What you carry at this position in your DNA and what research says about it.
Obesity Risk: 5/10 evidence, 58 publications.
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Sample genotype (not yours): A/A
Typical Obesity and Diabetes Risk
Two copies of the reference A allele are associated with typical leptin signaling and appetite regulation. This genotype is linked to a standard baseline risk for metabolic conditions.
What this genotype means: Typical leptin receptor sensitivity; Standard baseline risk for metabolic syndrome; Typical response to statin therapy.
Sample genotype (not yours): A/G
Slightly Increased Obesity and Diabetes Risk
Carrying one copy of the G allele is linked to a subtle reduction in leptin receptor sensitivity. This can lead to a slight increase in the risk of weight gain and metabolic challenges.
What this genotype means: Slightly reduced leptin receptor sensitivity; Mildly elevated risk of weight gain; Increased susceptibility to drug-induced weight gain.
Sample genotype (not yours): G/G
Increased Obesity and Diabetes Risk
Two copies of the G allele are associated with reduced leptin receptor sensitivity, which can elevate the risk of weight gain and type 2 diabetes.
What this genotype means: Reduced leptin receptor signaling efficiency; Elevated risk of obesity and metabolic syndrome; Reduced cholesterol-lowering response to simvastatin.
Gene function and biological role
Gene Function: The LEPR gene encodes the leptin receptor, a vital protein that spans the cell membrane and transmits signals from the hormone leptin [1]. Leptin is produced by fat cells and acts as a primary signal to the brain, specifically the hypothalamus, to regulate appetite and energy expenditure [1]. When leptin binds to its receptor, it triggers a cascade of signals that suppress hunger and promote calorie burning [2]. Genetic variations in this receptor can alter how efficiently these signals are transmitted, which can influence long-term body weight and metabolic health [2]. Deficiencies or severe mutations in this pathway are well-known causes of early-onset, severe obesity [3].
Variant Impact: The rs1137101 variant is a common missense mutation in exon 6 of the LEPR gene that results in an amino acid change from glutamine to arginine at position 223 [4]. This specific change, often designated as p.Gln223Arg, occurs in the extracellular domain of the receptor where leptin binds [4]. Altering the charge in this region is thought to slightly reduce the receptor's binding affinity for leptin, thereby dampening downstream signaling [3]. Because the receptor is less sensitive, the brain may receive weaker satiety signals, subtly shifting energy balance toward fat storage [3]. This single-letter change has been widely studied for its modest but consistent influence on body mass index and metabolic traits across diverse populations [5].
Key Insight: This variant alters the extracellular domain of the leptin receptor, subtly reducing its binding affinity for the satiety hormone leptin and dampening fullness signals.
Location: LEPR. Chromosome 1 · 1p31.3 · 65.6 Mb
Estimated prevalence by population
Global 25.5%; European 30.0%; African 19.7%; East Asian 1.5%; South Asian 26.1%; Americas 31.2%; Ashkenazi 33.8%; Finnish 16.5%; Middle Eastern 42.7%; Amish 53.0%.
Estimated AA genotype frequency.
Global 48.3%; European 49.6%; African 49.4%; East Asian 21.4%; South Asian 50.0%; Americas 49.3%; Ashkenazi 48.7%; Finnish 48.2%; Middle Eastern 45.3%; Amish 39.6%.
Estimated AG genotype frequency.
Global 26.2%; European 20.5%; African 31.0%; East Asian 77.1%; South Asian 23.9%; Americas 19.5%; Ashkenazi 17.5%; Finnish 35.3%; Middle Eastern 12.0%; Amish 7.4%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Cardiovascular & Metabolic
Obesity & Body Composition
Obesity. Evidence: 4/10. Source: PMID 31948470. Typical Risk.
Diabetes & Glycemic Traits
Type 2 Diabetes. Evidence: 3/10. Source: PMID 29903247. Typical Risk.
Pharmacogenomics
Antiepileptic & Mood-Stabilizer Response
Valproic Acid Weight Gain. Evidence: 6/10. Source: PMID 25740917. Increased Risk.
Antidepressant & Psychiatric Drug Response
Clozapine Metabolic Risk. Evidence: 5/10. Source: PMID 27681143. Typical Risk.
