Parent-of-origin of HLA-DRB1*1501 and age of onset of multiple sclerosis.

Multiple sclerosis (MS) is a complex neurological trait. Allelic variation in the MHC class II region exerts the single strongest effect on MS genetic risk. The clinical onset of the disease is extremely variable, and can range from the first to the ninth decade of life. Epidemiological studies have suggested a modest genetic component to the age of onset (AO) of MS. Previous studies have shown that HLA-DRB11501 may be associated with a younger AO. Here, we sought to uncover any effect of HLA-DRB11501 on the AO of MS in a large Canadian cohort. A total of 1816 MS patients were genotyped for HLA-DRB1. Patients carrying HLA-DRB11501 were shown to have a small, but significantly lower, AO than patients without the allele (P=0.03). HLA-DRB11501 was also shown to reduce the mean AO in both progressive and relapsing forms of the disease. An investigation of parent-of-origin effects indicated that the lower AO for HLA-DRB11501 patients arises from maternally transmitted HLA-DRB11501 haplotypes (maternal HLA-DRB11501 mean AO=28.4 years, paternal=30.3 years; P=0.009). HLA-DRB11501 exerts a modest, but significant effect on the AO of all forms of MS. Parent-of-origin effects at the MHC are further implicated in MS disease pathogenesis.