acting through impaired pancreatic beta-cell insulin secretion

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PTPRS rs1143699 — A Synonymous Variant That Tags Elevated Diabetes Risk in Men

The PTPRS gene encodes receptor protein tyrosine phosphatase sigma (RPTPσ), a cell-surface enzyme that belongs to the LAR subfamily of receptor-type phosphatases. Although expressed broadly across tissues, PTPRS is particularly abundant in adipose tissue and the brain11 particularly abundant in adipose tissue and the brain
GTEx: RPKM 30.9 in fat, 23.8 in brain, two organ systems central to the energy balance disrupted in type 2 diabetes. RPTPσ removes phosphate groups22 phosphate groups
Dephosphorylation: the removal of a phosphate group from a tyrosine residue, generally attenuating a signalling cascade that was activated by tyrosine kinase activity from tyrosine residues on target proteins, acting as a brake on signalling cascades that phosphorylation events have switched on.

rs1143699 sits in exon 34 of PTPRS on chromosome 19 (19p13.3). The gene is transcribed from the minus strand, so the variant appears as G>A on the plus (genomic) strand but as C>T in coding-strand notation — the same convention used in the original discovery paper. The nucleotide change causes no amino acid substitution (Asp1763 → Asp1763, GAC→GAT), making this a synonymous variant33 synonymous variant
Also called a silent variant: the DNA sequence changes but the protein sequence stays the same. Synonymous variants can still alter disease risk if they affect mRNA splicing, stability, or local codon usage that changes translation efficiency. The variant most likely acts as a haplotype tag — travelling on the same chromosomal segment as one or more functional changes elsewhere in the gene that alter RPTPσ expression level or activity.

The Mechanism

RPTPσ participates in glucose homeostasis at two levels. In pancreatic beta cells44 beta cells
The insulin-secreting cells of the islets of Langerhans in the pancreas; their capacity to release insulin in response to a glucose load is central to preventing type 2 diabetes, it dephosphorylates proteins that regulate insulin granule exocytosis, reducing the efficiency of glucose-induced insulin secretion. In peripheral tissues such as muscle and fat, RPTPσ acts on insulin receptor pathway components, attenuating the insulin signal. The Goto-Kakizaki diabetic rat model55 Goto-Kakizaki diabetic rat model
A spontaneously diabetic rat strain used to study T2D mechanisms; GK rats develop non-obese T2D through impaired insulin secretion and peripheral insulin resistance shows approximately 60% overexpression of PTP sigma in islets and liver compared with normoglycaemic controls. When that overexpression was pharmacologically suppressed with antisense oligonucleotides, glucose-induced insulin secretion recovered to near-normal levels, establishing a causal chain between elevated PTPRS activity and impaired beta-cell function.

Conversely, mice lacking PTPRS entirely display reduced fasting plasma glucose and insulin concentrations, together with enhanced whole-body insulin sensitivity, consistent with the idea that higher phosphatase activity suppresses insulin action and epigenetic studies66 epigenetic studies
DNA methylation analysis of islets from mice before the onset of diabetes rank PTPRS among the best predictors of future T2D (area under ROC curve 0.62–0.73).

The Evidence

The only published human genetic study of rs1143699 is a Swedish Caucasian case-control cohort77 Swedish Caucasian case-control cohort
Långberg et al. 2007, European Journal of Endocrinology — 497 NGT controls, 262 with impaired glucose tolerance, 298 with T2D (n=1,057 total). Three PTPRS variants were tested; rs1143699 was associated with T2D with an overall OR of 1.57 (p=0.029). Stratifying by sex, C/C homozygosity (GG on plus strand is wild-type; A/A on plus strand equals C/C in coding notation and is the risk genotype) conferred a substantially higher odds ratio of 2.19 (p=0.035) in men, with a weaker and non-significant association in women. The sex difference is unexplained but may reflect statistical power limitations in a cohort that was not pre-powered for sex-stratified analysis; both the original Swedish population studied and the limited replication record mean the evidence is best classified as moderate. The A allele frequency is approximately 10-11% in Europeans (gnomAD NFE), making AA homozygotes rare (~1%).

Practical Actions

For the small fraction of individuals who are AA homozygous (approximately 1% of Europeans), the core concern is that elevated RPTPσ activity may blunt both pancreatic insulin secretion and peripheral insulin sensitivity. Interventions that reduce the functional burden on beta cells — such as minimising glycaemic load, prioritising metabolic biomarker monitoring, and reducing adiposity through diet quality rather than generic calorie restriction — may be disproportionately useful. Because the variant is sex-specific in its strongest signal, men with the AA genotype have the most actionable risk profile.

Heterozygous AG carriers have a modest intermediate risk per the dose-response implied by the data. Standard cardiometabolic monitoring remains appropriate.

Interactions

PTPRS harbours two additional variants associated with T2D in the same Swedish cohort: rs4807015 (intronic, OR=1.74 in both sexes) and rs1978237 (intronic, OR=1.59 in both sexes). All three may tag the same haplotype block; their effects may not be additive. The relationship between these three variants in terms of haplotype structure and independence has not been formally assessed in a published follow-up study.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Risk Normal

Standard PTPRS expression — no elevated diabetes risk from this variant

The GG genotype corresponds to the reference sequence at rs1143699 and represents the typical RPTPσ haplotype background studied in the Swedish cohort (Långberg et al. 2007). No excess diabetes risk was observed in GG homozygotes relative to the general population. PTPRS expression in islets and insulin-sensitive tissues is within the normal range for this genotype.

AG One Risk Allele Intermediate

One copy of the risk allele — mildly elevated diabetes risk

Heterozygous AG carriers show a dose-intermediate profile between the common GG and the rare AA genotype. The Långberg et al. 2007 study did not separately report the AG genotype OR from the full logistic regression model, so the individual heterozygous effect size is uncertain. Given the additive biology of PTPRS activity on insulin signalling, some attenuation of insulin-secretory reserve is plausible but has not been quantified in this genotype class.

AA High-Risk Homozygote High Risk

Two copies of the risk allele — substantially elevated T2D risk in men

The AA genotype at rs1143699 (C/C in coding-strand notation) represents the high-expression PTPRS haplotype. In the GK diabetic rat model, ~60% overexpression of PTP sigma in islets directly impairs glucose-stimulated insulin secretion; suppressing this overexpression with antisense oligonucleotides restores near-normal insulin release (Ostenson et al. 2002, PMID 11866457). The human genetic association (Långberg et al. 2007, PMID 17893260) is consistent with this mechanism: men with two copies of the risk allele had OR=2.19 for T2D compared to T/T (GG on plus strand) homozygotes. The sex-specific effect may reflect statistical limitations of the cohort size (~298 T2D cases) rather than a true sex × genotype interaction; both men and women with this genotype should treat this as actionable.

Given that PTPRS also emerged as one of the top epigenetic predictors of future T2D in pre-diabetic mouse islets (Ouni et al. 2020, PMID 32816961), the convergence of genetic association and epigenetic data strengthens the biological plausibility even where human replication is limited.