title: Vitamin D status, filaggrin genotype, and cardiovascular risk factors: a Mendelian randomization approach.
abstract: BACKGROUND
  Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome.
  
  
  METHODS
  Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies.
  
  
  RESULTS
  Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference.
  
  
  CONCLUSIONS
  Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.
authors: Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark. tea.skaaby.01@regionh.dk
authors: Tea
authors: T
authors: Skaaby
authors: Lise Lotte Nystrup
authors: LL
authors: Husemoen
authors: Torben
authors: T
authors: Martinussen
authors: Jacob P
authors: JP
authors: Thyssen
authors: Michael
authors: M
authors: Melgaard
authors: Betina Heinsbæk
authors: BH
authors: Thuesen
authors: Charlotta
authors: C
authors: Pisinger
authors: Torben
authors: T
authors: Jørgensen
authors: Jeanne D
authors: JD
authors: Johansen
authors: Torkil
authors: T
authors: Menné
authors: Berit
authors: B
authors: Carlsen
authors: Pal B
authors: PB
authors: Szecsi
authors: Steen
authors: S
authors: Stender
authors: Runa Vavia
authors: RV
authors: Fenger
authors: Mogens
authors: M
authors: Fenger
authors: Allan
authors: A
authors: Linneberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D016014:Linear Models; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D012307:Risk Factors; D014807:Vitamin D / Q000097:blood*; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D014807:Vitamin D