{"doi":"10.1101/2023.08.02.23293554","title":"Strong protective effect of the <i>APOL1</i> p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease","abstract":"ABSTRACT Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.","journal":"medRxiv","year":2023,"id":394906,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":653745,"name":"David J. Friedman","orcid":"0000-0002-0301-9298","position":1,"is_corresponding":false},{"id":305349,"name":"Michelle T. McNulty","orcid":"0000-0002-2080-0940","position":2,"is_corresponding":false},{"id":63302,"name":"Atlas Khan","orcid":"0000-0002-6651-2725","position":3,"is_corresponding":false},{"id":707766,"name":"Brandon M. Lane","orcid":"0000-0002-1158-1117","position":4,"is_corresponding":false},{"id":530006,"name":"Chen Wang","orcid":"0000-0001-9127-0054","position":5,"is_corresponding":false},{"id":1024607,"name":"Juntao Ke","orcid":"0000-0003-2948-9359","position":6,"is_corresponding":false},{"id":694369,"name":"Gina Jin","orcid":null,"position":7,"is_corresponding":false},{"id":1024608,"name":"Benjamin Wooden","orcid":"0000-0003-4286-5005","position":8,"is_corresponding":false},{"id":1024609,"name":"Andrea L. Knob","orcid":"0009-0007-6477-0724","position":9,"is_corresponding":false},{"id":704221,"name":"Tze Yin Lim","orcid":null,"position":10,"is_corresponding":false},{"id":244112,"name":"Gerald B. Appel","orcid":null,"position":11,"is_corresponding":false},{"id":708317,"name":"Kinsie Huggins","orcid":null,"position":12,"is_corresponding":false},{"id":242611,"name":"Lili Liu","orcid":"0000-0002-2622-9669","position":13,"is_corresponding":false},{"id":703482,"name":"Adele Mitrotti","orcid":"0000-0002-7037-7773","position":14,"is_corresponding":false},{"id":1025064,"name":"Megan C. Stangl","orcid":null,"position":15,"is_corresponding":false},{"id":242625,"name":"Andrew S. Bomback","orcid":"0000-0001-5449-1667","position":16,"is_corresponding":false},{"id":705265,"name":"Rik Westland","orcid":"0000-0003-4960-4078","position":17,"is_corresponding":false},{"id":242621,"name":"Monica Bodria","orcid":"0000-0001-9690-9945","position":18,"is_corresponding":false},{"id":242623,"name":"Maddalena Marasà","orcid":"0000-0003-0712-2329","position":19,"is_corresponding":false},{"id":558574,"name":"Ning Shang","orcid":"0000-0001-7040-5204","position":20,"is_corresponding":false},{"id":239731,"name":"David J. Cohen","orcid":"0000-0001-9163-724X","position":21,"is_corresponding":false},{"id":356482,"name":"Russell J. Crew","orcid":"0000-0002-6507-8939","position":22,"is_corresponding":false},{"id":1024610,"name":"William Morello","orcid":"0000-0002-4833-4128","position":23,"is_corresponding":false},{"id":240855,"name":"Pietro A. Canetta","orcid":"0000-0003-1130-5486","position":24,"is_corresponding":false},{"id":237295,"name":"Jai Radhakrishnan","orcid":"0000-0003-3157-5141","position":25,"is_corresponding":false},{"id":703483,"name":"Jeremiah Martino","orcid":"0000-0001-8398-2801","position":26,"is_corresponding":false},{"id":1025065,"name":"Qingxue Liu","orcid":null,"position":27,"is_corresponding":false},{"id":23578,"name":"Wendy K. Chung","orcid":"0000-0003-3438-5685","position":28,"is_corresponding":false},{"id":1025066,"name":"Angelica Espinoza","orcid":null,"position":29,"is_corresponding":false},{"id":58247,"name":"Yuan Luo","orcid":"0000-0003-0195-7456","position":30,"is_corresponding":false},{"id":58249,"name":"Wei‐Qi Wei","orcid":null,"position":31,"is_corresponding":false},{"id":58243,"name":"Qiping Feng","orcid":"0000-0002-6213-793X","position":32,"is_corresponding":false},{"id":2012,"name":"Chunhua Weng","orcid":"0000-0002-9624-0214","position":33,"is_corresponding":false},{"id":948140,"name":"Yilu Fang","orcid":"0000-0002-2681-1931","position":34,"is_corresponding":false},{"id":58250,"name":"Iftikhar J. Kullo","orcid":"0000-0002-6524-3471","position":35,"is_corresponding":false},{"id":1024611,"name":"Mohammadreza Naderian","orcid":"0000-0003-1827-3173","position":36,"is_corresponding":false},{"id":386043,"name":"Nita A. Limdi","orcid":"0000-0002-4672-8406","position":37,"is_corresponding":false},{"id":24975,"name":"Marguerite R. Irvin","orcid":"0000-0002-1442-2023","position":38,"is_corresponding":false},{"id":25027,"name":"Hemant K. Tiwari","orcid":null,"position":39,"is_corresponding":false},{"id":104006,"name":"Sumit Mohan","orcid":"0000-0002-5305-9685","position":40,"is_corresponding":false},{"id":272834,"name":"Maya