rs3787348 — PTPN1 PTPN1 intronic variant

Intronic PTPN1 tag SNP within the 100-kb insulin-resistance haplotype block; carriers of the T allele show reduced weight loss response to lifestyle intervention and blunted leptin reduction, consistent with elevated PTP1B activity dampening insulin and leptin signaling

See your personal result for PTPN1

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

PTP1B's Brake on Weight Loss — The PTPN1 rs3787348 Variant

When you try to lose weight, two hormones drive most of the work: insulin directs your cells to take up glucose, and leptin tells your hypothalamus to suppress appetite and ramp up energy expenditure. Both signals are time-limited — an enzyme called PTP1B, encoded by the PTPN1 gene on chromosome 20, dephosphorylates and inactivates their receptors, ending each signaling pulse. When PTP1B is more active or more abundant, those windows close faster, and both insulin efficiency and leptin responsiveness decline.

rs3787348 sits within an intron of PTPN1, inside the same ~100-kb haplotype block11 ~100-kb haplotype block
A region of DNA inherited together because it rarely recombines; all associated PTPN1 variants fall within this block, identified by Bento et al. 2004 that harbors every PTPN1 variant linked to insulin resistance and type 2 diabetes in human genetics studies. The T allele tags the risk haplotype. The signal at rs3787348 is intronic — the variant itself does not change the PTP1B protein, but it marks a regulatory haplotype associated with higher PTPN1 transcript levels through a functional 3'-UTR insertion22 3'-UTR insertion
A variant in the untranslated region at the end of the PTPN1 mRNA that stabilizes the transcript, increasing the amount of PTP1B protein produced in skeletal muscle in the same block.

The Mechanism

PTP1B terminates insulin signaling by removing phosphate groups from activated tyrosine residues on the insulin receptor kinase domain — the same step that initiates glucose uptake in muscle and fat cells. In the hypothalamus, PTP1B dephosphorylates JAK233 JAK2
Janus kinase 2, the first intracellular enzyme activated when leptin binds its receptor in the hypothalamus; its inactivation by PTP1B blunts leptin's appetite-suppressing and thermogenic signals, terminating the leptin signal. When the PTPN1 risk haplotype drives higher PTP1B expression, both dephosphorylation events happen faster and more completely — producing a state of simultaneously reduced insulin sensitivity and reduced leptin sensitivity. In whole-body PTP1B knockout mice this dual pathway effect manifests as insulin hypersensitivity and resistance to diet-induced obesity; in the context of the human risk haplotype, the converse obtains.

The additive dose-response of rs3787348 — with each copy of the T allele increasing the weight-loss blunting effect — is consistent with a codominant regulatory mechanism where the risk haplotype progressively elevates PTPN1 expression.

The Evidence

The primary functional evidence for rs3787348 specifically comes from Yamakage et al. 202144 Yamakage et al. 2021
Yamakage H et al. Association of protein tyrosine phosphatase 1B gene polymorphism with the effects of weight reduction therapy on bodyweight and glycolipid profiles in obese patients. J Diabetes Investig, 2021, a prospective cohort study of 447 obese Japanese patients who underwent a standardised 3-month lifestyle intervention (caloric restriction to 25 kcal/kg ideal body weight, 60% carbohydrate, more than 30 minutes of moderate exercise at least 3 days per week). Genotyping rs3787348 and a second PTPN1 tag SNP (rs6067484) revealed a striking genotype-dependent gradient in weight loss outcomes: GG homozygotes lost 5.1 ± 0.5 kg on average, GT heterozygotes lost 4.1 ± 0.2 kg, and TT homozygotes lost only 3.1 ± 0.3 kg (p = 0.001). BMI reductions followed the same pattern (−1.9, −1.5, and −1.2 kg/m², respectively; p = 0.001), as did waist circumference reductions and leptin reductions during therapy. The T allele was also associated with higher baseline BMI (p = 0.041), consistent with a chronic dampening of leptin-mediated energy balance.

The broader haplotype context was established by Bento et al. 200455 Bento et al. 2004
Bento JL et al. Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes. Diabetes, 2004, who identified the 100-kb LD block and estimated an odds ratio of approximately 1.3 for type 2 diabetes from the risk haplotype — with a population-attributable risk of 17-20%, among the highest for any noncoding T2D locus. Florez et al. 200466 Florez et al. 2004
Florez JC et al. Association of PTPN1 polymorphisms with measures of glucose homeostasis in Hispanic Americans: the IRAS Family Study. Diabetes, 2004 confirmed these findings in 811 Hispanic Americans, with all 20 common haplotype-block SNPs associating with the insulin sensitivity index and fasting glucose.

Notably, a 2025 meta-analysis of 75,595 individuals across multiple cohorts found no statistically significant association between rs3787348 and type 2 diabetes risk (OR = 1.02, 95% CI 0.95–1.08), confirming that the T2D risk at this locus is likely distributed across multiple correlated variants in the LD block rather than residing uniquely at rs3787348 itself. The clearest individual signal for this SNP is in treatment response, not incident T2D.

