Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects.

BACKGROUND

The association of HLA A02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw05 significantly enhanced (threefold) the protective effect of HLA A*02.

OBJECTIVES AND METHODS

Since A02-Cw05 is carried by two HLA extended haplotypes characterised by the B4402 and B1801 alleles, respectively, the association analysis was extended to HLA B44 and B18 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 A02-Cw05 combination carrying B44 (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 A02 alone. Logistic regression showed that A02-Cw05 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 B44. Different from A02, the other HLA class I tested markers individually showed no significant (Cw05, B18) 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 A02-Cw05 and A02, 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 A02 and Cw*05 or to a direct interaction between these alleles.