rs2282679 — GC

Intronic GWAS tag variant in the vitamin D binding protein gene, the strongest common genetic determinant of circulating 25-hydroxyvitamin D levels

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The Lead Genetic Signal for Vitamin D Status

Among all common genetic variants in the human genome, rs2282679 in the GC gene11 GC gene
Group-specific component, encoding vitamin D binding protein (VDBP/DBP). This 58-kDa glycoprotein produced primarily by the liver carries 85-90% of circulating 25(OH)D and 85% of 1,25(OH)₂D in the bloodstream produces the single strongest association with circulating 25-hydroxyvitamin D22 25-hydroxyvitamin D
The major circulating form of vitamin D measured by standard blood tests, abbreviated 25(OH)D. It reflects total vitamin D status from both sun exposure and dietary intake levels. This intronic variant does not change the VDBP protein sequence itself, but acts as a tag SNP33 tag SNP
A genetic variant that marks — through linkage disequilibrium — a nearby functional variant. Because they are co-inherited, the tag SNP serves as a reliable proxy in genetic studies for the functional coding variants rs4588 and rs7041 that define the three major VDBP isoforms. It is the most commonly reported variant at this locus in GWAS literature and Mendelian randomization studies of vitamin D.

The Mechanism

rs2282679 sits in intron 12 of the GC gene on chromosome 4q13.3. The GC gene is transcribed on the minus strand, so the plus-strand G allele (risk allele) corresponds to C on the coding strand — matching the "A>C" notation seen in many publications. This intronic variant is in strong linkage disequilibrium44 linkage disequilibrium
A statistical association between alleles at different loci, meaning they are inherited together more often than expected by chance. r² values range from 0 (independent) to 1 (perfect proxy) with the missense variant rs4588 (r² > 0.8 in Northern Europeans, approaching 1.0 in HapMap CEU), which encodes the Thr436Lys substitution that defines the Gc2 isoform. It has moderate LD with rs7041 (r² ≈ 0.4), the Asp432Glu variant that distinguishes Gc1f from Gc1s.

The G allele at rs2282679 tags a haplotype carrying the rs4588 T allele (Gc2), which produces a VDBP isoform with reduced O-glycosylation55 O-glycosylation
A post-translational modification where a sugar attaches to the threonine at position 436. The Gc2 isoform (lysine) cannot be glycosylated at this site, reducing protein stability and binding affinity, lower binding affinity for vitamin D metabolites, and lower serum concentration. The net effect is lower total 25(OH)D on standard blood tests — though the bioavailable fraction may be preserved or even increased due to reduced protein binding.

The Evidence

The SUNLIGHT consortium66 SUNLIGHT consortium
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 GWAS of 33,996 Europeans identified rs2282679 as the lead variant at the GC locus with extraordinary significance (P = 1.9 × 10⁻¹⁰⁹). A parallel GWAS of 4,501 Europeans77 GWAS of 4,501 Europeans
Ahn J et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010 confirmed the signal (P = 2.0 × 10⁻³⁰) and showed rs2282679 exhibited the strongest association among GC variants, with rs7041 showing weaker evidence after conditioning on rs2282679. The combined meta-analysis reached P = 1.8 × 10⁻⁴⁹. Homozygous GG carriers had 25(OH)D levels 6-34% lower (median 18.3%) than TT carriers across cohorts.

The largest vitamin D GWAS to date88 largest vitamin D GWAS to date
Revez JA et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun, 2020 of 417,580 Europeans identified 143 loci, yet GC remained the single strongest signal genome-wide.

In a study of 712 southern Chinese women99 study of 712 southern Chinese women
Cheung CL et al. Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency. J Hum Genet, 2013, each G allele was associated with lower 25(OH)D (β = -0.066) and a 51% increase in vitamin D insufficiency risk (OR = 1.51, 95% CI 1.19-1.93).

A supplementation trial in 913 infants1010 supplementation trial in 913 infants
Enlund-Cerullo M et al. Genetic variation of the vitamin D binding protein affects vitamin D status and response to supplementation in infants. J Clin Endocrinol Metab, 2019 demonstrated that GG homozygotes had 25(OH)D concentrations 3.8-10.8 nmol/L lower than TT carriers at every timepoint, and the genotype significantly modified response to high-dose supplementation (30 μg/day vitamin D3).

rs2282679 has also been used as a genetic instrument in Mendelian randomization studies1111 Mendelian randomization studies
Manousaki D et al. Genome-wide association study for vitamin D levels reveals 69 independent loci. Am J Hum Genet, 2020 providing evidence that genetically determined lower 25(OH)D causally increases the risk of multiple sclerosis.

