rs10305420 — GLP1R Pro7Leu

GLP1R Pro7Leu — Your GLP-1 Medication Efficacy and Side Effect Profile

The GLP-1 receptor (GLP1R) is the molecular target of semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro, Zepbound), liraglutide (Saxenda), and other GLP-1 agonist medications prescribed for weight loss and type 2 diabetes. rs10305420 causes a proline-to-leucine substitution at position 7 of the receptor's signal peptide¹¹ signal peptide
a short amino acid sequence that directs newly synthesized proteins to the cell surface. Unlike other GLP1R pharmacogenomic variants that alter the drug-binding domain, this variant affects how efficiently the receptor reaches the cell membrane.

The Mechanism

The Pro7Leu substitution replaces proline — which introduces a structural kink — with leucine, a more hydrophobic amino acid that strengthens the signal peptide's hydrophobic core²² hydrophobic core
the water-repelling central region that is recognized by cellular machinery for membrane insertion. This is predicted to enhance signal recognition particle (SRP) binding³³ signal recognition particle (SRP) binding
the molecular complex that captures newly made proteins and directs them into the endoplasmic reticulum for processing and improve receptor trafficking to the plasma membrane. The result is more GLP-1 receptor molecules on the cell surface⁴⁴ more GLP-1 receptor molecules on the cell surface
Su et al. Genetic predictors of GLP1 receptor agonist weight loss and side effects. Nature, 2026, amplifying the cellular response to both natural GLP-1 and pharmaceutical agonists.

This mechanism explains a dual pharmacogenomic effect: more receptor on the cell surface means both greater drug efficacy (more weight loss) and greater susceptibility to GI side effects (more nausea and vomiting). Co-localization analysis in the Nature 2026 study confirmed that the efficacy, nausea, and vomiting signals at this locus share the same underlying causal variant.

The Evidence

The definitive evidence comes from a GWAS of 27,885 GLP-1 medication users⁵⁵ GWAS of 27,885 GLP-1 medication users
Su et al. Nature, 2026 conducted by the 23andMe Research Institute. The T allele (leucine) was associated with an additional 0.641% BMI loss per allele, equivalent to approximately 0.76 kg of extra weight loss per copy (P = 2.9 x 10^-10). The effect was additive with no evidence of dominance — two copies confer roughly twice the benefit. A trans-ancestry meta-analysis strengthened the signal further (P = 1.1 x 10^-12), with consistent directionality across European, Latino, African American, East Asian, South Asian, and Middle Eastern populations.

The association was independently replicated in 4,855 participants⁶⁶ independently replicated in 4,855 participants
All of Us Research Program cohort using EHR data with EHR-derived weight measurements (P = 0.001, effect = -0.47% BMI).

The same study identified an important gene-gene interaction with GIPR⁷⁷ gene-gene interaction with GIPR
rs1800437 Glu354Gln in near-perfect LD with rs10423928: individuals homozygous for risk alleles at both the GLP1R and GIPR loci had 14.8-fold increased odds of tirzepatide-induced vomiting (95% CI 6.2-35.8). This interaction was specific to tirzepatide, which targets both GLP1R and GIPR, and was absent in semaglutide-treated patients.

Two earlier, smaller studies reported opposite directionality — Jensterle et al. 2015⁸⁸ Jensterle et al. 2015 (n=57 PCOS women, liraglutide) and Yu et al. 2019⁹⁹ Yu et al. 2019 (n=285 Chinese T2D patients, exenatide) both found the T allele associated with less weight loss. These studies used different drugs, different populations, and had limited statistical power. The 23andMe study is approximately 100-fold larger and was independently replicated.

Practical Implications

This variant is common — approximately 48% of Europeans are heterozygous and 15% are homozygous for the T allele. Unlike rare pharmacogenomic variants, this affects a substantial fraction of GLP-1 medication users. The enhanced efficacy is clinically meaningful: homozygous TT carriers can expect roughly 1.5 kg more weight loss than CC carriers on the same regimen.

The trade-off is gastrointestinal tolerability. Carriers experiencing significant nausea or vomiting on GLP-1 agonists may benefit from slower dose titration. For tirzepatide users specifically, the interaction with GIPR variants can dramatically amplify vomiting risk — making GIPR genotype (rs10423928/rs1800437) clinically relevant information for prescribers choosing between semaglutide and tirzepatide.

Interactions

The GLP1R locus harbors multiple pharmacogenomic variants. rs6923761 (Gly168Ser) alters the extracellular binding domain, primarily affecting gastric emptying and glycemic response. rs3765467 (Arg131Gln) changes the ligand-binding pocket, modifying drug affinity. rs10305492 (Ala316Thr) affects intracellular signaling. Pro7Leu acts through a distinct mechanism — receptor trafficking rather than receptor function — and its effects are largely independent of these binding-site variants.

The tirzepatide-specific interaction with GIPR is unique to this variant among known GLP1R pharmacogenomic markers. The GIPR variant rs10423928 (in near-perfect LD with the coding variant rs1800437 Glu354Gln) reduces GIP receptor function. When combined with increased GLP1R surface expression from Pro7Leu, the balance between GLP-1 and GIP signaling is disrupted, unmasking the nausea-inducing effects of the GLP-1 component that GIP receptor activation normally buffers.