rs10305492 — GLP1R A316T

Rare protective missense variant in the GLP-1 receptor associated with lower fasting glucose, reduced T2D risk, and coronary heart disease protection

See your personal result for GLP1R

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.

GLP-1 Receptor A316T -- A Rare Protective Variant

Among the thousands of genetic variants linked to type 2 diabetes, very few are genuinely protective. The rs10305492 variant in the GLP-1 receptor gene11 GLP-1 receptor gene
GLP1R encodes the receptor targeted by semaglutide (Ozempic/Wegovy) and liraglutide (Victoza/Saxenda) is one of them. This low-frequency missense variant (about 1.6% allele frequency in Europeans, rare or absent in other populations) substitutes alanine with threonine at position 316 in the receptor's fifth transmembrane domain. Carriers enjoy lower fasting glucose, reduced risk of type 2 diabetes, and protection against coronary heart disease.

The Mechanism

The A316T substitution sits in the fifth transmembrane helix22 fifth transmembrane helix
One of seven helices that span the cell membrane and form the receptor's signaling core of the GLP-1 receptor, a region critical for receptor activation.

The Evidence

The protective effect was first identified in a large exome chip meta-analysis33 large exome chip meta-analysis
Wessel et al. Low-frequency and rare exome chip variants associate with fasting glucose and T2D susceptibility. Nature Comms, 2015 of 60,564 non-diabetic individuals, where the A allele was associated with lower fasting glucose (beta = -0.09 mmol/L per allele, P = 3.4 x 10-12) and reduced T2D risk (OR 0.86, 95% CI 0.76-0.96, P = 0.010) in 16,491 cases and 81,877 controls. Notably, the variant was also associated with higher 2-hour glucose and lower early insulin secretion, suggesting the protective effect operates through improved fasting state rather than enhanced meal-time response.

A subsequent therapeutic target validation study44 therapeutic target validation study
Scott et al. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for CHD. Sci Transl Med, 2016 extended these findings to cardiovascular outcomes. In 61,846 coronary heart disease cases and 163,728 controls, the glucose-lowering allele was associated with CHD protection -- and the protective effect was larger than what would be predicted from glucose lowering alone, suggesting direct cardiovascular benefits of GLP-1R signaling.

Practical Actions

If you carry the A allele, your natural GLP-1 receptor function is protective -- your fasting glucose tends to be lower and your cardiovascular risk is reduced compared to non-carriers.

Drug Interactions

semaglutide reduced_efficacy literature
liraglutide reduced_efficacy literature
exenatide reduced_efficacy literature
dulaglutide reduced_efficacy literature
tirzepatide reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard GLP-1 Receptor Normal

Standard GLP-1 receptor without protective A316T variant

You have the standard GLP-1 receptor sequence at position 316. About 97% of people globally share this genotype. You do not carry the protective A316T variant associated with lower fasting glucose and reduced cardiovascular risk.

Standard dosing of GLP-1 receptor agonists (semaglutide, liraglutide) should produce typical responses at this receptor position.

AA Protective (Homozygous) Beneficial

Two copies of protective GLP-1 receptor variant -- strongly reduced fasting glucose and cardiovascular risk

With both receptor copies carrying the threonine substitution at position 316, this provides metabolic benefits including lower fasting glucose and cardioprotection.

AG Protective Carrier Beneficial

One copy of protective GLP-1 receptor variant -- lower fasting glucose and cardiovascular risk

The cardiovascular protection identified in 61,846 CHD cases suggests direct cardioprotective effects of enhanced GLP-1R signaling beyond just glucose lowering.