Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals

Brain Behav Immun. 2011 Oct;25(7):1460-7. doi: 10.1016/j.bbi.2011.05.015. Epub 2011 Jun 12.

Abstract

Multiple sclerosis (MS) is an autoimmune disease with a multifactorial etiology. The HLA-DRB1*15 allele, is the main genetic risk factor for MS in Caucasians; recent findings showed that the transcription of this molecule is regulated by the vitamin D/vitamin D receptor (VDR) complex. We analyzed SNPs within the VDR gene in association with the HLA-DRB1 locus in 641 MS patients diagnosed according to McDonald criteria and 558 age- and sex-matched healthy controls, to verify possible correlations between the vitamin D/VDR complex, HLA-DRB1, and susceptibility to MS. Results confirmed that HLA-DRB1*15 is a strong predisposing allele (p<1×10(-7); OR: 3.04; 95% CI: 2.02-4.60) for MS. Cosegregation analyses of VDR SNPs with HLA-DRB1*15 indicated a reduction of risk for MS given by the presence of the -DRB1*15-rs731236 T VDR haplotype (p=9.5×10(-5); OR: 2.52; 95% CI: 1.56-4.06) and, conversely, an augmented risk for disease associated with the -DRB1*15-rs731236 C VDR haplotype. Analyses performed on HLA-DRB1*15-positive MS patients and HC alone confirmed the protective role of rs731236 TT VDR genotype (p(y)=0.004; OR: 0.53; 95% CI: 0.33-0.83); notably, FACS, PCR, and confocal microscopy analyses showed that rs731236 TT genotype is associated with an augmented VDR expression in MBP-stimulated PBMC from patients. In conclusion, rs731236 TT VDR genotype modulates VDR expression and confers protection against MS in HLA-DRB1*15-positive individuals. Results herein offer a model justifying the interaction between the major genetic (HLA-DRB*15) and environmental (vitamin D) factors associated with MS onset.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • HLA-DRB1 Chains / immunology
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology
  • Polymorphism, Single Nucleotide*
  • Receptors, Calcitriol / genetics*
  • Risk Factors
  • White People / genetics

Substances

  • HLA-DRB1 Chains
  • HLA-DRB1*15 antigen
  • Receptors, Calcitriol