Background The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02.
Objectives and methods Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios).
Results A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10-5) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10-4) and in a combined cohort of UK families and case–controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10-7; UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers.
Conclusions This study identified at least two independent protective effects which are tagged by A*02–Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.
- Multiple sclerosis
- HLA class I markers
- genetic association
- molecular genetics
- immunology (including allergy)
- multiple sclerosis
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Funding NB and LC were supported by a fellowship from FISM (2003/B/2, 2009/B/1). LB was supported by a PhD Lagrange Fellowship.
Competing interests None to declare.
Ethics approval This study was conducted with the approval of the local ethics committee of the different clinical centres.
Provenance and peer review Not commissioned; externally peer reviewed.
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