K. Rao","orcid":null,"position":41,"is_corresponding":false},{"id":319710,"name":"Geoffrey K. Dube","orcid":"0000-0003-0206-5652","position":42,"is_corresponding":false},{"id":397017,"name":"Ninad S. Chaudhary","orcid":"0000-0003-1350-1093","position":43,"is_corresponding":false},{"id":261906,"name":"Orlando M. Gutiérrez","orcid":"0000-0001-6593-3571","position":44,"is_corresponding":false},{"id":74972,"name":"Suzanne E. Judd","orcid":"0000-0001-7594-6587","position":45,"is_corresponding":false},{"id":51219,"name":"Mary Cushman","orcid":"0000-0002-7871-6143","position":46,"is_corresponding":false},{"id":515141,"name":"Leslie A. Lange","orcid":"0000-0002-8077-4975","position":47,"is_corresponding":false},{"id":11309,"name":"Ethan M. Lange","orcid":"0000-0001-7075-4287","position":48,"is_corresponding":false},{"id":1025067,"name":"Daniel L. Bivona","orcid":null,"position":49,"is_corresponding":false},{"id":1024612,"name":"Miguel Verbitsky","orcid":"0000-0002-7066-0552","position":50,"is_corresponding":false},{"id":33037,"name":"Cheryl A. Winkler","orcid":"0000-0001-5552-0917","position":51,"is_corresponding":false},{"id":225761,"name":"Jeffrey B. Kopp","orcid":"0000-0001-9052-186X","position":52,"is_corresponding":false},{"id":312067,"name":"Dominick Santoriello","orcid":"0000-0001-5854-4236","position":53,"is_corresponding":false},{"id":312069,"name":"Ibrahim Batal","orcid":"0000-0002-0686-5457","position":54,"is_corresponding":false},{"id":1024613,"name":"Sérgio Veloso Brant Pinheiro","orcid":"0000-0002-2164-2374","position":55,"is_corresponding":false},{"id":1169732,"name":"Eduardo Oliveira","orcid":"0000-0002-8863-6139","position":56,"is_corresponding":false},{"id":1024614,"name":"Ana Cristina Simões e Silva","orcid":"0000-0001-9222-3882","position":57,"is_corresponding":false},{"id":242658,"name":"Isabella Pisani","orcid":"0000-0002-7770-2647","position":58,"is_corresponding":false},{"id":263579,"name":"Enrico Fiaccadori","orcid":"0000-0002-6532-7675","position":59,"is_corresponding":false},{"id":436105,"name":"Fangming Lin","orcid":"0000-0003-0858-5472","position":60,"is_corresponding":false},{"id":242649,"name":"Loreto Gesualdo","orcid":"0000-0002-4861-0911","position":61,"is_corresponding":false},{"id":242665,"name":"Antonio Amoroso","orcid":"0000-0002-9437-9407","position":62,"is_corresponding":false},{"id":242657,"name":"Gian Marco Ghiggeri","orcid":"0000-0003-3659-9062","position":63,"is_corresponding":false},{"id":240850,"name":"Vivette D. D’Agati","orcid":"0000-0001-7760-6965","position":64,"is_corresponding":false},{"id":1024615,"name":"Riccardo Magistroni","orcid":"0000-0002-3319-0248","position":65,"is_corresponding":false},{"id":24490,"name":"Eimear E. Kenny","orcid":"0000-0001-9198-759X","position":66,"is_corresponding":false},{"id":1082,"name":"Ruth J. F. Loos","orcid":"0000-0002-8532-5087","position":67,"is_corresponding":false},{"id":1024616,"name":"Giovanni Montini","orcid":"0000-0002-7350-4475","position":68,"is_corresponding":false},{"id":317473,"name":"Friedhelm Hildebrandt","orcid":"0000-0002-7130-0030","position":69,"is_corresponding":false},{"id":51474,"name":"Dirk S. Paul","orcid":"0000-0002-8230-0116","position":70,"is_corresponding":false},{"id":40850,"name":"Slavé Petrovski","orcid":"0000-0002-1527-961X","position":71,"is_corresponding":false},{"id":30756,"name":"David B. Goldstein","orcid":"0000-0002-1111-2820","position":72,"is_corresponding":false},{"id":5968,"name":"Matthias Kretzler","orcid":"0000-0003-4064-0582","position":73,"is_corresponding":false},{"id":305348,"name":"Rasheed Gbadegesin","orcid":"0000-0001-5641-6644","position":74,"is_corresponding":false},{"id":240854,"name":"Ali G. Gharavi","orcid":"0000-0003-2801-233X","position":75,"is_corresponding":false},{"id":58245,"name":"Krzysztof Kiryluk","orcid":"0000-0002-5047-6715","position":76,"is_corresponding":false},{"id":242627,"name":"Matthew G. Sampson","orcid":"0000-0001-9560-076X","position":77,"is_corresponding":false},{"id":54020,"name":"Martin R. Pollak","orcid":"0000-0002-2396-9725","position":78,"is_corresponding":false},{"id":242626,"name":"Simone Sanna‐Cherchi","orcid":"0000-0002-6185-948X","position":79,"is_corresponding":false},{"id":1034274,"name":"Yask Gupta","orcid":"0000-0003-3473-0100","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:18.686170Z","pmid":"37577628","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}