Practical Actions

The weight-loss blunting effect of the T allele has a direct clinical implication: carriers who invest in a calorie-restriction and exercise program should expect a more modest BMI response than the population average, not a failure of adherence. Concretely, at the TT genotype, a 3-month structured program produces roughly 40% less weight loss than the GG reference — a difference that often goes undiagnosed and leads to premature discontinuation of a working intervention.

Exercise is specifically valuable because moderate-intensity aerobic activity transiently reduces PTP1B protein activity in skeletal muscle, extending the effective insulin signaling window — a direct pharmacological bypass of the PTP1B-mediated brake. Higher exercise volumes and more frequent sessions maintain this suppression for more hours per week. Monitoring leptin and adiponectin levels during a weight loss program provides objective data on whether the hormonal response to weight loss is proportional — T allele carriers may see blunted leptin reductions even as weight falls.

Interactions

The most relevant interaction is with rs6067484, the closely linked PTPN1 tag SNP that co-tags the same 100-kb risk haplotype. In the Yamakage 2021 study, rs6067484 showed only nominal association with waist circumference response, while rs3787348 showed the stronger and broader effect on BMI, bodyweight, and leptin reduction. Carriers of the T allele at rs3787348 who also carry the G allele at rs6067484 represent the densest haplotype coverage of the PTPN1 risk block.

PTP1B also interacts with the leptin receptor (LEPR) pathway — animal studies demonstrate that PTP1B × leptin receptor interactions compound the degree of hypothalamic leptin resistance. Carriers of rs3787348 T allele and risk variants in LEPR may experience additive impairment of energy balance regulation.

Nutrient Interactions

glucose altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard PTP1B Activity Normal

Two G alleles — normal PTPN1 function, standard weight loss response

You carry two copies of the G allele at rs3787348 — the reference genotype, shared by approximately 37% of people globally. This genotype is not associated with elevated PTP1B expression from the PTPN1 risk haplotype at this locus.

In the Yamakage 2021 intervention study, GG individuals achieved the largest average weight loss: −5.1 ± 0.5 kg and −1.9 ± 0.2 kg/m² BMI reduction over 3 months. Your insulin and leptin signaling pathways are not blunted by this PTPN1 variant.

GT Mildly Reduced Response Intermediate

One T allele — moderately blunted weight loss response, mildly higher baseline BMI tendency

The PTPN1 risk haplotype — tagged by the T allele at rs3787348 — is associated with higher PTPN1 mRNA stability through a 3'-UTR variant in the same LD block (Bento et al. 2004, PMID 15504984). More stable mRNA translates to more PTP1B protein, which more rapidly dephosphorylates and inactivates both the insulin receptor kinase (reducing glucose uptake in muscle) and JAK2 (reducing leptin signaling in the hypothalamus).

For weight loss in particular, blunted leptin signaling means the hypothalamus responds less robustly to falling adipose tissue leptin levels during caloric restriction — the "this is working, reduce appetite further" signal is attenuated, making it harder to sustain a caloric deficit. The intervention data from Yamakage 2021 reflects this biology: the dose-response across GG → GT → TT was statistically significant at p = 0.001 for weight loss and p < 0.001 for waist circumference.

The broader T2D risk from the PTPN1 haplotype (OR ~1.3 per copy; PAR 17–20%; Bento et al. 2004) applies to GT carriers at approximately half the impact of TT carriers. A 2025 meta-analysis of 75,595 individuals found OR = 1.02 (95% CI 0.95–1.08) specifically for rs3787348 and T2D, suggesting the T2D signal is distributed across the haplotype block rather than concentrated at this single SNP.

TT Substantially Reduced Response High Risk

Two T alleles — substantially blunted weight loss response and leptin reduction, elevated PTP1B activity

Homozygous T allele carriage represents the maximal expression of the PTPN1 risk haplotype from this locus. The mechanistic pathway is consistent: two copies of the haplotype that includes a 3'-UTR variant stabilizing PTPN1 mRNA produce the highest PTP1B protein levels, resulting in faster termination of both insulin receptor and JAK2 signaling. The consequences converge on energy balance through two independent channels:

  1. Peripheral insulin resistance: each insulin pulse is terminated faster, requiring higher insulin secretion to achieve the same glucose uptake. Over decades this creates the conditions for progressive beta- cell exhaustion.

  2. Central leptin resistance: JAK2 dephosphorylation is accelerated, blunting leptin's inhibitory effect on appetite (via STAT3/POMC pathways) and its activation of thermogenesis. This is why TT carriers show both higher baseline BMI and blunted leptin reduction during weight loss — the hypothalamus is slower to register and respond to falling adipose-derived leptin.

PTP1B knockout mouse data confirm that eliminating PTP1B from hypothalamic neurons produces a lean phenotype with enhanced leptin sensitivity and increased energy expenditure, while whole-body knockout additionally produces insulin hypersensitivity (Tsou and Bence 2012, PMC3395189). The human TT genotype represents the pharmacological opposite of this knockout state.

A 2025 meta-analysis of 75,595 individuals found OR = 1.02 for rs3787348 and T2D specifically (Indarto et al. 2025, PMCID PMC12746214), indicating that the T2D signal is distributed across multiple correlated haplotype SNPs rather than concentrated at this locus alone. The most clinically relevant and individually specific finding for this SNP remains the weight-loss response data from Yamakage et al. 2021.