A genetic variant in the IGFBP7 gene associated with amyotrophic lateral sclerosis (ALS) reversal was identified in a recent study.
A recent genome-wide association study published in Neurology investigated genetic factors linked to the rare ALS reversal phenotype, where patients initially diagnosed with ALS or progressive muscular atrophy exhibit significant and sustained clinical improvement. Whole-genome sequencing data from 22 patients with the ALS reversal subtype was compared with data from 243 patients with typically progressive ALS from the Clinical Research in ALS and Related Disorders for Therapeutic Development Consortium (CReATe) and Target ALS cohorts. The study used genetic regulatory markers and expression quantitative trait loci (eQTL) analysis to validate significant findings.
The participant counts for each group were: 22 ALS reversal patients, 103 ALS patients from the CReATe Consortium, and 140 ALS patients from the Target ALS cohort. Seven participants reported having a family history of neurological disorders such as ALS, dementia, Parkinson's disease, multiple sclerosis, narcolepsy, and essential tremor.
Two genetic loci were found to be significantly associated with the ALS reversal phenotype. The primary locus, rs4242007, located in the intron of IGFBP7, was associated with an odds ratio of 12.0 for ALS reversal (95% confidence interval = 4.1-34.6) and showed decreased IGFBP7 expression in eQTL data sets. Three patients with the ALS reversal phenotype were homozygous for rs4242007, while none of the 243 of the patients with typically progressive ALS shared this genotype. The second identified genetic locus, near GRIP1, lacked evidence of an effect on gene transcription, making its significance uncertain.
The study identified a significant association between the ALS reversal phenotype and a noncoding variant in IGFBP7. This variant may inhibit the insulin growth factor-1 (IGF-1) receptor, a pathway that could offer neuroprotective effects. The small sample size of the study limits the findings, and additional research is required to validate the role of IGF-1 signaling in ALS, said the study authors.
The authors reported no potential conflict of interest.
