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From skin tone to rare mutations, scientists uncover how your genes influence vitamin D levels, and why standard supplements may not work the same for everyone.

Review: Genetic Variants Influencing Individual Vitamin D Status. Image Credit: Zerbor / Shutterstock

In a recent study published in the journal Nutrients, researchers in Canada reviewed the genetic mechanisms contributing to individual variation in vitamin D (VD) levels in circulation.

Humans can efficiently synthesize VD, which requires ultraviolet B (UVB) radiation exposure in the form of sunlight. However, at southern and northern latitudes distal to the equator, sunlight and skin temperature are inadequate for the synthesis of cholecalciferol (VD3) for several months of the year. As such, this could result in VD deficiency and adverse health outcomes in the absence of dietary sources.

Studies suggest that calcidiol (a major VD metabolite) levels of 60 ng/ml may be associated with a lower risk of certain health conditions. However, the optimal VD status is debated, and proposed thresholds vary across studies and expert groups. Importantly, most thresholds are derived from European cohorts, and their applicability across ancestries remains debated. Besides dietary and seasonal factors, genetics contribute to individual variation in VD. Gene-by-environment interactions, including skin tone and latitude, may also influence these outcomes. As such, the present study reviewed the genetic variants influencing individual VD status.

VD synthesis, regulation, and metabolism

VD can be acquired from diet, supplements, and endogenous synthesis. It is typically consumed as VD3 from dietary supplements and animal-based foods and ergocalciferol (VD2) from plant-based foods. VD is endogenously produced in humans under ideal conditions. Skin exposure to UVB light leads to the conversion of 7-dehydrocholesterol (7-DHC) into pre-VD3, which, after thermal isomerization, produces VD3.

Moreover, UVB irradiation converts pre-VD3 to tachysterol and lumisterol isomers, and VD3 to inactive suprasterols. This allows for VD regulation in the skin and prevents toxicity. The presence of lipids enhances the absorption of VD. The secretion of gastric lipase is required to hydrolyze esterified VD for its absorption. Subsequently, pancreatic lipases and bile acids in the small intestine promote the formation of micelles that solubilize VD.

Following absorption, VD is packaged and transported to the portal vein or indirectly via the lymphatic system to the blood. In circulation, VD3 binds to transport proteins that carry it to the liver. VD-binding protein (DBP) accounts for most of VD transport (85%) due to high binding affinity, while albumin transports about 15% of VD, leaving around 0.4% free VD in circulation.

Synthesis, transport, and metabolism of vitamin D throughout the body (created using BioRender): 7-dehydrocholesterol (7-DHC), cholesterol-binding proteins (CTPs), scavenger receptor class B type 1 (SR-BI), Niemann-Pick C1-Like 1 (NPC1L1), vitamin D binding protein (DBP), fibroblast growth factor (FGF)-23 (FGF-23), parathyroid hormone (PTH).

Genetic variants influencing VD status

Genome-wide association studies (GWASs) and candidate gene association studies (CGASs) have investigated polymorphisms in the VD receptor (VDR) gene associated with non-skeletal and skeletal health. Nevertheless, information on the association with genes related to VD synthesis, metabolism, and transport is lacking. GWASs have reported associations with single-nucleotide polymorphisms (SNPs) in 7-DHC reductase (DHCR7) and VD levels.

Several DHCR7 mutations that reduce its expression during fetal development are responsible for a rare autosomal recessive disease, Smith-Lemli-Opitz syndrome. Loss-of-function mutations in both DHCR7 alleles (biallelic frameshift mutations) result in impaired cholesterol biosynthesis. Common SNPs in DHCR7, such as rs12785878, are associated with lower serum VD and are more prevalent in northern populations, suggesting potential evolutionary adaptation to latitude. In the context of VD synthesis, lower functional DHCR7 levels would reduce 7-DHC-to-cholesterol conversion, increasing the availability of 7-DHC for VD synthesis.

The GC gene encodes DBP, the primary transporter of VD metabolites. Two missense SNPs define the common isoforms of GC: GC1s, GC2, and GC1f, which differ in VD binding affinity and DBP concentration. The GC1f allele has been associated with lower serum levels of calcidiol and increased risk of hypovitaminosis D in infants.

