Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus

Abstract

Objective: We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE.

Methods: 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE.

Results: Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04).

Conclusions: Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.

Keywords: Epidemiology; Gene Polymorphism; Systemic Lupus Erythematosus.

Figure 1. Vitamin D metabolic pathway

Vitamin D-related genes are represented by the gray boxes. GC, group specific component (vitamin D binding protein). Vitamin D is bound to vitamin D binding protein (encoded by the GC gene) in the blood and transported to the liver, where it is converted to 25-hydroxyvitamin D (25[OH]D). This is then transported to the kidney via vitamin D binding protein, where it is converted into the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]₂D) by 1-alpha hydroxylase (encoded by the CYP27B1 gene), which affects several immune modulatory pathways that can affect disease risk. When 1,25[OH]₂D is sufficiently available, some of it is converted to the inactive 24,25-dihydroxyvitamin D (24,25[OH]₂D) by 1-alpha, 25 dihydroxyvitamin D 24-hydroxylase (encoded by the CYP24A1 gene) in the kidney.

Figure 2. The Association between Vitamin D at Baseline and Transitioning to SLE Differs by Number of CYP24A1 rs4809959 Minor Alleles

All models are adjusted for age, sex, and ancestry. A). Lower 25[OH]D levels are significantly associated with transitioning to SLE in individuals with 2 copies of the minor allele at rs4809969. Interaction p-value: p=0.001. Odds ratio = 0.91 (0.84–0.98) (B). Vitamin D deficiency is significantly associated with transitioning to SLE in individuals with 2 copies of the minor allele at rs4809969. Interaction p-value: p=0.02. Odds ratio = 4.90 (1.33–18.04) C). After limiting analyses to European Americans, lower 25[OH]D levels are still significantly associated with transitioning to SLE in individuals with 2 copies of the minor allele at rs4809969. Interaction p-value: p=0.03. Odds ratio = 0.87 (0.79–0.97).