Identification and analysis of 35 genes associated with vitamin D deficiency: A systematic review to identify genetic variants uri icon


  • © 2019 Elsevier LtdVitamin D deficiency is a public health concern associated with, but not limited to, skeletal anomalies, chronic diseases, immune conditions, and cancer, among others. Hypovitaminosis D is mainly associated with environmental and lifestyle factors that affect sunlight exposure. However, genetic factors also influence 25-hydroxyvitamin D (25[OH]D) serum concentration. Although there is available information of genes with clear biological relevance or markers identified by Genome-Wide Association Studies, an overall view and screening tool to identify known genetic causes of altered serum levels of 25(OH)D is lacking. Moreover, there are no studies including the total genetic evidence associated with abnormal serum concentration of 25(OH)D. Therefore, we conducted a de-novo systematic literature review to propose a set of genes comprehensive of all genetic variants reported to be associated with deficiency of vitamin D. Abstracts retrieved from PubMed search were organized by gene and curated one-by-one using the PubTerm web tool. The genes identified were classified according to the type of genetic evidence associated with serum 25(OH)D levels and were also compared with the few commonly screened genes related to vitamin D status. This strategy allowed the identification of 35 genes associated with serum 25(OH)D concentrations, 27 (75%) of which are not commercially available and are not, therefore, analyzed in clinical practice for genetic counseling, nor are they sufficiently studied for research purposes. Functional analysis of the genes identified confirmed their role in vitamin D pathways and diseases. Thus, the list of genes is an important source to understand the genetic determinants of 25(OH)D levels. To further support our findings, we provide a map of the reported functional variants and SNPs not included in ClinVar, minor allelic frequencies, SNP effect sizes, associated diseases, and an integrated overview of the biological role of the genes. In conclusion, we identified a comprehensive candidate list of genes associated with serum 25(OH)D concentrations, most of which are not commercially available, but would prove of importance in clinical practice in screening for patients that should respond to supplementation because of alterations in absorption, patients that would have little benefit because alterations in the downstream metabolism of vitamin D, and to study non-responsiveness to supplementation with vitamin D.

Publication date

  • February 1, 2020