Although not as well-studied as GC, several candidate transport proteins (CTPs) have been proposed to influence VD absorption and distribution. Cholesterol-transport proteins (CTPs) transport VD, vitamin K, α-tocopherol, and carotenoids, among others, throughout the body. A study found that mice deficient in a CTP, scavenger receptor class B type 1 (SCARB1), had elevated levels of deuterated VD3 in serum, heart, adipose tissue, and kidney, but reduced levels of deuterated calcidiol in kidney, serum, and liver. While direct associations between human CTP variants and serum calcidiol are lacking, established effects on the transport of other fat-soluble vitamins indicate their involvement is plausible. Emerging research also highlights similar transport roles for CD36 and NPC1L1, though more evidence is needed to confirm their contribution to VD status. Overall, while the role of CTPs in VD regulation remains plausible, further validation in human studies is required.

Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) is responsible for the hydroxylation of VD3 to calcidiol. Various GWASs and CGASs have uncovered associations between SNPs in CYP2R1 and VD status. A study reported that 21 non-synonymous polymorphisms in CYP2R1 decreased CYP2R1 activity, while two SNPs increased activity. A risk allele, rs10741657, in CYP2R1 was reported to be associated with a higher likelihood of VD insufficiency.

Further, CYP27B1 accounts for the hydroxylation of calcidiol to calcitriol. SNPs in CYP27B1 have been associated with circulating VD levels. For instance, rs4646536, an intronic SNP in CYP27B1, has been associated with VD deficiency risk. Besides, loss-of-function mutations in CYP27B1 cause VD-dependent rickets type 1A (VDDR1A). VDDR1A patients with biallelic loss-of-function mutations in CYP27B1 have undetectable or low calcitriol, requiring life-long calcitriol supplementation.

CYP24A1 is responsible for calcitriol inactivation. Various SNPs in CYP24A1 have been associated with VD concentrations. A case-control study reported that specific CYP24A1 SNP genotypes (intronic rs2585428 and rs4809960) were associated with VD deficiency risk. Another study found that a CYP24A1 SNP, rs172167070, was associated with calcidiol levels and VD responder status in a pediatric population with cystic fibrosis. Rare CYP24A1 loss-of-function mutations may underlie hypersensitivity to VD supplementation, suggesting a role for genetic testing in specific clinical scenarios.

Additionally, the review discusses two other genes not commonly addressed in prior studies: CYP11A1, which generates alternative bioactive vitamin D metabolites, especially in the skin. CYP3A4, a hepatic enzyme involved in the inactivation of both calcidiol and calcitriol, where a rare gain-of-function mutation was linked to rickets in children.

Concluding remarks

VD status is a polygenic trait affected by polymorphisms in genes regulating its synthesis, metabolism, and transport, and rare mutations that can alter VD metabolism. Variants in the vitamin D receptor (VDR) may also indirectly influence circulating levels via gene regulation mechanisms. These genetic factors, as well as seasonal variation, mean that sufficient VD levels cannot always be attained through standard dietary recommendations. Understanding the cumulative effects of the environment, genetics, and gene-environment interactions is necessary to develop precise recommendations.

The review also highlights clinical implications. Vitamin D genetic risk scores (GRSs) may eventually help identify individuals at risk of deficiency or toxicity, enabling more tailored supplementation strategies. However, these tools require further validation in diverse populations. In clinical practice, a phenotype-driven approach remains most feasible, though emerging methods, such as high-dose cholecalciferol challenges, could assess individual bioavailability and metabolic response.

Having a larger waistline, high blood pressure and other risk factors that make up metabolic syndrome is associated with an increased risk of Parkinson’s disease, according to a study published on August 20, 2025, in Neurology^®, the medical journal of the American Academy of Neurology. The study does not prove that metabolic syndrome causes Parkinson’s disease; it only shows an association.

Metabolic syndrome is defined as having three or more of the following risk factors: excess belly fat, high blood pressure, high blood sugar, higher than normal triglycerides, which are a type of fat found in the blood, and low high-density lipoprotein (HDL) cholesterol, or “good” cholesterol.

