{"doi":"10.1101/2022.03.29.22273133","title":"Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors","abstract":"Abstract Loss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A , most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found ∼1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10 -7 ), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9 . In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors.","journal":"medRxiv","year":2022,"id":302907,"datarank":0.11090354888959127,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.006931471805599452,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.006931471805599452,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9428,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":995285,"name":"B Kavitha","orcid":null,"position":1,"is_corresponding":false},{"id":420190,"name":"Siqi Hu","orcid":"0000-0002-6171-4635","position":2,"is_corresponding":false},{"id":847216,"name":"Roi Isaac","orcid":null,"position":3,"is_corresponding":false},{"id":236908,"name":"Minxian Wang","orcid":"0000-0002-3753-508X","position":4,"is_corresponding":false},{"id":61768,"name":"Xiaomi Du","orcid":"0000-0002-1543-2717","position":5,"is_corresponding":false},{"id":995286,"name":"Camila De Arruda Saldanha","orcid":null,"position":6,"is_corresponding":false},{"id":995287,"name":"Jenny Gylys","orcid":null,"position":7,"is_corresponding":false},{"id":307460,"name":"Ruben Abagyan","orcid":"0000-0001-9309-2976","position":8,"is_corresponding":false},{"id":338082,"name":"Laeya A. Najmi","orcid":null,"position":9,"is_corresponding":false},{"id":38951,"name":"Viswanathan Mohan","orcid":"0000-0001-5038-6210","position":10,"is_corresponding":false},{"id":995288,"name":"Alnylam Human Genetics","orcid":null,"position":11,"is_corresponding":false},{"id":557682,"name":"Jason Flannick","orcid":"0000-0002-3618-795X","position":12,"is_corresponding":false},{"id":24655,"name":"Gina M. Peloso","orcid":"0000-0002-5355-8636","position":13,"is_corresponding":false},{"id":106556,"name":"Philip L.S.M. Gordts","orcid":"0000-0001-7224-4328","position":14,"is_corresponding":false},{"id":246518,"name":"Sven Heinz","orcid":"0000-0002-4665-1007","position":15,"is_corresponding":false},{"id":863151,"name":"Aimée M. Deaton","orcid":"0000-0003-0365-3077","position":16,"is_corresponding":false},{"id":27292,"name":"Amit V. Khera","orcid":"0000-0001-6535-5839","position":17,"is_corresponding":false},{"id":310454,"name":"Jerrold M. Olefsky","orcid":"0000-0003-0392-1705","position":18,"is_corresponding":false},{"id":995017,"name":"Venkatesan Radha","orcid":"0000-0002-4281-0250","position":19,"is_corresponding":false},{"id":828418,"name":"Amit R. Majithia","orcid":"0000-0001-9978-2644","position":20,"is_corresponding":false},{"id":828417,"name":"Natalie DeForest","orcid":"0000-0002-7699-8327","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:20.348385Z","pmid":null,"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":[]}