Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements .
The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics .
However , for vitamin D2 supplementation , increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods .
Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease , cancer , and other causes .
Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with  mortality from cardiovascular , cancer , or other conditions  , under various circumstances .
Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.
CONTEXT Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large , prospect i ve community-based studies . Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity , and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE To investigate whether common variation within genes encoding the vitamin D-binding protein , megalin , cubilin , CYP27B1 , CYP24A1 , and the vitamin D receptor ( VDR ) modify associations of low 25-hydroxyvitamin D with major clinical outcomes . DESIGN , SETTING , AND PARTICIPANTS Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants ( who were recruited from 4 US regions ) from the community-based Cardiovascular Health Study . Participants had serum 25-hydroxyvitamin D measurements in 1992 - 1993 and were followed up for a median of 11 years ( through 2006 ) . Replication meta-analyses were conducted across the independent , community-based US 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 . MAIN OUTCOME MEASURE Composite outcome of incident hip facture , myocardial infa rct ion , cancer , and mortality over long-term follow-up . RESULTS Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta- analysis . Among Cardiovascular Health Study participants , low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 ( 95 % CI , 1.12 - 1.74 ) for those who had 1 minor allele at rs7968585 and 1.82 ( 95 % CI , 1.31 - 2.54 ) for those with 2 minor alleles at rs7968585 . In contrast , there was no evidence of an association ( estimated hazard ratio , 0.93 [ 95 % CI , 0.70 - 1.24 ] ) among participants who had 0 minor alleles at this single-nucleotide polymorphism . CONCLUSION Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor
Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements .
The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics .
However , for vitamin D2 supplementation , increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods .
Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease , cancer , and other causes .
Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with  mortality from cardiovascular , cancer , or other conditions  , under various circumstances .