rs1155563 — GC

A Third Independent Signal in the Vitamin D Carrier Gene

The GC gene¹¹ GC gene
Also called the group-specific component gene or DBP gene. It encodes vitamin D binding protein (VDBP), a 58-kDa glycoprotein made mainly by the liver that carries 85-90% of circulating 25(OH)D and 85% of 1,25(OH)₂D in the bloodstream has long been known as the dominant genetic determinant of circulating vitamin D levels in the blood. Most research has focused on two functional missense variants — rs7041 (Asp432Glu) and rs4588 (Thr436Lys) — and one intronic GWAS tag (rs2282679). rs1155563 is a fourth GC region variant that behaves as a third independent signal²² third independent signal
Independent signal means it retains statistical significance even after conditioning on the other GC variants in the same statistical model, indicating it captures genetic variation not already tagged by rs2282679, rs7041, or rs4588 at the locus, confirmed in the Ahn et al. 2010 GWAS³³ Ahn et al. 2010 GWAS
Ahn J et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010 of 4,501 Europeans (P = 3.8 × 10⁻²⁵).

The Mechanism

rs1155563 sits within an intron of the GC gene on chromosome 4 (position 71,777,771, GRCh38) and lies slightly further from the two coding missense variants (rs7041 at 71,752,617 and rs4588 at 71,752,606) than the previously described tag SNP rs2282679 (at 71,742,666). Like all intronic SNPs, it does not change the amino acid sequence of VDBP. Instead, it likely acts as a tag SNP⁴⁴ tag SNP
A genetic variant that, through linkage disequilibrium — the tendency for nearby alleles to be inherited together — reliably marks a haplotype block carrying one or more functional variants that directly alter protein expression or function for an independently segregating haplotype within the GC locus that influences VDBP expression level, mRNA stability, or splicing efficiency.

The C allele (minor allele, ~28% frequency in Europeans) is the effect allele associated with lower circulating 25(OH)D. Because GC is transcribed on the minus strand, the coding-strand notation used in many publications differs from the plus-strand alleles reported here (plus-strand T is reference; C is the effect allele). The effect is additive: each additional C allele reduces serum 25(OH)D, and CC homozygotes show the greatest reduction.

The Evidence

The Ahn et al. 2010 GWAS⁵⁵ Ahn et al. 2010 GWAS
Ahn J et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010 of 4,501 European-ancestry participants identified rs1155563 as a genome-wide significant GC locus variant (P = 3.8 × 10⁻²⁵), with the C allele associated with lower circulating 25(OH)D, remaining significant after conditioning on the two established coding variants. The parallel SUNLIGHT consortium GWAS⁶⁶ SUNLIGHT consortium GWAS
Wang TJ et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010 of 33,996 Europeans confirmed the GC locus dominance (P = 1.9 × 10⁻¹⁰⁹ for the lead variant rs2282679) and showed that individual variants at this locus can independently tag different VDBP haplotypes.

Cross-ethnic replication came from a study of 3,210 Chinese Hans⁷⁷ study of 3,210 Chinese Hans
Lu L et al. Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans. Hum Genet, 2012, which confirmed GC variants including rs1155563 as significant determinants of 25(OH)D (beta −0.036 to −0.076 per risk allele across GC SNPs).

A pediatric GWAS in 761 Finnish infants⁸⁸ pediatric GWAS in 761 Finnish infants
Kämpe A et al. Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children. PLoS Genet, 2019 found rs1155563 to be the lead SNP at the GC locus in this young cohort (beta = −9.49 nmol/L per C allele), with the effect being substantially larger in infants receiving high-dose supplementation (30 µg/day) than in those receiving standard doses (10 µg/day), demonstrating that this variant modifies the biological response to vitamin D3.

In the Western Australian Raine Study⁹⁹ Western Australian Raine Study
Anderson D et al. Genome-wide association study of vitamin D levels in children. Genes Immun, 2014 of 1,140 adolescents, rs1155563 reached genome-wide significance for vitamin D levels at age 14 (P = 3.9 × 10⁻⁹), providing independent replication in a different ancestry context.

Practical Actions

Because rs1155563 is a GC locus intronic variant, its primary clinical meaning mirrors that of the other GC tag SNPs: C allele carriers have lower total serum 25(OH)D on standard blood tests. The total/free vitamin D paradox still applies — reduced VDBP binding capacity means a larger fraction of vitamin D circulates free and bioavailable, partly buffering the apparent deficit on total 25(OH)D assays.

The most actionable implication is for supplementation dosing. The Kämpe 2019 pediatric GWAS showed that C allele effects were amplified under high-dose vitamin D3 — CC carriers receiving 30 µg/day still had lower 25(OH)D than non-carriers — suggesting these individuals need to supplement more consistently and may need to retest more frequently to verify dose adequacy.

Cholecalciferol (vitamin D3) taken with a fat-containing meal remains the standard recommendation. Monitoring total 25(OH)D annually, and interpreting borderline results in light of this genotype, gives the most actionable picture.

Interactions

rs1155563 is one of at least three partially independent signals at the GC locus — the others being rs2282679 (the lead GWAS tag) and the two missense variants rs7041 (Asp432Glu) and rs4588 (Thr436Lys). The combined haplotype structure of this locus determines the net VDBP isoform (Gc1s, Gc1f, or Gc2) and its associated transport capacity.

Upstream and downstream pathway partners compound GC effects. CYP2R1 (rs10741657) governs hepatic 25-hydroxylation; DHCR7/NADSYN1 (rs12785878) affects skin synthesis efficiency. Multi-SNP genetic scores combining GC variants with CYP2R1 and DHCR7 variants confer approximately two-fold increased vitamin D deficiency risk in susceptible haplotype carriers.