Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis.

Accumulating data linking hypovitaminosis D to cardiovascular (CV) events has contributed to large increases in vitamin D testing and supplementation. To evaluate the merits of this practice, we conducted a systematic review with meta-analysis providing a framework for interpreting the literature associating hypovitaminosis D with increased CV events. Prospective studies were identified by search of MEDLINE and EMBASE from inception to January 2010, restricted to English language publications. Two authors independently extracted data and graded study quality. Pooled relative risks (RR) were calculated using a random effects model. Ten studies met criteria for review and 7 were included in meta-analysis. Pooled RR for CV events using FAIR and GOOD quality studies was 1.67 (95% confidence interval, 1.23-2.28) during an average follow-up of 11.8 years. There was evidence of significant heterogeneity across studies (Q statistics = 16.6, P = 0.01, I = 63.8%), which was eliminated after omitting 2 studies identified by sensitivity analysis (RR, 1.34 [1.08-1.67]; P for heterogeneity =0.33). When restricting analysis to GOOD quality studies (RR, 1.27 [1.04-1.56]), no significant heterogeneity was found (P = 0.602). Systematic review identified significant shortcomings in the literature, including variability in defining vitamin D status, seasonal adjustments, defining and determining CV outcomes, and the use of baseline vitamin D levels. In conclusion, a modest increased risk of CV events associated with hypovitaminosis D is tempered by significant limitations within the current literature. These findings underscore the importance of critical appraisal of the literature, looking beyond reported risk estimates before translating results into clinical practice.

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules.

CD1d molecules bind lipid antigens in the endocytic pathway, and access to the pathway is important for the development of CD1d-restricted natural killer T (NKT) cells. Saposins, derived from a common precursor, prosaposin, are small, heat-stable lysosomal glycoproteins required for lysosomal degradation of sphingolipids. Expression of prosaposin is required for efficient lipid binding and recognition of human CD1d molecules by NKT cells. Despite high sequence homology among the four saposins, they have different specificities for lipid substrates and different mechanisms of action. To determine the saposins involved in promoting lipid binding to CD1d, we expressed prosaposin deletion mutants lacking individual saposins in prosaposin-negative, CD1d-positive cells. No individual saposin proved to be absolutely essential, but the absence of saposin B resulted in the lowest recognition of alpha-galactosylceramide by NKT cells. When recombinant exogenous saposins were added to the prosaposin-negative cells, saposin B was the most efficient in restoring CD1d recognition. Saposin B was also the most efficient in mediating alpha-galactosylceramide binding to recombinant plate-bound CD1d and facilitating NKT cell activation. Saposin B could also mediate lipid binding to soluble CD1d molecules in a T cell-independent assay. The optimal pH for saposin B-mediated lipid binding to CD1d, pH 6, is higher than that of lysosomes, suggesting that saposin B may facilitate lipid binding to CD1d molecules throughout the endocytic pathway.