HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course

Abstract

Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.

Figure 1

Proportion of affected and unaffected individuals within 549 families with MS grouped by HLA-DR2 genotypes. The data set contained 2,382 individuals comprising 808 patients with MS and 1,574 unaffected family members. A total of 26.9% (n=319) DRX/DRX and 38.7% (n=395) DR2/DRX individuals were affected, in contrast to 52.8% (n=94) DR2/DR2 individuals, demonstrating a dose effect of HLA-DR2 on susceptibility.

Figure 2

A comparison of HLA-DR genotypes for patient subgroups of mild and nonmild MS. Analyses were restricted to patients with disease duration of at least 10 years (n=480). P values are from PROC GENMOD (SAS version 8.2), using logistic regression with correction for familial correlations and adjustment for age at onset and sex. OR of mild MS for DR2 homozygotes (DR2/DR2)=0.3, 95% CI=0.1–0.9, P<.05. Reference group = DRX/DRX genotype. When DR2/DR2 individuals were compared with individuals with DR2/DRX genotype, OR=0.3, 95% CI=0.1–1.1, P<.10. There was no evidence for increased risk of mild MS phenotype in individuals carrying just one copy of HLA-DR2 haplotype, OR=0.8, 95% CI=0.5–1.4, P>.10. Because no DR2/DR2 individuals were present in analyses of mild MS ⩾15 years from onset, the statistical methods used above were not appropriate. Therefore, to determine statistical significance, unrelated mild MS cases were compared to other randomly selected unrelated cases using Fisher’s exact test, as implemented in PROC FREQ (version 8.2, SAS; P<.01; data not shown). Logistic regression modeling with correction for familial correlations and adjustments for age at onset and sex was also used for comparisons of HLA-DR genotypes in patient subgroups of severe and nonsevere MS (data not shown). See text for results.

Figure 3

HLA-DR genotype frequencies for all patients (index cases only, n=549) and most extreme phenotypes, patients with mild (<3 for ⩾15 years) and severe MS. Because no DR2/DR2 individuals were present in the patient group with mild MS, unrelated mild MS cases (n=39) were compared with unrelated severe cases (n=33), using Fisher’s exact test, as implemented in PROC FREQ (version 8.2, SAS). The overall difference between genotype distributions for patients with mild and severe MS was significant (P<.01); 18.2% of patients with severe MS were homozygous for HLA-DR2, compared with 0% in patients with mild MS.