Abstract
The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10−8) and rs6451692 on chromosome 5 (p = 2.55 x 10−8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis.
Highlights
Epidemiological studies have linked variation in the circulating inactive form of vitamin D, 25-hydroxyvitamin D3 (25D), to risk of autoimmune diseases such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus [1,2,3,4,5,6,7], consistent with the known effects of vitamin D as an immune system modulator [8,9,10,11,12]
We primarily focused on African-American individuals as epidemiological data indicate that they have a higher proportion of 25D deficiency, and should be considered prime targets of supplementation studies, which in turn could benefit from knowledge of genetic variation affecting response to supplementation
We found no significant correlations between cell type proportions, as well as baseline levels of the vitamin D receptor gene (VDR), and Imax (S4 Table)
Summary
Epidemiological studies have linked variation in the circulating inactive form of vitamin D, 25-hydroxyvitamin D3 (25D), to risk of autoimmune diseases such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus [1,2,3,4,5,6,7], consistent with the known effects of vitamin D as an immune system modulator [8,9,10,11,12]. Immune cells express the vitamin D receptor (VDR), which when bound by the active 1,25D, forms a heterodimer with the retinoid X receptor (RXR) and translocates to the nucleus, resulting in transcriptional regulation of vitamin D-responsive genes [8, 9, 11, 12, 16]. The genes regulated by 1,25D are involved in various pathways including metabolic regulation, antimicrobial response and inflammatory cytokine response [7, 17,18,19,20,21,22,23]
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