PMID- 22509268
OWN - NLM
STAT- MEDLINE
DCOM- 20120820
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple 
      sclerosis in Sardinia.
PG  - e33972
LID - 10.1371/journal.pone.0033972 [doi]
LID - e33972
AB  - INTRODUCTION: 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. METHODS AND 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 = 7.6x10(-3)), *04:05-*03:01 (OR = 2.4, 
      P = 4.4x10(-6)) and *03:01-*02:01 (OR = 2.1, P = 1.0x10(-15)) haplotype. In 
      contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4x10(-11)) and the *15:02-*06:01 
      (OR = 0.3, P = 1.5x10(-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.
FAU - Cocco, Eleonora
AU  - Cocco E
AD  - Department Public Health, Clinical and Molecular Medicine, University of 
      Cagliari, Cagliari, Italy.
FAU - Sardu, Claudia
AU  - Sardu C
FAU - Pieroni, Enrico
AU  - Pieroni E
FAU - Valentini, Maria
AU  - Valentini M
FAU - Murru, Raffaele
AU  - Murru R
FAU - Costa, Gianna
AU  - Costa G
FAU - Tranquilli, Stefania
AU  - Tranquilli S
FAU - Frau, Jessica
AU  - Frau J
FAU - Coghe, Giancarlo
AU  - Coghe G
FAU - Carboni, Nicola
AU  - Carboni N
FAU - Floris, Matteo
AU  - Floris M
FAU - Contu, Paolo
AU  - Contu P
FAU - Marrosu, Maria Giovanna
AU  - Marrosu MG
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120411
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Case-Control Studies
MH  - Disease Resistance/*genetics
MH  - Female
MH  - Genetic Predisposition to Disease/*genetics
MH  - HLA-DQ beta-Chains/*genetics
MH  - HLA-DRB1 Chains/*genetics
MH  - *Haplotypes
MH  - Humans
MH  - Inheritance Patterns/genetics
MH  - Italy
MH  - Male
MH  - Multiple Sclerosis/*genetics/immunology
PMC - PMC3324467
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/04/18 06:00
MHDA- 2012/08/21 06:00
PMCR- 2012/04/11
CRDT- 2012/04/18 06:00
PHST- 2012/01/19 00:00 [received]
PHST- 2012/02/24 00:00 [accepted]
PHST- 2012/04/18 06:00 [entrez]
PHST- 2012/04/18 06:00 [pubmed]
PHST- 2012/08/21 06:00 [medline]
PHST- 2012/04/11 00:00 [pmc-release]
AID - PONE-D-12-01934 [pii]
AID - 10.1371/journal.pone.0033972 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e33972. doi: 10.1371/journal.pone.0033972. Epub 2012 Apr 11.