HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

Abstract

Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P ¼ 0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P ¼ 0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P ¼ 0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P ¼ 0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

Risk conferring genes in multiple sclerosis

“…In a recent study HLA‐B*44 positive patients, especially if HLA‐DRB1*1501 negative, are characterized by lower brain atrophy and T2‐lesion volume. In the presence of HLA‐DRB1*1501, however, HLA‐DRB1*10 was protective, but HLA‐DRB1*04 and HLA‐DRB1*14 were associated with higher T2‐lesion volume [19]. In contrast, an Australian study did not detect any influence of HLA‐DRB1 on disease severity, brain atrophy or cognition [20].…”

HLA-DRB*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

“…Other HLA-variants have been linked with the risk of developing MS and subsequent disease severity, and these may interact with HLA-DRB*1501: For example, Liguori et al found in a longitudinal study of 518 people with MS, that in HLA-DRB1*1501 positive people, HLA-DRB1*10 was associated with a lower rate of WM lesion accrual (Liguori et al, 2011). Because of the limited number of subjects in our cohort we have focused on HLA-DRB1*1501 but future studies are warranted to explore the impact of other polymorphisms on MRI measures in MS.…”

The Role of HLA in MS Susceptibility and Phenotype

“…The only other HLA-DR molecule that has been reported to be positively associated with MS severity is DRB1*04, but only when DRB1*15:01 (Liguori et al 2011) or DRB1*01 (Romero-Pinel et al 2011) is also present in the genotype. These two studies only reported HLA typing to the 2 digit level, but given that DRB1*04 contains a mixture of alleles that do or do not encode proteins with an E at β71/β74 of the HLA-DR molecule, as discussed above, and that the presence or absence of an E at β71/β74 appears to skew the likelihood that the genotype will contain DRB1*15:01, it could be speculated that the correlation with disease severity might only occur in those DRB1*04 molecules with an E at β71/β74.…”

“…The presence of HLA-B*44 (Healy et al 2010), DRB1*14 (in DRB1*15:01 negative genotypes) (Liguori et al 2011) or DRB1*10 (in DRB1*15:01 positive genotypes) (Liguori et al 2011) has been reported to preserve brain parenchymal volume and reduce the burden of T2 hyperintense lesions. Using an extremes of outcome design, in which only patients from the extremes of distribution of long-term outcome are considered, DRB1*01 was found to be underrepresented in malignant vs benign cases of MS (DeLuca et al 2007).…”