Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype.

Autor:	Crayle JI; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Rampersaud E; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Myers JR; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Wuu J; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Taylor JP; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Wu G; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Benatar M; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN., Bedlack RS; From the Department of Neurology (J.I.C., R.S.B.), Duke University School of Medicine, Durham, NC; Department of Neurology (J.I.C.), Washington University in Saint Louis, MO; Center for Applied Bioinformatics (E.R., J.R.M., G.W.), St. Jude Children's Research Hospital, Memphis, TN; Department of Neurology (J.W., M.B.), University of Miami Miller School of Medicine, FL; and Department of Cell and Molecular Biology (J.P.T.), St. Jude Children's Research Hospital, Memphis, TN.
Jazyk:	angličtina
Zdroj:	Neurology [Neurology] 2024 Aug 27; Vol. 103 (4), pp. e209696. Date of Electronic Publication: 2024 Jul 30.
DOI:	10.1212/WNL.0000000000209696
Abstrakt:	Background and Objectives: The term "ALS Reversal" describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype. Methods: Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium's Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis. Results: WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1 , is uncertain given the absence of an associated effect on nearby gene transcription. Discussion: We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS. Trial Registration Information: This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.
Databáze:	MEDLINE
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