rs7936142 — CYP2R1 CYP2R1 rs7936142

CYP2R1 rs7936142 — Your Hepatic Vitamin D Activation Gate

The CYP2R1 gene encodes vitamin D 25-hydroxylase¹¹ vitamin D 25-hydroxylase
A microsomal cytochrome P450 enzyme expressed primarily in the liver that performs the first obligatory hydroxylation step in vitamin D activation, converting cholecalciferol (D3) or ergocalciferol (D2) into 25-hydroxyvitamin D (25(OH)D), the major circulating form measured in blood tests, the liver enzyme responsible for the first and rate-limiting step in converting dietary or sun-derived vitamin D into the form measured in your bloodstream. Without functional CYP2R1, vitamin D cannot be converted into its bioactive metabolite, regardless of how much sun exposure or supplementation you receive.

rs7936142 is an intronic variant within the CYP2R1 gene on chromosome 11. It was first deployed as a haplotype-tagging marker in linkage studies of CYP2R1 mutations causing vitamin D-deficiency rickets and is now recognized as part of the broader CYP2R1 haplotype block associated with inter-individual variation in circulating 25(OH)D concentrations. The T allele is the minor risk allele, with a global frequency of approximately 9–11%.

The Mechanism

rs7936142 sits in an intronic region of CYP2R1 and does not itself alter the protein sequence. Its association with vitamin D status operates through linkage disequilibrium²² linkage disequilibrium
When two variants on the same chromosome are inherited together more often than chance predicts, so that one variant can serve as a proxy marker for another nearby functional variant with functional variants in the CYP2R1 regulatory or coding regions that reduce enzyme expression or activity. The CYP2R1 protein hydroxylates vitamin D at carbon-25, producing 25-hydroxyvitamin D³³ 25-hydroxyvitamin D
Also written 25(OH)D or calcidiol; this is the storage and transport form measured in clinical vitamin D blood tests, and is the substrate for the kidney enzyme CYP27B1 which makes the active hormone calcitriol (1,25(OH)₂D) — the main circulating form that is subsequently converted to the active hormone calcitriol in the kidneys.

When CYP2R1 expression or activity is reduced by haplotype variants tagged by rs7936142, the liver converts a smaller proportion of incoming vitamin D to 25(OH)D. This creates a state where serum 25(OH)D falls lower than expected for a given vitamin D intake or sunlight exposure — and where the biological ceiling for supplementation response is genetically constrained.

The Evidence

The foundational work establishing CYP2R1's primacy came from Cheng et al. 2004⁴⁴ Cheng et al. 2004
Cheng JB et al. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. PNAS, 2004, who identified a patient with a homozygous L99P mutation in CYP2R1 who had profoundly low 25(OH)D despite normal sun exposure — providing the first genetic proof that CYP2R1 is the principal hepatic 25-hydroxylase in humans.

The clinical relevance of rs7936142 as a haplotype marker was established by Thacher et al. 2015⁵⁵ Thacher et al. 2015
Thacher TD et al. CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency. J Clin Endocrinol Metab, 2015, who used rs7936142 as one of six linkage markers to map CYP2R1 mutations in Nigerian families with hereditary rickets. Heterozygous carriers of pathogenic CYP2R1 mutations showed markedly reduced 25(OH)D responses to supplementation, confirming semidominant inheritance — a pattern consistent with the intermediate effects seen in common variant heterozygotes.

At the population level, the CYP2R1 locus (tagged by rs7936142 and its haplotype partners rs10741657 and rs10766197) is one of the most replicated GWAS hits for circulating 25(OH)D. A meta-analysis of 52,417 participants⁶⁶ meta-analysis of 52,417 participants
Duan L et al. Effects of CYP2R1 gene variants on vitamin D levels and status: a systematic review and meta-analysis. Gene, 2018 found CYP2R1 risk allele homozygotes had OR 1.42 for vitamin D deficiency (95% CI 1.11–1.83, P = 0.006).

Critically, CYP2R1 variants modulate not just baseline 25(OH)D but also the response to supplementation. An RCT in 616 adolescent girls⁷⁷ RCT in 616 adolescent girls
Khayyatzadeh SS et al. A variant in CYP2R1 predicts circulating vitamin D levels after supplementation with high-dose vitamin D in healthy adolescent girls. J Cell Physiol, 2019 found that rs10741657 AA genotype carriers achieved 539% increases in 25(OH)D after high-dose supplementation versus only 363% in GG carriers — a 50% larger response. This genotype × dose interaction means carriers of the CYP2R1 risk haplotype (including rs7936142 T allele) need higher vitamin D3 doses to reach the same serum 25(OH)D target.

In the MrOS Sweden cohort of 2,870 elderly Swedish men, rs7936142 was successfully genotyped as part of an eight-SNP CYP2R1 haplotype panel. Six of the eight SNPs, including those tagging the haplotype block containing rs7936142, showed 4.6–18.5% differences in mean 25(OH)D values between genotype groups, with the pattern consistent across all markers in the block.

Practical Actions

Carriers of the T allele at rs7936142 — particularly those homozygous for T — tend to run lower in 25(OH)D for a given intake and respond more variably to supplementation. The actionable implication is that standard vitamin D3 doses (600–2,000 IU/day) may be insufficient to maintain 25(OH)D above 30 ng/mL (75 nmol/L), and periodic serum 25(OH)D monitoring is valuable to guide dosing. Using vitamin D3 (cholecalciferol) rather than D2 (ergocalciferol) is advisable since CYP2R1 hydroxylates D3 more efficiently. Cofactors that support CYP2R1 function — particularly magnesium, which is required by all cytochrome P450 enzymes — should be adequate in the diet or supplemented.

Interactions

rs7936142 is a haplotype marker within the CYP2R1 locus and is in linkage disequilibrium with the more extensively studied rs10741657 and rs10766197 variants in the same gene. Individuals carrying risk alleles at multiple CYP2R1 haplotype markers have cumulative reductions in 25(OH)D.

Beyond the CYP2R1 locus, the vitamin D pathway involves four additional genetic bottlenecks: DHCR7/NADSYN1 (skin pre-vitamin D synthesis), GC (transport via vitamin D binding protein, rs4588 and rs7041), CYP27B1 (renal activation), and VDR (receptor sensitivity, rs2228570). The largest GWAS data show that individuals carrying risk alleles across CYP2R1, GC, and DHCR7 can have 2.47-fold increased odds of vitamin D insufficiency compared to those carrying no risk alleles. If you carry risk alleles in multiple pathway genes, the combined effect on 25(OH)D status substantially exceeds any single variant's contribution.

Magnesium is a cofactor for CYP2R1 and other vitamin D pathway enzymes. Magnesium insufficiency (common in modern diets) can impair 25-hydroxylation independent of genetic variation, compounding the effect of CYP2R1 haplotype risk.