Practical Implications

Because rs2282679 is in strong LD with the functional variant rs4588, the clinical implications are essentially identical: carriers of the G allele (particularly GG homozygotes) will tend to show lower total 25(OH)D on standard blood tests. This reflects lower VDBP concentration and binding affinity rather than necessarily lower bioavailable vitamin D.

The key distinction is that rs2282679 is an intronic tag SNP — it does not change the protein but reliably marks the Gc2 haplotype. Many large-scale studies and genetic risk scores use rs2282679 rather than rs4588 because it was the lead GWAS signal. For users who have data for rs2282679 but not rs4588 (or vice versa), both variants provide equivalent information about VDBP isoform status.

GG carriers should interpret borderline 25(OH)D results (20-30 ng/mL) with awareness that their bioavailable vitamin D may be adequate. Those with truly low levels (below 20 ng/mL) or deficiency symptoms benefit from cholecalciferol (D3) supplementation at higher doses, taken with dietary fat.

Interactions

rs2282679 is in strong LD with rs4588 (Thr436Lys) and moderate LD with rs7041 (Asp432Glu). Together, these three variants capture the common genetic variation at the GC locus. While rs2282679 and rs4588 provide largely redundant information, rs7041 captures additional, partially independent variation in VDBP function — particularly the distinction between Gc1f and Gc1s isoforms.

Variants in other vitamin D pathway genes — CYP2R1 (rs10741657, hepatic 25-hydroxylation), DHCR7/NADSYN1 (rs12785878, skin synthesis), and CYP24A1 (degradation) — compound the effect of GC variants. A multi-SNP genetic risk score combining rs2282679, rs12785878, and rs10741657 conferred approximately two-fold increased risk of vitamin D deficiency in multiple populations.

Nutrient Interactions

vitamin D altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

TT Standard VDBP Tag Normal

No GWAS risk alleles — standard vitamin D transport and blood test accuracy

The TT genotype at rs2282679 tags the haplotype carrying the rs4588 G allele (Thr436), which preserves O-glycosylation and full VDBP binding affinity. In the SUNLIGHT consortium GWAS and subsequent studies, TT carriers served as the reference group with the highest mean total 25(OH)D concentrations.

With standard VDBP function, your total serum 25(OH)D measurement closely reflects your true vitamin D status, and conventional clinical thresholds (30 ng/mL for sufficiency, 20 ng/mL for deficiency) apply normally. You respond to vitamin D supplementation in the expected manner documented in clinical trials.

GT Reduced VDBP Tag Intermediate

One copy of the GWAS risk allele — moderately lower total 25(OH)D on blood tests

The GT genotype means you carry one copy of the haplotype tagged by the G allele, which is in strong linkage disequilibrium with the functional missense variant rs4588 (Thr436Lys). In the SUNLIGHT consortium GWAS of 33,996 Europeans, each copy of the G allele was associated with lower circulating 25(OH)D at genome-wide significance (P = 1.9 × 10⁻¹⁰⁹).

In practical terms, heterozygotes show approximately 3-5 nmol/L lower total 25(OH)D compared to TT homozygotes. In a supplementation trial of 913 infants, GT carriers showed intermediate 25(OH)D concentrations between TT and GG groups, with a slightly reduced response to high-dose vitamin D3 supplementation.

The lower total 25(OH)D partly reflects reduced VDBP concentration and binding affinity associated with the tagged Gc2 isoform, meaning a greater fraction of your vitamin D circulates in the free, bioavailable form.

GG Low VDBP Tag Reduced

Two copies of the GWAS risk allele — significantly lower total 25(OH)D on blood tests

The GG genotype marks homozygosity for the haplotype carrying the functional rs4588 T allele (Gc2 isoform), which lacks O-glycosylation at position 436 of the VDBP protein. In the landmark SUNLIGHT consortium GWAS, GG carriers had 25(OH)D levels 6-34% lower (median 18.3%) than TT carriers across cohorts.

In a supplementation trial of 913 infants, GG carriers had 25(OH)D concentrations approximately 10.8 nmol/L lower than TT carriers and showed a significantly blunted response to high-dose vitamin D3 supplementation (30 μg/day). In postmenopausal women, the G allele was associated with a 2.36-fold increased risk of metabolic syndrome, partly mediated through vitamin D deficiency.

Importantly, the lower total 25(OH)D does not necessarily indicate functional deficiency. The Gc2 isoform's reduced binding affinity means more vitamin D circulates in the free, bioavailable form. The total/free vitamin D paradox means standard blood tests may overestimate the degree of deficiency in GG carriers.