rs563694 — ABCB11 G6PC2/ABCB11 fasting glucose locus

Intronic variant in ABCB11 in strong linkage disequilibrium with G6PC2 regulatory SNPs; the A allele tags higher G6PC2 expression in pancreatic beta cells, elevating the fasting blood glucose set-point by ~0.065 mmol/L per allele

See your personal result for ABCB11

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.

The Fasting Glucose Set-Point Gene: How ABCB11 and G6PC2 Tune Your Baseline Blood Sugar

Every morning before you eat, your blood glucose settles at a level determined largely by your pancreatic beta cells. These cells continuously sense glucose and calibrate insulin release to keep fasting levels within a narrow window — typically 4.0–5.6 mmol/L. The rs563694 variant sits in an intron of ABCB11 (the bile salt export pump gene) but its biological effect operates through a neighboring gene, G6PC2, via a regulatory enhancer element embedded within ABCB11's genomic sequence.

The Mechanism

G6PC211 G6PC2
glucose-6-phosphatase catalytic subunit 2; also called IGRP, islet-specific glucose-6-phosphatase related protein is expressed almost exclusively in pancreatic islet beta cells, where it dephosphorylates glucose-6-phosphate (G6P) back to glucose. This opposes the action of glucokinase22 glucokinase
the glucose "sensor" of the beta cell — GCK phosphorylates glucose to G6P, trapping it inside and triggering insulin secretion. Higher G6PC2 expression means more G6P recycled back to glucose, blunting the glycolytic signal that triggers insulin release. The result is a higher blood glucose concentration needed to provoke the same insulin response — a shifted set-point.

A 2023 study33 A 2023 study
O'Brien et al., Diabetes 2023 used CRISPR to delete a 653-base-pair enhancer in intron 25 of the mouse Abcb11 gene and found it reduced G6pc2 expression by approximately 50% in pancreatic islets. Human GWAS data confirm that variants in this extended genomic region (spanning G6PC2 and ABCB11) are among the strongest common-variant determinants of fasting glucose in non-diabetic populations. rs563694, located in intron 19 of ABCB11, is in high linkage disequilibrium44 linkage disequilibrium
r² = 0.84 with the functional G6PC2 splice-site variant rs560887 and tags the same biological signal.

The Evidence

The association of rs563694 with fasting glucose was discovered in a 2008 GWAS55 2008 GWAS
Chen et al., JCI 2008; n=5,088 Finnish and Sardinian non-diabetic individuals, followed by replication in 18,436 Europeans across seven studies. The A allele raised fasting glucose by approximately 0.065 mmol/L per allele (p = 6.4×10⁻³³ in combined analysis). This effect size, while modest per allele, is among the largest for common glycemic loci — the locus explains roughly 1% of total variance in fasting glucose.

A follow-up Danish cohort study66 Danish cohort study
Rose et al., Diabetologia 2009; n up to 5,899 in the Inter99 cohort showed that risk allele carriers had not only elevated fasting plasma glucose but also higher basal hepatic glucose production (p=0.04) and increased acute insulin response after both oral and intravenous glucose loads, pointing to a systemic shift in glucose homeostasis rather than an isolated beta-cell effect. Risk allele carriers had an OR of 1.26 (95% CI 1.08–1.47) for impaired fasting glycemia.

Mouse knockout studies validate the causal pathway: beta-cell-specific deletion of G6pc277 beta-cell-specific deletion of G6pc2
Boortz et al., Molecular Endocrinology 2020 lowered fasting blood glucose by approximately 15% without altering fasting insulin, demonstrating that G6PC2 specifically raises the glucose set-point in beta cells. G6PC2 is now considered a drug target for fasting hyperglycemia and prediabetes.

