title: HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia.
abstract: BACKGROUND
  Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS.
  
  
  RESULTS
  A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10(-3)), *04:05-*03:01 (OR = 2.4, P = 4.4×10(-6)) and *03:01-*02:01 (OR = 2.1, P = 1.0×10(-15)) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10(-11)) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10(-3)) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05:02, *06:01 alleles.
  
  
  CONCLUSIONS
  These findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS.
authors.affiliation: Department Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cocco
authors.forename: Claudia
authors.initials: C
authors.lastname: Sardu
authors.forename: Enrico
authors.initials: E
authors.lastname: Pieroni
authors.forename: Maria
authors.initials: M
authors.lastname: Valentini
authors.forename: Raffaele
authors.initials: R
authors.lastname: Murru
authors.forename: Gianna
authors.initials: G
authors.lastname: Costa
authors.forename: Stefania
authors.initials: S
authors.lastname: Tranquilli
authors.forename: Jessica
authors.initials: J
authors.lastname: Frau
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Coghe
authors.forename: Nicola
authors.initials: N
authors.lastname: Carboni
authors.forename: Matteo
authors.initials: M
authors.lastname: Floris
authors.forename: Paolo
authors.initials: P
authors.lastname: Contu
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
mesh_terms: D016022:Case-Control Studies; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007558:Italy; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains