Genetic determinants of vitamin D status and susceptibility to acute respiratory infection

Abstract

Acute respiratory infections (ARI) are a major global cause of morbidity and mortality. Vitamin D deficiency has been reported to associate with susceptibility to ARI and with greater severity and poorer control of asthma and chronic obstructive pulmonary disease (COPD). Clinical trials of vitamin D for the prevention of ARI have yielded heterogeneous results, with some showing protection and others not. This may reflect variation in the frequency of genetic variants influencing response to vitamin D supplementation in different populations. The impact that genetic variation in the vitamin D pathway has on vitamin D status, disease phenotype and response to vitamin D supplementation in prevention of ARI has not been comprehensively investigated. Methods: I conducted: 1. A systematic review and meta-analysis of clinical studies which have investigated vitamin D as a potential therapy for ARI; 2. Three cross-sectional studies (in n=297 adult asthma patients, n=278 COPD patients, and n=272 older adults) to investigate potential environmental determinants (lifestyle and anthropometric) and genetic determinants (35 single nucleotide polymorphisms [SNP] in 11 vitamin D related genes) of serum 25-hydroxyvitamin D concentration (25[OH]D) and clinical phenotype; 3. Three prospective studies investigating the influence of genetic variation in the vitamin D pathway on a) susceptibility to ARI (main effects analysis) and b) efficacy of vitamin D supplementation for the prevention of ARI (interaction analysis). Results: My systematic review identified consistent reports of an inverse association between vitamin D status and risk of ARI in observational studies, and heterogeneous reports from clinical trials. My cross-sectional studies identified a range of classical environmental factors which predict vitamin D status in the three study populations, but did not identify any genetic variants in the vitamin D pathway that associate with vitamin D status. I identified an association between vitamin D deficiency and decreased lung function in COPD patients, but no associations between vitamin D deficiency and asthma phenotype. Finally, my analysis identified a haplotype of 5 single nucleotide polymorphisms in the vitamin D receptor (VDR) gene which significantly modify the effect of vitamin D supplementation on risk of upper respiratory infection in COPD patients. Conclusions: I identified environmental determinants that predict 25(OH)D concentrations in all three study populations, but only found an association between vitamin D deficiency and disease severity in COPD patients. Furthermore, I identified a haplotype in VDR which modifies the effect of vitamin D supplementation in COPD patients to result in a significantly reduced risk of ARI.