Will Your Immune Genes Make Interferon-β Responded
Interferon-β has been the frontline disease-modifying therapy for people with relapsing–remitting multiple sclerosis (RRMS) for nearly three decades, yet up to half of all patients experience little or no benefit. Predicting in advance who will—and will not—respond could spare non-responders years of unnecessary injections and allow them to start more effective alternatives sooner. Mazdeh et al. explored whether our highly variable human-leukocyte-antigen (HLA) genes, which fine-tune immune responses, can offer that predictive power.
Study design and population
The team followed 231 adults starting low-dose intramuscular interferon-β-1a (the locally produced formulation “CinnoVex”). All participants had RRMS of fewer than ten years’ duration, and none had been treated with another disease-modifying drug. Over the ensuing two years each patient underwent regular neurological examinations and MRI scans. A strict definition of treatment response was used: no clinical relapses and no confirmed progression on the Expanded Disability Status Scale (EDSS).
To put the genetic results in context, the investigators also genotyped 180 ethnically matched healthy volunteers. All HLA-A, -B and -DRB1 alleles were typed with polymerase-chain-reaction sequence-specific primers.
Genetic signals that stood out
After two years, roughly half the cohort met the responder definition. When their HLA makeup was compared with that of non-responders, three signals emerged:
HLA-DRB1*04 appeared almost twice as often in responders as in non-responders, hinting that this class-II allele may enhance interferon efficacy.
A three-locus haplotype—HLA-A*03, B*44, DRB1*04—was found exclusively among responders, raising the possibility that class-I and class-II molecules can cooperate to shape treatment outcome.
Conversely, HLA-B*15 was more common in non-responders, suggesting it might flag patients unlikely to benefit.
Although statistically significant with conventional tests, these associations fell just short of ultra-conservative corrections for multiple comparisons, so they should be viewed as strong leads rather than definitive markers.
How the findings fit the bigger MS puzzle
HLA genes are already the strongest inherited risk factors for developing MS; seeing them influence drug response strengthens the case that the very pathways driving auto-immunity also determine how well immunomodulators work. One plausible mechanism is neutralising antibodies: certain HLA class-II molecules present interferon-β-derived peptides to T-helper cells, prompting an antibody response that blunts the drug. Intriguingly, previous European studies linked DRB1*04 to higher antibody titres, whereas here the same allele tagged responders—a discrepancy that may reflect differences in ancestry, dosing regimen, or the intramuscular route used.
Strengths and caveats to keep in mind
A key strength is the relatively large, ethnically homogeneous Middle-Eastern cohort—an under-represented population in MS pharmacogenetics. The tight clinical endpoint and two-year follow-up add robustness. On the flip side, the HLA typing was low-resolution, meaning different sub-alleles of DRB1*04 (e.g., *04:01 vs *04:05) could not be disentangled. Nor did the study measure neutralising antibodies, so a biologic link between genotype and treatment failure remains hypothetical. Finally, being single-centre and single-ethnicity, replication in other populations is essential.
Clinical take-home message
We are not yet at the point where a quick HLA test can guide first-line therapy in RRMS. Nevertheless, if future multicentre studies verify that DRB1*04 carriers tend to respond well and B*15 carriers fare poorly, neurologists could soon: predict likely benefit before the first injection, steer probable non-responders toward alternative drugs such as fingolimod or ocrelizumab, and tailor monitoring intensity—earlier MRI or antibody testing—for genetically “at-risk” patients.
Looking ahead
High-resolution HLA sequencing combined with genome-wide association and transcriptomic data should pinpoint the exact amino-acid motifs that modulate interferon action. The ultimate goal is a multi-omic response score that outperforms any single biomarker. As newer MS agents proliferate, such precision-medicine tools will make empiric “try-and-see” prescribing a relic of the past.
Bottom line
Mazdeh et al. provide compelling evidence that the same HLA codebook that predisposes people to multiple sclerosis may also dictate how warmly—or coldly—the immune system greets interferon-β therapy. The data are preliminary, yet they move us a step closer to a future where MS treatment is chosen by genotype rather than by trial-and-error.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Mazdeh, M., Taheri, M., Sayad, A., Bahram, S., Omrani, M. D., Movafagh, A., ... & Solgi, G. (2016). HLA genes as modifiers of response to IFN-β-1a therapy in relapsing-remitting multiple sclerosis. Pharmacogenomics, 17(5), 489-498.