Antipsychotic Weight Gain. Evidence: 5/10. Source: PMID 21510767. Typical Risk.
Lipid-Lowering Drug Response
Simvastatin Response. Evidence: 5/10. Source: PMID 14625131. Typical Response.
Showing effects for A/G genotype
Obesity. Evidence: 4/10. Source: PMID 31948470. Slightly Higher Risk.
Type 2 Diabetes. Evidence: 3/10. Source: PMID 29903247. Slightly Higher Risk.
Valproic Acid Weight Gain. Evidence: 6/10. Source: PMID 25740917. Increased Severity.
Clozapine Metabolic Risk. Evidence: 5/10. Source: PMID 27681143. Increased Risk.
Antipsychotic Weight Gain. Evidence: 5/10. Source: PMID 21510767. Increased Risk.
Showing effects for G/G genotype
Simvastatin Response. Evidence: 5/10. Source: PMID 14625131. Poorer Response.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Leptin receptors function with standard efficiency when two copies of the glutamine-encoding A allele are present [1]. This typical signaling capacity helps maintain normal communication between fat tissue and the brain's appetite centers [1]. Research indicates that this genotype is associated with a lower baseline risk of obesity and type 2 diabetes compared to carrying the G variant [2]. In clinical studies, postmenopausal women with this genetic profile demonstrated lower body mass index and fat mass [1]. Furthermore, these individuals do not show the elevated susceptibility to weight gain often seen during certain medication therapies [3]. Standard responses to cholesterol-lowering medications like simvastatin are also typical for this group [4]. Maintaining a balanced diet and regular exercise remains highly effective for supporting metabolic health with this baseline profile.
Typical leptin receptor sensitivity; Standard baseline risk for metabolic syndrome; Typical response to statin therapy.
Sample genotype: AG (Heterozygous)
A single copy of the arginine-encoding G allele introduces a slight structural change to the extracellular domain of the leptin receptor [1]. This alteration is associated with a mild dampening of satiety signals, which can subtly increase appetite and food intake over time [1]. Population studies have linked this heterozygous genotype to a slightly elevated risk of obesity and type 2 diabetes [2]. Additionally, individuals with this genetic makeup may experience a higher susceptibility to weight gain when taking specific medications, such as valproic acid or certain antipsychotics [3] [4]. There is also a slightly increased likelihood of developing metabolic syndrome under certain drug treatments [5]. Metabolic health can still be effectively managed through proactive lifestyle choices, including regular physical activity and a fiber-rich diet. Understanding this genetic tendency helps explain why some individuals find weight management slightly more challenging.
Slightly reduced leptin receptor sensitivity; Mildly elevated risk of weight gain; Increased susceptibility to drug-induced weight gain.
Sample genotype: GG (Homozygous)
Possessing two copies of the arginine-encoding G allele leads to a more pronounced reduction in leptin receptor signaling efficiency [1]. This decreased sensitivity means the brain requires higher levels of leptin to register fullness, potentially leading to increased calorie intake [1]. Clinical research has consistently linked this homozygous genotype to higher body mass index, increased waist circumference, and an elevated risk of type 2 diabetes [2] [3]. Furthermore, these individuals show a significantly higher risk of experiencing substantial weight gain and metabolic side effects when prescribed medications like valproic acid or antipsychotics [4] [5]. There is also evidence that this genotype may limit the cholesterol-lowering effectiveness of statins like simvastatin [6]. Some studies suggest that this variant might also influence bone mass development in early life [7]. Implementing structured lifestyle interventions, such as portion control and consistent aerobic exercise, is particularly beneficial for managing these genetic risks.
Reduced leptin receptor signaling efficiency; Elevated risk of obesity and metabolic syndrome; Reduced cholesterol-lowering response to simvastatin.
Variants with shared genetic architecture
rs1805094 · LEPR Gene · Chr 1 · Leptin Receptor Levels
rs1805096 · LEPR Gene · Chr 1 · Systemic Inflammation Risk
rs1892534 · LEPR Gene · Chr 1 · C-Reactive Protein Levels
Leptin protects host cells from Entamoeba histolytica cytotoxicity by a STAT3-dependent mechanism.
A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children.
Genetic Determinants of Clozapine-Induced Metabolic Side Effects.
ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese.
Content updated August 2026.
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