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.
Neurology. 2024 Aug 27;103(4):e209696. doi: 10.1212/WNL.0000000000209696. Epub 2024 Jul 30.
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.
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.
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 ≤ 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 intron and is in near-perfect linkage disequilibrium with a SNV in the promoter region. Both SNVs are associated with decreased frontal cortex 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 , is uncertain given the absence of an associated effect on nearby gene transcription.
We found a significant association between the Reversal phenotype and an noncoding SNV that is associated with 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.
This study was registered with ClinicalTrials.gov (NCT03464903) on March 14, 2018. The first participant was enrolled on June 22, 2018.
“ALS 逆转”一词描述了最初符合肌萎缩侧索硬化症（ALS）诊断标准或具有最符合进行性肌萎缩症（PMA）临床特征但随后表现出明显和持续临床改善的患者。本全基因组关联研究（GWAS）的目的是确定这种不寻常临床表型的相关因素。
参与者从先前创建的具有 ALS 逆转表型的个体数据库中招募。对全基因组测序（WGS）数据与通过 CReATe 联盟的表型-基因型-生物标志物（PGB）研究招募的通常进行性 ALS 的匹配种族患者进行比较。使用来自靶向 ALS 的独立匹配种族 WGS 数据集对这些结果进行复制。具有遗传调控标记和表达数量性状基因座（eQTL）分析的可用数据库进一步探索了显著结果。
对 22 名记录在案的 ALS 逆转患者的 WGS 与 PGB 主要队列（n=103）和靶向 ALS 验证队列（n=140）进行了比较。两个遗传位点达到了统计学意义的预设标准（双侧置换≤0.01），并且在精细映射后仍然合理。第一个位点的主要单核苷酸变异（SNV）是 rs4242007（主要队列 GWAS OR=12.0，95%CI 4.1 至 34.6），它位于内含子中，与启动子区域中的 SNV 近乎完美连锁不平衡。这两个 SNV 都与 eQTL 数据集中的前额皮质表达降低有关。值得注意的是，3 名逆转患者（n=243）均为 rs4242007 纯合子，但没有一名典型进展患者为纯合子。由于附近基因转录没有相关影响，位于附近的第二个位点的重要性尚不确定。
我们发现逆转表型与非编码 SNV 之间存在显著关联，该 SNV 与 IGFBP7 表达相关。这在生物学上是相关的，因为 IGFBP7 是一种报道的胰岛素生长因子-1（IGF-1）受体抑制剂，可激活可能具有神经保护作用的 IGF-1 信号通路。这一发现受到样本量小的限制，但表明进一步探索 IGF-1 通路信号作为 ALS 的治疗机制可能具有一定意义。
本研究于 2018 年 3 月 14 日在 ClinicalTrials.gov（NCT03464903）注册。第一个参与者于 2018 年 6 月 22 日入组。
