Effect Modifications Between 25[OH]D and Related Genes on SLE Risk

CYP24A1, a gene involved in physiologically active 1,25[OH]2D degradation appears to play an important role in the association of lower levels of 25[OH]D and increased risk of SLE

Levels of vitamin D and CYP24A1 status may both have a role in the transition to systemic lupus erythematosus (SLE) among individuals who have an increased genetic risk of developing SLE, according to recent data published in the Annals of Rheumatic Diseases.

The etiology of SLE has not been determined, although prior studies have suggested that it is caused by a combination of genetic and environmental influences, prompting researchers to examine the association between vitamin D and the transition to SLE among individuals with relatives with SLE.

A number of genes play a role in the processing of vitamin D including CYP24A1 which is implicated in the degradation of 1,25-hydroxyvitamin D (1,25[OH]2D).

High Yield Data Summary

  • CYP24A1, a gene involved in  physiologically active 1,25[OH]2D degradation appears to play an important role in the association of lower levels of 25[OH]D and increased risk of SLE

The researchers evaluated 436 individuals who have a relative with SLE but did not have SLE themselves. The participants were evaluated at baseline and after an average of 6.3 ± 3.9 years later. Of these, 56 individuals developed SLE, which was defined as having American College of Rheumatology criteria ≥4.

They also measured 25-hydroxyvitamin D (25[OH]D) levels with enzyme-linked immunosorbent assay (ELISA) and genotyped 6 single-nucleotide polymorphisms in 4 vitamin D genes.

All individuals, regardless of whether or not they transitioned to SLE, had similar mean baseline 25[OH]D levels (P=.42) and vitamin D supplementation (P=.65). However, vitamin D deficiency was greater among individuals who transitioned to SLE compared with those who did not (46% vs 33%; P=.05).

The association between 25[OH]D and risk of SLE was affected by CYP24A1 minor alleles at rs4809959. Every additional minor allele that increased 25[OH]D was associated with decreased SLE risk: no minor alleles (adjusted odds ratio [OR]: 1.03; 95% confidence interval [CI]: 0.98-1.09), 1 minor allele (adjusted OR: 1.01; 95% CI: 0.97-1.05), and 2 minor alleles (adjusted OR: 0.91; 95% CI: 0.84-0.98).

Vitamin D deficiency also significantly increased the risk of transitioning to SLE among those with 2 minor alleles at rs4809959 (adjusted OR: 4.90; 95% CI: 1.33-18.04).

“In individuals with 2 copies of the minor allele rs4809959, increasing 25[OH]D levels were associated with decreased risk of transitioning to SLE, and vitamin D deficiency was associated with increased risk of transitioning to SLE,” the authors concluded.

“Given that CYP24A1 encodes the enzyme responsible for initiating the degradation of 1,25[OH]2D, these results may indicate genetic evidence for a pathogenic role for low levels of 1,25[OH]2D in SLE,” they stated.

Summary and Clinical Applicability

The results indicate that CYP24A1 is important in the association of low levels of 25[OH]D and increased risk of SLE. Further studies should follow patients prospectively to allow for investigators to study time to SLE diagnosis in this patient population, which would determine how vitamin D deficiency is affecting development of SLE.

“In addition, there should be further exploration of the pathophysiological pathways responsible for the vitamin D and SLE association, including expression of CYP24A1 variants in organs and tissues involved in SLE, such as the skin, heart, lungs, blood vessels, brain, kidneys and connective tissue,” they suggested.

Serum vitamin D measurement, along with the presence of genetic variations in vitamin D metabolism, may help identify individuals at increased risk of transitioning to SLE.

Limitations and Disclosures

The majority of the patient population in this study was European American, and the authors note that studying a more diverse at-risk population would allow investigators to further explore the association between vitamin D and SLE.


Young KA, Munroe ME, Guthridge JM, et al. Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus. Ann Rheum Dis. 2016; doi: 10.1136/annrheumdis-2016-209157.

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