Practical Actions

The primary relevance of rs563694 for AA homozygotes is an elevated fasting glucose set-point — not necessarily pathological, but positioned meaningfully higher than average. Fasting glucose in the 5.6–6.9 mmol/L range (impaired fasting glucose) carries real risk for progression to type 2 diabetes. The key modifiable inputs at this locus are dietary carbohydrate composition and beta-cell glucose flux. Monitoring fasting glucose and HbA1c allows early detection if the elevated set-point begins to progress toward dysglycemia.

Dietary strategies that lower hepatic glucose output and improve beta-cell sensitivity — specifically time-restricted eating, reduction of refined carbohydrate load, and reduction of fructose intake — have mechanistic rationale here because they lower the basal glucose signal the beta cell must respond to. These are not generic lifestyle recommendations; they directly address the G6PC2-driven glucose flux mechanism.

Interactions

rs563694 is in strong LD with rs560887 (G6PC2 intron 3, r²=0.84) and rs853789 (ABCB11 intron 19). The causal variants are likely multiple functional G6PC2 SNPs (rs560887 affecting splicing, rs2232316 and rs13431652 affecting promoter activity) acting together. Carriers of multiple risk alleles at this locus may have additive increases in fasting glucose. The GCK variant rs1799884 shows additive effects on both fasting glucose and insulin secretion when combined with G6PC2/ABCB11 locus variants — the two genes act at opposite sides of the same glucokinase-G6PC2 substrate cycle.

Genotype Interpretations

What each possible genotype means for this variant.

CC Low Glucose Set-Point Beneficial

Protective C/C genotype — lower fasting glucose set-point

The CC genotype corresponds to having no copies of the A allele, which is the allele that tags higher G6PC2 expression in pancreatic beta cells. With lower G6PC2 activity, the beta-cell glucokinase enzyme faces less opposition: glucose-6-phosphate accumulates more readily, glycolytic flux is higher at a given blood glucose concentration, and insulin secretion kicks in at a lower glucose threshold. The result is a fasting glucose set-point that is on average 0.13 mmol/L lower than AA homozygotes — a modest but measurable shift. Beta-cell-specific G6pc2 deletion in mice produces approximately 15% reduction in fasting blood glucose, consistent with the human genetics.

AC Intermediate Glucose Set-Point Intermediate

One A allele — mildly elevated fasting glucose set-point

The AC genotype produces an intermediate G6PC2 expression level in pancreatic islets. The effect is additive: each A allele contributes approximately 0.065 mmol/L to fasting glucose. The Danish Inter99 study (n=5,899) found that heterozygotes had modestly higher fasting glucose than CC carriers, with the heterozygous state also associated with slightly elevated insulin response to glucose loads. The odds ratio for impaired fasting glycemia (glucose 5.6–6.9 mmol/L) was 1.26 per risk allele in the Danish cohort — meaning your risk sits partway between CC and AA carriers.

AA High Glucose Set-Point High Risk

Two A alleles — highest fasting glucose set-point from this locus

The AA genotype produces the highest G6PC2 expression in pancreatic beta cells, maximally opposing glucokinase activity. The glucokinase–G6PC2 substrate cycle determines how sensitively beta cells respond to rising blood glucose: G6PC2 recycles glucose-6-phosphate back to glucose, reducing the glycolytic signal that triggers insulin secretion. With maximum G6PC2 activity, a higher blood glucose level is required before adequate insulin release occurs — the set-point shifts up. Mouse knockout data show that eliminating G6pc2 expression lowers fasting blood glucose by ~15%; the human AA-to-CC difference (~0.13 mmol/L) is consistent with a partial version of this effect through regulatory variation rather than complete loss of function.

The Danish Inter99 study (n=5,899) found AA carriers had elevated post-OGTT serum insulin and increased acute insulin response during intravenous glucose tolerance testing, suggesting the beta cells are not failing — they are simply calibrated to fire at a higher glucose threshold. This pattern of elevated fasting glucose plus intact (even higher) insulin secretion is a risk signature for eventual beta-cell exhaustion if sustained hyperglycemia stresses the system long-term.