Asthma more closely associated with poor VDBP gene than with poor Vitamin D level – June 2014

Effect of Vitamin D Binding Protein (DBP) Genotype on the Development of Asthma in Children

Ann Allergy Asthma Immunol. 2014 Jun; 112(6): 519–524. doi: 10.1016/j.anai.2014.03.017
Aledie Navas-Nazario, M.D.,1 FangYong Li, MPH, MD,2 Veronika Shabanova, MPH,2 Pnina Weiss, M.D.,1 David EC Cole, M.D., Ph.D.,3 Thomas O. Carpenter, M.D.,4 and Alia Bazzy-Asaad, M.D.1

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Introduction
Recently there has been extensive interest in “non classical” functions of vitamin D, in contrast to the classical role of vitamin D in the regulation of total body calcium homeostasis. As vitamin D has been implicated in the regulation of immune cells, such as T and B lymphocytes, macrophages and dendritic cells1–3, we considered the possibility of a role for vitamin D in the mediation of inflammatory diseases including asthma.

Several studies have found that circulating 25-hydroxyvitamin D (25-(OH)D) levels are associated with risk for developing childhood asthma2,3, wheezing4–6asthma severity and asthma control7–11. Maternal vitamin D intake during pregnancy was found to be inversely related to asthma symptoms in early childhood12,13. Higher 25-(OH)D levels have been associated with significantly reduced odds of hospitalizations for asthma, while low serum levels of this metabolite were associated with increased rates of hospitalization for asthma, increased use of controller medications and increased airway responsiveness.9. African American adolescents with asthma had significantly lower serum 25-(OH)D levels compared to control subjects without asthma14. In contrast to these findings, there have also been reports of lack of a relation between 25-(OH)D levels and asthma,5,15–17 raising the question whether factors in the vitamin D metabolism pathway other than metabolite level may be a determining factor for asthma risk.

Vitamin D deficiency, as indicated by levels of 25-(OH)D less than 20 ng/ml (50 nmol/L), is not infrequent in the general population18 or in children19. Known risk factors for vitamin D deficiency include lack of sunlight exposure, non-white ethnicity and increased skin pigmentation, obesity, and indoor confinement14. However 25-(OH)D levels may be influenced by other unidentified factors, raising the distinct consideration of genetic influences on circulating levels. Candidate genes that have been identified as potential determinants of circulating 25-(OH)D in GWAS studies include VDR (encoding the vitamin D receptor), CYP2R1 (encoding the microsomal 25-hydroxylase), and GC, encoding the vitamin D binding protein (DBP), which binds circulating vitamin D metabolites20. GC is a highly polymorphic gene located at 4q11–1321. Many variants of DBP have been characterized by isoelectric focusing22, but attention has increasingly centered on the two most common genetic variants—D432E (rs.7041 – c.1296TNG) and T436K (rs.4588 – c.1307CNA). These single nucleotide polymorphisms (SNPs) in the coding region of exon 11 of GC encode the electrophoretically distinguishable proteins Gc1F/Gc1S and Gc2, respectively. Both variants show ethnic-specific allele frequencies based on large population studies23, and have been shown to correlate with vitamin D metabolite levels24–26. More recently we have shown that the T436K variant in DBP is an important determinant of 25-(OH)D levels in healthy infants and toddlers27. We therefore hypothesized that specific DBP variants associated with circulating 25-(OH)D levels would be associated with increased risk for developing asthma in children.