{"doi":"10.1101/2024.12.28.630625","title":"Apolipoprotein-L1 G1 variant contributes to hydrocephalus but not to atherosclerosis in apolipoprotein-E knock-out mice","abstract":"Abstract Introduction In USA, six million individuals with Sub-Saharan ancestry carry two APOL1 high-risk variants, which increase the risk for kidney diseases. Whether APOL1 high-risk variants are independent risk factors for cardiovascular diseases is unclear and requires further investigation. Methods We characterized a mouse model to investigate the role of APOL1 in dyslipidemia and cardiovascular diseases. Transgenic mice carrying APOL1 (G0 and G1 variants) on bacterial artificial chromosomes (BAC/APOL1 mice) were crossed with the ApoE knock-out (ApoE-KO) atherosclerosis mouse model. The compound transgenic mice were evaluated for the impact of APOL1 on systemic phenotypes. Results ApoE-KO mice carrying APOL1-G0 and APOL1-G1 did not show differences in the extent of atherosclerotic lesions or aortic calcification, as evaluated by Sudan IV staining and radiographic examination, respectively. However, ∼20% of ApoE-KO; BAC/APOL1-G1 mice developed hydrocephalus and required euthanasia. The hydrocephalus was communicating and likely was due to excess cerebrospinal fluid produced by the choroid plexus, where epithelial cells expressed APOL1. Single-nuclear RNA-seq of choroid plexus identified solute transporter upregulation and mTORC2 pathway activation in APOL1-G1-expressing epithelial cells. Further, in the All of Us cohort, we found higher hydrocephalus prevalence among individuals with the APOL1-G1 variant in both recessive and dominant models, supporting the mouse findings. Conclusion While APOL1-G1 expression in ApoE-KO mice did not worsen cardiovascular disease phenotypes, we uncovered hydrocephalus as a novel APOL1 risk allele-mediated phenotype. These findings extend the spectrum of APOL1-associated pathologies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":508112,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":242908,"name":"Zhihong Yang","orcid":"0000-0002-4133-5099","position":1,"is_corresponding":false},{"id":1326826,"name":"Shinji Ashida","orcid":"0000-0002-2287-2649","position":2,"is_corresponding":false},{"id":242702,"name":"Zu‐Xi Yu","orcid":"0000-0002-1341-4486","position":3,"is_corresponding":false},{"id":921186,"name":"Shashi Shrivastav","orcid":null,"position":4,"is_corresponding":false},{"id":873352,"name":"Krishna Vamsi Rojulpote","orcid":null,"position":5,"is_corresponding":false},{"id":939925,"name":"Piroz Bahar","orcid":"0000-0003-0798-3188","position":6,"is_corresponding":false},{"id":872721,"name":"David Nguyen","orcid":"0000-0002-0548-4564","position":7,"is_corresponding":false},{"id":299704,"name":"Danielle Springer","orcid":"0000-0002-6261-9744","position":8,"is_corresponding":false},{"id":285355,"name":"Jeeva Munasinghe","orcid":"0000-0002-5295-5437","position":9,"is_corresponding":false},{"id":389943,"name":"Matthew F. 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