Genetic variation may modify associations between low vitamin D levels and adverse health outcomes

Findings from a study suggest that certain variations in vitamin D metabolism genes may modify the association of low serum 25-hydroxyvitamin D concentrations with health outcomes such as hip fracture, heart attack, cancer, and death, according to a study appearing in the November 14 issue of JAMA.

Vitamin D status is defined by the circulating concentration of 25-hydroxyvitamin D. Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases, prompting ongoing clinical trials to test whether vitamin D supplementation can reduce the risk of disease development. Certain complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D, according to background information in the article.

Gregory P. Levin, Ph.D., of the University of Washington, Seattle, and colleagues conducted a study to investigate whether known relationships between serum 25-hydroxyvitamin D and certain diseases would differ according to common variation in 25-hydroxyvitamin D metabolism genes. The study consisted of an examination of 141 single-nucleotide polymorphisms (SNPs) in a group of 1,514 white participants from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median (midpoint) of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based U.S. Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

The researchers found a SNP within the vitamin D receptor (VDR) gene that significantly modified associations of low serum 25-hydroxyvitamin D concentration with major health outcomes of hip fracture, heart attack, cancer, and death over long-term follow-up. "Findings were observed within a large community-based study of older adults in the United States and were consistent in magnitude and direction across individual disease outcomes, and replicated in a meta-analysis of 3 large independent cohorts. An additional vitamin D receptor SNP significantly modified the low 25-hydroxyvitamin D-disease association in a meta-analysis that included results from the discovery and replication cohorts. The discovered SNPs, which are common in European populations, identified subsets of individuals for whom associations between low 25-hydroxyvitamin D concentration and disease outcomes were either strongly positive vs. null. These results suggest that individuals with specific 25-hydroxyvitamin D metabolism genotypes maybe particularly susceptible to, or protected from, the potential adverse health effects of low vitamin D."

The authors add that "these findings represent a first step toward identifying what may be clinically relevant effects of 25-hydroxyvitamin D metabolism genes and may contribute to a better understanding of the biological impact of genetic variation within the vitamin D receptor. Further studies are needed to confirm these observed associations and to enhance knowledge of how variation in vitamin D metabolism genes may stratify individuals as to their susceptibility to vitamin D deficiency. Evaluating the identified interactions in randomized clinical trials of vitamin D supplementation, when available, would help to assess the validity of our results and pave the way toward identifying individual patients who may benefit most from vitamin D interventions."