Expanded Genetic Spectrum and Variable Disease Onset in <scp><i>AOPEP</i></scp>‐Associated Dystonia

Menden, Benita; Gutschalk, Alexander; Wunderlich, Gilbert; Haack, Tobias B.

doi:10.1002/mds.29021

Cited by 3 publications

(1 citation statement)

References 6 publications

(17 reference statements)

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“…Observational studies have shown that Lachnospiraceae and Aminopeptidase O Protein co-regulate angiotensin and muscle metabolism (Bai et al, 2021 ; Bajaj et al, 2021 ; Schulz et al, 2021 ; Sun et al, 2021 ). Additionally, research has identified pathogenic genes related to muscle atrophy, such as AOPEP (Fevga et al, 2022 ; Garavaglia et al, 2022 ; Menden et al, 2022 ; Zech et al, 2022 ; Lin et al, 2023 ; Thomsen et al, 2023 ), suggesting a potential novel approach for patients with cachexia to improve muscle symptoms by altering the composition of gut microbiota. Both investigations adopted an observational design.…”

Section: Discussionmentioning

confidence: 99%

Aminopeptidase O Protein mediates the association between Lachnospiraceae and appendicular lean mass

Gao,

Zhou,

Chen

et al. 2024

Front. Microbiol.

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ObjectiveInvestigating the causal relationship between Lachnospiraceae and Appendicular lean mass (ALM) and identifying and quantifying the role of Aminopeptidase O Protein (AOPEP) as a potential mediator.MethodsThe summary statistics data of gut microbiota composition from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen Consortium (n = 13,266). Appendicular lean mass data were obtained from the UK-Biobank (n = 450,243). We conducted bidirectional two-sample Mendelian randomization (MR) analysis using summary-level data from GWAS to investigate the causal relationship between Lachnospiraceae and ALM. Additionally, we employed a drug-targeted MR approach to assess the causal relationship between AOPEP and ALM. Finally, a two-step MR was employed to quantitatively estimate the proportion of the effect of Lachnospiraceae on ALM that is mediated by AOPEP. Cochran's Q statistic was used to quantify heterogeneity among instrumental variable estimates.ResultsIn the MR analysis, it was found that an increase in genetically predicted Lachnospiraceae [OR = 1.031, 95% CI (1.011–1.051), P = 0.002] is associated with an increase in ALM. There is no strong evidence to suggest that genetically predicted ALM has an impact on Lachnospiraceae genus [OR = 1.437, 95% CI (0.785–2.269), P = 0.239]. The proportion of genetically predicted Lachnospiraceae mediated by AOPEP was 34.2% [95% CI (1.3%−67.1%)].ConclusionOur research reveals that increasing Lachnospiraceae abundance in the gut can directly enhance limb muscle mass and concurrently suppress AOPEP, consequently mitigating limb muscle loss. This supports the potential therapeutic modulation of gut microbiota for sarcopenia. Interventions such as drug treatments or microbiota transplantation, aimed at elevating Lachnospiraceae abundance and AOPEP inhibition, synergistically improve sarcopenia in the elderly, thereby enhancing the overall quality of life for older individuals.

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