The link between the mutation — called IL6R–Asp358Ala, rs2228145; or the C allele — and disease severity was first identified in asthma patients in 2012 by Gregory A. Hawkins, PhD, and colleagues at Wake Forest School of Medicine.
They found that people with asthma who inherited this gene variation, or C allele, developed more severe asthma than those who did not.
IL6R codes part of a receptor on cells that binds to and transmits the signals given by interleukin-6 (IL6), a potent signaling molecule (cytokine) that regulates cell growth and differentiation, and plays an important role in the immune response.
Dysregulated production of IL6 and its receptor are implicated in the development of numerous diseases, such as blood cancers, autoimmune disorders, and prostate cancer.
“We knew that interleukin 6 had many functions in the lung, as shown in asthma, but also in muscle and nerves, all three of which are affected in ALS,” Carol Milligan, PhD, a professor of neurobiology and anatomy at the Wake Forest school and the study’s senior author, said in a press release.
IL6 signaling has distinct, localized roles throughout ALS disease progression, including in peripheral muscles, the diaphragm (the dome-shaped muscle at the base of the chest that allows breathing) and lungs, and in the spinal cord and brain, “with some potentially being beneficial and others exacerbating disease progression,” the researchers wrote.
In fact, IL6 is viewed by some as a potential treatment target in ALS. The safety and tolerability of tocilizumab (brand name, Actemra, an arthritis treatment), a IL6R-blocking antibody, was studied for ALS in a Phase 2 clinical trial (NCT02469896) that ended in July 2018. Results do not yet appear to be available.
“We wondered if what they found in asthma may also have a role in ALS patients or maybe explain why the disease progressed faster in some patients but not others,” Milligan said.
To test if ALS patients with the C allele variation in the IL6R gene have worse disease progression than non-mutation carriers, Milligan and her team conducted an observational, case-controlled retrospective study of two groups of patients.
First, they examined blood and cerebrospinal fluid samples (CSF, the fluid that flows in and around the brain and spinal cord) from 47 ALS patients and, as control groups, 46 healthy people, and 23 neurologic diseases (people with other neurological condition that may mimic ALS, such as myasthenia gravis and hereditary spastic paraplegia).
Samples were provided by the Northeastern ALS Consortium (NEALS) Biofluid Repository.
Results confirmed that patients with ALS who carried the C allele had the highest levels of IL6 in their CSF, compared to healthy people and those with other neurological diseases. Elevated IL6 levels were also seen in blood (serum) samples from all ALS patients, compared to healthy subjects, but not in samples from people with other neurological diseases.
To examine if the genetic variation might account for differences in disease progression, the investigators also looked at another group of 35 ALS patients, referred to the Wake Forest Baptist ALS Center Biorepository.
This second group, importantly, had clinical data collected within a year of symptom onset, which was used to determine changes in ALSFRS-R scores, a scale for monitoring disability progression in ALS.
Researchers compared disease progression between those who had the genetic variant and those who did not. Work here concluded that in carriers, the disease progressed faster.
Patients with the IL6R C allele lost more points in the ALSFRS-R per month than non-carriers.
“These results suggest that for individuals inheriting the IL6R C allele, the cytokine [IL6] exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies,” the study concluded.
“This study is the first to show that this polymorphism may modify the course of ALS,” Milligan said. “We hope that our findings may provide a target for a new treatment and lay the groundwork for future clinical trials.”