HLA genetic risk burden extends to MS outcomes

By Lucy Piper

Human leukocyte antigen (HLA) alleles not only increase susceptibility to multiple sclerosis (MS), but also influence the course of the disease, suggests research.

The findings, published in JAMA Neurology, show a robust link between HLA alleles and specific clinical and magnetic resonance imaging (MRI) phenotypic traits.

Cumulative HLA genetic burden (HLAGB) was significantly higher among 586 patients with MS than among 455 individuals without the condition, at a median of 0.7 versus 0.0, and it explained 14.7% of MS risk.

While HLAGB was similar between the 95.8% of patients with relapsing-onset MS and the 4.2% with progressive-onset MS, there was evidence of a gender effect, with both HLAGB scores and HLA-DRB1*15:01 allele load higher in the 68.9% of women. As a result, associations with phenotypic variables were assessed separately for men and women.

Women with high HLAGB scores developed MS at a younger age than those with low scores. This association was mainly driven by the HLA-DRB1*15:01 allele, with each copy associated with a 1.78-year reduction in age at disease onset.

The HLA-DRB1*15:01 allele was also the primary mediator of women with a high HLAGB and a clinically isolated syndrome progressing to clinically definite MS more rapidly than women with low HLAGB, with evidence of a moderate dose effect.

MRI showed that higher HLAGB, again mediated mainly by the HLA-DRB1*15:01 allele, drove the shrinkage of subcortical grey matter fraction and cerebral white matter fraction in women, and, in men, the ratio of cervical cord grey matter area to upper cervical cord area.

Other than this effect, HLAGB was not associated with phenotypes in men, which Roland Henry (University of California, San Francisco, USA) and colleagues say "confirms the existence of sex-specific genotype-phenotype interactions."

The researchers note that subcortical grey matter fraction was the only MS outcome that remained significantly associated with HLAGB after multiple corrections.

Protective effects were seen with the disease resistance HLA class I allele HLA-B*44:02, the presence of which inhibited the decrease of subcortical grey matter fraction, but this did not pass multiple testing corrections.

To overcome linkage disequilibrium and better determine the existence of causal relationships, the team tested the effects of the common HLA-DRB1*15:01 haplotypes separately and found that only the HLA-A*24:02-HLA-B*07:02-HLA-DRB1*15:01 haplotype was significantly associated with the shrinkage of subcortical grey matter fraction.

The other four common *15:01 haplotypes were not, despite accounting for more than half of the study patients with HLA-DRB1*15:01.

In a related editorial, Erin Longbrake and David Hafler, from Yale School of Medicine in New Haven, Connecticut, USA, say that this finding will need to be replicated but that it "is an exciting development in the ongoing effort to elucidate the link between genetics and MS phenotype."

They conclude: "This work underscores the power of large genetic data sets to aid discovery of clinically meaningful genetic markers."

Source: JAMA Neurol 2016; Advance online publication

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