title: Genetic Variants in the Vitamin D Pathway, 25(OH)D Levels, and Mortality in a Large Population-Based Cohort Study.
abstract: Low 25-hydroxyvitamin D [25(OH)D] concentrations have been consistently associated with excess mortality in epidemiological studies, but this association could be due to confounding by health impairments associated with low 25(OH)D levels. An association of vitamin D-related genetic variants with all-cause mortality could strengthen the claims of causality, because this association is assumed to be unaffected by confounding.
  
  
  
  To assess the associations of low 25(OH)D with mortality in the presence or absence of genetic variants in the vitamin D pathway.
  
  
  
  The study consisted of a population-based cohort of 8417 German older adults in whom genetic variants were genotyped.
  
  
  
  The primary outcome measure was all-cause mortality.
  
  
  
  Two single nucleotide polymorphisms (SNPs), rs3755967 (GC) and rs11603330 (DHCR7), were associated with higher risk of low vitamin D status [odds ratio (95% confidence interval) per minor allele, 1.27 (1.18 to 1.36) and 1.16 (1.08 to 1.25), respectively]. Low 25(OH)D (less than the season-specific 33rd percentile) was associated with increased mortality. However, none of the SNPs was associated with increased mortality. Furthermore, the increase in mortality for those with low 25(OH)D was generally smaller in the presence of the risk alleles for low 25(OH)D ["genetically low 25(OH)D"] than in the absence of those risk alleles ["otherwise low 25(OH)D"].
  
  
  
  Although we may have been limited by a low statistical power to detect small associations, our study showed that the strong relationship between low 25(OH)D and increased mortality may be at least partly due to other factors related to low 25(OH)D levels.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.|Network Aging Research, Heidelberg University, 69115 Heidelberg, Germany.|Nuffield Department of Primary Care Health Sciences, University of Oxford, OX2 6GG, Oxford, Great Britain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Ordóñez-Mena
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.|Network Aging Research, Heidelberg University, 69115 Heidelberg, Germany.
authors.forename: Haifa
authors.initials: H
authors.lastname: Maalmi
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.|Network Aging Research, Heidelberg University, 69115 Heidelberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Schöttker
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Saum
authors.affiliation: Saarland Cancer Registry, 66119 Saarbrücken, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Holleczek
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Molecular Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.|Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Division of Clinical Epidemiology and Aging Research, and.|Network Aging Research, Heidelberg University, 69115 Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D000483:Alleles; D015444:Exercise / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood / Q000235:genetics*; D014808:Vitamin D Deficiency / Q000097:blood / Q000235:genetics* / Q000401:mortality*
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D