Genetic Ancestry, Skin Reflectance and Pigmentation Genotypes in Association with Serum Vitamin D Metabolite Balance

Abstract

Background: Lower serum vitamin D (25(OH)D) among individuals with African ancestry is attributed primarily to skin pigmentation. However, the influence of genetic polymorphisms controlling for skin melanin content has not been investigated. Therefore, we investigated differences in non-summer serum vitamin D metabolites according to self-reported race, genetic ancestry, skin reflectance and key pigmentation genes (SLC45A2 and SLC24A5).

Materials and methods: Healthy individuals reporting at least half African American or half European American heritage were frequency matched to one another on age (+/- 2 years) and sex. 176 autosomal ancestry informative markers were used to estimate genetic ancestry. Melanin index was measured by reflectance spectrometry. Serum vitamin D metabolites (25(OH)D3, 25(OH)D 2 and 24,25(OH)2D3) were determined by high performance liquid chromatography (HPLC) tandem mass spectrometry. Percent 24,25(OH)2D3 was calculated as a percent of the parent metabolite (25(OH)D3). Stepwise and backward selection regression models were used to identify leading covariates.

Results: Fifty African Americans and 50 European Americans participated in the study. Compared with SLC24A5 111Thr homozygotes, individuals with the SLC24A5 111Thr/Ala and 111Ala/Ala genotypes had respectively lower levels of 25(OH)D3 (23.0 and 23.8 nmol/L lower, p-dominant=0.007), and percent 24,25(OH)2D3 (4.1 and 5.2 percent lower, p-dominant=0.003), controlling for tanning bed use, vitamin D/fish oil supplement intake, race/ethnicity, and genetic ancestry. Results were similar with melanin index adjustment, and were not confounded by glucocorticoid, oral contraceptive, or statin use.

Conclusions: The SLC24A5 111Ala allele was associated with lower serum vitamin 25(OH)D3 and lower percent 24,25(OH)2D3, independently from melanin index and West African genetic ancestry.

Keywords: 24,25-Dihydroxyvitamin D 3; 25-hydroxyvitamin D; African Continental Ancestry Group; European Continental Ancestry Group; SLC24A5.

Figures

Figure 1. Selected Vitamin D3 Metabolites

Following skin exposure to UVB light, 7-dehydrocholesterol is converted to pre-vitamin D3, which undergoes a thermal isomerization to form vitamin D3, undergoing activation and catabolism via three main cytochrome P450 enzymes. Vitamin D3 is hydroxylated at C-25 by CYP2R1 [96] to generate the major circulating metabolite, 25(OH)D3. A second hydroxylation step at C-1a occurs in the kidney by CYP27B1 [97], and produces the active form of vitamin D (calcitriol, or 1,25(OH)2D3). CYP24A1 [98] then catabolizes both 25(OH)D3 and 1,25(OH)2D3 via hydroxylation at C-24 and further hydroxylation steps eventually leading to calcitroic acid or 1,25(OH)2D3-26,23 lactone. Major circulating metabolites are shown [99].

Figure 2

Scatter plot of serum 25(OH)D3 levels according to skin melanin index among individuals Homozygous for the SLC24A5 Thr111 allele (Figure 2a) and homozygous or heterozygous for the Ala111 allele (Figure 2b). Regression lines and R2 values appear in the figures. The regression line and R2 value for melanin index in relation to serum 25(OH)D3 for all subjects in the study, regardless of genotype: y = −1.15x + 98.58, R2 = 0.268.