rs705117 — GC

GC rs705117 — When Low Total Vitamin D May Not Mean What You Think

The GC gene encodes vitamin D binding protein (VDBP/DBP)¹¹ vitamin D binding protein (VDBP/DBP)
A 58-kDa glycoprotein produced mainly by the liver that carries 85-90% of all circulating 25(OH)D and 85% of 1,25(OH)₂D in the bloodstream. Less than 1% of vitamin D metabolites circulate unbound (free). Only the free fraction and the smaller albumin-bound fraction are considered biologically available to enter cells, the principal carrier that transports vitamin D metabolites through the blood. rs705117 is an intronic variant in GC that has been independently associated with circulating VDBP concentrations — separate from the well-known isoform-defining variants rs4588 and rs7041. Individuals carrying certain alleles at rs705117 produce systematically lower VDBP, which creates an important paradox: lower total 25(OH)D on a standard blood test may coexist with normal or even elevated free, biologically active vitamin D²² lower total 25(OH)D on a standard blood test may coexist with normal or even elevated free, biologically active vitamin D
The "free hormone hypothesis" holds that only unbound hormone is biologically active. When VDBP is genetically low, a smaller fraction of vitamin D is sequestered, raising the free fraction. The net biological effect depends on how much VDBP is reduced and on other pathway variants.

The Mechanism

rs705117 sits in intron 10 of the GC gene on chromosome 4 (GRCh38 position 71742398). As an intronic variant, it does not alter the VDBP protein sequence directly; instead, it likely influences GC gene transcription or mRNA processing³³ GC gene transcription or mRNA processing
Intronic variants can affect splicing efficiency, polyadenylation signals, or regulatory element binding — all of which modulate how much protein the gene produces without changing its amino acid sequence, resulting in measurably different circulating VDBP concentrations between genotype groups.

In a targeted genome-wide association study of serum VDBP⁴⁴ genome-wide association study of serum VDBP
Moy KA et al. Genome-wide association study of circulating vitamin D-binding protein. Am J Clin Nutr, 2014, rs705117 emerged as one of two independent signals in the GC gene significantly associated with circulating DBP levels (P = 4.7 × 10⁻⁹¹). Mean DBP concentrations differed three-fold across genotype groups. This effect was observed independently of the classical isoform-defining variants (rs7041 Asp432Glu), demonstrating that rs705117 captures a separate component of genetically determined VDBP variation.

The T allele at rs705117 haplotypes with the rs2282679-G allele (the main GWAS signal at the GC locus for lower 25(OH)D) and is part of the GC haplotype TGA⁵⁵ GC haplotype TGA
rs705117-T + rs2282679-G + rs1491710-A; identified in a Chinese haplotype analysis as the risk combination for lower 25(OH)D concentration. Zhang et al. 2013 (PMID 23505139) associated with lower vitamin D levels.

The Evidence

The GWAS by Moy et al. 2014⁶⁶ Moy et al. 2014
Moy KA et al. Genome-wide association study of circulating vitamin D-binding protein. Am J Clin Nutr, 2014;99(6):1424-31 in 1,380 men demonstrated a striking dose-response relationship at rs705117: individuals with 0, 1, or 2 copies of the minor allele had mean VDBP concentrations of 6,339, 4,280, and 2,341 nmol/L, respectively — an approximate three-fold difference between homozygote groups.

A haplotype analysis in 2,897 healthy Chinese subjects⁷⁷ 2,897 healthy Chinese subjects
Zhang Z et al. An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population. J Bone Miner Res, 2013;28(8):1784-92 confirmed rs705117 as part of a GC haplotype associated with lower 25(OH)D (each additional risk allele associated with a 0.12-fold decrease in log-25(OH)D, P = 3.7 × 10⁻¹²). The overall GC locus — encompassing rs705117, rs2282679, rs4588, and rs7041 — is the strongest common genetic determinant of vitamin D status, accounting for approximately 2-7% of variance in 25(OH)D concentrations in most European populations.

The landmark SUNLIGHT consortium GWAS⁸⁸ SUNLIGHT consortium GWAS
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010;376(9736):180-8 of 33,996 Europeans found that a composite genetic risk score combining GC and two other loci conferred an OR of 2.47 (95% CI 2.20-2.78) for vitamin D insufficiency. rs705117 sits within the same GC region.

The free-vitamin-D paradox has clear clinical implications: a review by Jassil et al. 2017⁹⁹ Jassil et al. 2017
Jassil NK et al. Vitamin D binding protein and 25-hydroxyvitamin D levels: emerging clinical applications. Endocr Pract, 2017;23(5):605-13 confirms that because less than 1% of vitamin D circulates unbound, any genetic reduction in VDBP necessarily shifts the free-to-total ratio — meaning standard serum 25(OH)D measurements systematically underestimate available vitamin D in low-VDBP carriers.

Practical Implications

TT carriers face a decision point when their serum 25(OH)D comes back in the borderline range (20-30 ng/mL or 50-75 nmol/L): the result may reflect genetically lower VDBP concentration rather than true vitamin D deficiency. Requesting a free 25(OH)D measurement alongside the standard total test provides a more complete picture. When supplementing, TT carriers should target the mid-range of the sufficiency window (40-60 ng/mL total) rather than pushing to the upper limit, since their free fraction may already be adequate.

Interactions

rs705117 operates within the same GC gene as rs4588 (Thr436Lys, isoform-defining) and rs7041 (Asp432Glu, isoform-defining), and is in partial linkage disequilibrium with the GWAS tag SNP rs2282679. The T allele at rs705117 co-haplotypes with the lower-VDBP alleles at these neighboring variants, compounding their effects. A carrier of both rs705117-TT and rs4588-TT (Gc2/Gc2) will have substantially lower total 25(OH)D than either variant alone predicts, with the greatest potential discordance between total and free vitamin D status.

Downstream, the practical effect of low VDBP intersects with the VDR receptor (rs2228570 / rs1544410) and the 25-hydroxylase CYP2R1 (rs10741657). If hepatic activation of vitamin D is also reduced (CYP2R1 risk allele), lower VDBP compounds the insufficiency because there is less 25(OH)D to distribute in the first place.