Parkinson’s disease is the second most common neurodegenerative disorder among older adults after Alzheimer’s disease, and metabolic syndrome affects an estimated one in four adults and is highly modifiable. Our findings suggest that metabolic syndrome may be a modifiable risk factor for Parkinson’s disease. Future studies are needed to see whether working to control metabolic syndrome could help prevent Parkinson’s disease.”

Weili Xu, PhD, study author, Karolinska Institutet, Stockholm, Sweden

The study involved 467,200 people with an average age of 57; of those 38% had metabolic syndrome. The participants were followed for a median of 15 years. During that time, 3,222 people developed Parkinson’s disease. For people without metabolic syndrome, the incidence rate for Parkinson’s was 4.87 cases per 10,000 person-years, compared to 5.21 cases per 10,000 person-years for people who had metabolic syndrome. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

After adjusting for age, smoking status, physical activity and genes that increase the risk of Parkinson’s disease, researchers found that people with metabolic syndrome were about 40% more likely to develop Parkinson’s disease than people without the syndrome.

The researchers also conducted a meta-analysis of all studies on this topic and confirmed the finding that people with metabolic syndrome have an increased risk of Parkinson’s disease. Combining the current study with eight previous studies, the researchers found that people with metabolic syndrome were 29% more likely to develop Parkinson’s disease than people without the syndrome.

“We also found a higher risk of Parkinson’s disease for people with both metabolic syndrome and a genetic susceptibility for Parkinson’s disease,” Xu said. “This suggests that maintaining metabolic health may be especially important for people who have genes that increase their risk for Parkinson’s disease.”

A limitation of the study was that most of the participants were white people, so the results may not be the same for other groups.

The study was supported by the Swedish Research Council for Health, Working Life and Welfare, and the Swedish Dementia Foundation.

Many direct to consumer menopause services are unnecessary and do not improve care, warn experts in The BMJ today.

They argue that the sharp rise in commercial services for women seeking relief for menopausal symptoms raises concerns about the reliability and potential commercial bias of the information, and that symptoms are best assessed by a thorough clinical history with treatment decisions guided by clinical response and patient preferences.

One of the most troubling trends arising from this surge is the promotion of routine hormone panel testing for the evaluation of menopausal symptoms, they write. These tests can cost hundreds of dollars and are marketed to patients and clinicians as necessary for “individualising” hormone therapy.

Yet in reality, these tests are of limited clinical use because there is no clearly defined therapeutic window for menopausal hormone therapy, and some testing techniques do not offer accurate or precise assessment of hormone levels.

For perimenopause and menopause, hormone testing offers no reliable way to determine who will benefit from treatment, when the final menstrual period will occur, or whether it is safe to discontinue contraception, they explain.

Clinical guidelines from the British Menopause Society, National Institute for Health and Care Excellence, American College of Obstetricians and Gynecologists and others agree: in women over age 45 presenting with validated symptoms of menopause, including menstrual irregularity, menopause is a clinical diagnosis, and hormone testing is unnecessary.

Despite this, many women now present with detailed hormone panels from wellness providers or online services that are often used to justify taking custom-made hormone preparations or supplements based on marginal deviations from hormone thresholds that are not grounded in evidence, write the authors.

Such custom-made hormone preparations (known as compounded hormone regimens) are not regulated in the same way as standard menopausal hormone therapy and have not been tested for effectiveness and safety.

There is also concern that inconsistencies in the quantities of oestrogen or progestogen in compounded hormone regimens can result in abnormal cell growth or cancer in the womb (uterus) lining, they add.

Until we can establish individualised target hormone levels, there is no role for commercial hormonal panel testing to guide therapy, they argue. In the meantime, such testing offers only a false sense of precision.

They acknowledge that innovation is needed but suggest that the normalisation of hormone panel testing could be a symptom of a larger problem: the commercialisation of women’s health and a movement away from evidence based practice. 

For midlife women, effective treatment begins not with numbers, but with listening, they conclude.