title: Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals.
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.
authors.affiliation: Don C. Gnocchi Foundation ONLUS, P.le Morandi 6, 20121 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Agliardi
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.forename: Marina
authors.initials: M
authors.lastname: Saresella
authors.forename: Domenico
authors.initials: D
authors.lastname: Caputo
authors.forename: Maurizio A
authors.initials: MA
authors.lastname: Leone
authors.forename: Milena
authors.initials: M
authors.lastname: Zanzottera
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolognesi
authors.forename: Ivana
authors.initials: I
authors.lastname: Marventano
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fasano
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Daghri
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen; D018167:Receptors, Calcitriol