A study of more than 300,000 UK Biobank participants suggests that vitamin D deficiency is a significant risk factor for all-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality. The findings were published in Annals of Internal Medicine.
 
Researchers from the University of South Australia, Adelaide, recruited 307,601 participants in a nonlinear mendelian randomization study to track serum concentrations of 35 confirmed variants of 25-(OH)D, and calculated all-cause and cause-specific mortality for a follow-up period of 14 years which ended in June 2020. They also tracked genetic predictors of low vitamin D status, in order to understand how genetic data related to single measurements of vitamin D status.
 
The average measured concentration of the participants was 45.2 nmol/L, slightly below recommended concentrations of 50 nmol/L. 11.71% of participants fell within the deficiency range, between 10 and 24.9 nmol/L. Higher vitamin D concentrations were found in those living in southern areas, non-smokers, those with higher levels of physical activity, less socioeconomic deprivation, and lower body mass index.
 
During the follow-up, 6.08% (18,700) participants died, with overrepresentation among those with no declared educational status and those who were smokers at baseline.
 
Participants whose vitamin D concentrations were lower than 25 nmol/L were at significantly greater risk of all-cause, cancer, CVD, and respiratory mortality compared to those whose concentrations were above 50 nmol/L. Benefits appeared to plateau when concentrations reached 75 nmol/L.
 
For all four outcomes, the fully adjusted odds for all cause mortality were 36% higher for participants at 25 nmol/L compared with 50 nmol/L. Genetic predictors of vitamin D deficiency were linked to significant associations in all-cause, CVD, and cancer mortality, however, the relationship between genetic predictors and respiratory mortality was not significant.
 
The authors noted that establishing the causal effects of low vitamin D status is challenging to establish, due to a challenge in recruiting people with severe deficiency. They also noted that estimates of the prevalence of vitamin D deficiency range from 5% to 50%, with rates varying by geographic location and population characteristics.
 
“Our study affirms the potential for a notable effect on premature death and the continued need for efforts to abolish vitamin D deficiency,” the authors concluded. “A primary strength of our study is its genetic approach, which has allowed us to safely explore the effects of raising 25-(OH)D in persons with very low concentrations, in contrast with RCTs, where participants would be subjected to potential harm if left deficient […] This is the first study to our knowledge to use the nonlinear Mendelian randomization approach, and we were powered to include more specific causes of death than prior stratified Mendelian randomization work undertaken in this same population.”