Can Genes Contribute to Vitamin D Deficiency? (GC)

Vitamin D Functions & Deficiency

Vitamin D is crucial for many functions and processes, such as [R, R]:

• Calcium absorption and bone health
• Immunity
• Heart health
• Joint health
• Cancer prevention
• Blood sugar balance

According to some estimates, one billion people worldwide have vitamin D deficiency, while nearly half of the world's population has insufficient levels [R].

Doctors define vitamin D deficiency as blood levels <20 ng/mL (<50 nmol/L) and insufficiency as <30 ng/mL (<70 nmol/L) [R, R, R]. 

Vitamin D is essential for bone health, immunity, heart health, and more. Vitamin D deficiency, defined as blood levels <20 ng/mL, is a global health concern.

The Role of GC

The GC gene encodes the vitamin D-binding protein (DBP). This protein enables the storage, transport, and delivery of vitamin D and its metabolites to target organs [R, R, R].

Studies have found a direct link between DBP and vitamin D blood levels, confirming a key role of this protein in vitamin D metabolism. They have also discussed the importance and diagnostic value of DBP levels in different conditions associated with vitamin D status, including thyroid disorders, diabetes, and multiple sclerosis [R, R].

Given the importance of GC for vitamin D metabolism, scientists have studied the potential link between variants or SNPs in this gene and vitamin D blood levels. Let's see what they found!

Rs2282679

In a meta-analysis of 15 clinical trials and over 30,000 European descendants, rs2282679 showed the strongest association with vitamin D status. The minor “G” allele correlated with 63% and 49% higher odds of vitamin D insufficiency and deficiency, respectively [R].

According to the authors, rs2282679 had the same impact on vitamin D levels as supplementation, and its impact was slightly lower than seasonal variations (sun exposure)!

Another SNP, rs4588, showed comparable effects due to a nearly perfect overlap with rs2282679, so it wasn’t an independent genetic factor [R].

Among 4,476 Thai individuals, rs2282679-G was associated with 80% higher odds of vitamin D deficiency, independent of age, weight and other risk factors [R].

This variant may also influence the outcomes of vitamin D supplementation during pregnancy; in 682 white women, each “T” allele correlated with 4.2 nmol/L higher vitamin D levels upon delivery [R].

The “G” allele at rs2282679 has shown a strong correlation with vitamin D deficiency, independent of age, race, and different risk factors.

Rs7041

Another SNP with a meaningful impact on vitamin D status is rs7041. The above meta-analysis and another review of 17 studies confirmed the association between the “A” allele and lower vitamin D levels [R, R].

In 448 vitamin D-deficient Chinese people, variants including rs7041 had a stronger influence on supplementation (2000 IU/day) outcomes than age, sex, and other factors. People with the "C" allele had significantly higher vitamin D levels [R].

A study of 234 patients from Saudi Arabia came to a similar conclusion: those carrying the "A" allele at rs7041 were 3.7 times more likely to remain vitamin D-deficient despite supplementation. All patients were receiving 1000 IU of vitamin D per day for four months, suggesting that people with rs7041-A may benefit from higher doses [R].

The “A” allele at rs7041 is associated with lower vitamin D levels and reduced efficacy of supplementation with standard doses.

A meta-analysis of 7,258 African and 1,361 Hispanic subjects replicated the link between the above variants and vitamin D levels in these ethnic groups. However, the variants have a more robust impact on people of European (Caucasian) ancestry [R].

Clinical Significance

In two trials of nearly 12,000 participants, rs2282679 showed no association with vitamin D-related conditions, such as diabetes, heart disease, osteoporosis, and cancer [R, R].

A meta-analysis of 28 studies confirmed the lack of association between GC SNPs and different types of cancer [R].

Among 6,181 older adults, rs7041 and rs4588 correlated with higher odds of osteoporosis, but only when dietary calcium intake was low (<1 g/day) [R].

In a trial of 414 ex-smokers, those with the “AA” genotype at rs7041 had 25% lower vitamin D levels and two times higher odds of chronic obstructive pulmonary disease (COPD) [R]. The same genotype was associated with severe depression among 265 adults but only in combination with low-protein diets [R].

Most studies observed no clinical significance of GC SNPs. However, under certain conditions, they may correlate with osteoporosis, lung disease, and depression.

How It Works

As mentioned, Vitamin D Binding Protein (DBP) blood levels directly influence vitamin D status and metabolism. Variants in the GC gene may interfere with vitamin D by changing gene expression and DBP levels.

Two studies of nearly 4,000 participants confirmed the link between rs2282679-G and lower DBP levels [R, R].

SNP Summary and Table

Primary SNPs:

GC rs2282679

• ‘G’ = associated with lower vitamin D levels and higher odds of deficiency
• ‘T’ = not associated with vitamin D levels

GC rs4588

• ‘T’ = associated with lower vitamin D levels and higher odds of deficiency
• ‘G’ = not associated with vitamin D levels

Population Frequency: These two variants are almost always inherited together. Around 39% of European descendants carry one copy and 5% carry both copies of the ‘problematic’ alleles (G and T, respectively). They are much less common in African populations (10%).

GC rs7041

• ‘A’ = associated with lower vitamin D levels 
• ‘C’ = not associated with vitamin D levels

Population Frequency: Around 50% of European descendants carry one copy and 16% carry both copies of the “A” allele. It’s much more common in East Asian and African populations.