{"doi":"10.17615/p2f9-t736","title":"Loss-of-function mutations in SLC30A8 protect against type 2 diabetes","abstract":"Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.","journal":"UNC Libraries","year":2020,"id":141703,"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":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":608140,"name":"Jeff K. Trimmer","orcid":null,"position":1,"is_corresponding":false},{"id":90171,"name":"Pål R. Njølstad","orcid":"0000-0003-0304-6728","position":2,"is_corresponding":false},{"id":38875,"name":"Allan Linneberg","orcid":"0000-0002-0994-0184","position":3,"is_corresponding":false},{"id":256445,"name":"Kāri Stefánsson","orcid":"0000-0003-1676-864X","position":4,"is_corresponding":false},{"id":80560,"name":"David R. Cox","orcid":null,"position":5,"is_corresponding":false},{"id":7046,"name":"Unnur Þorsteinsdóttir","orcid":"0000-0002-7049-2827","position":6,"is_corresponding":false},{"id":547707,"name":"Yik Ying Teo","orcid":null,"position":7,"is_corresponding":false},{"id":45188,"name":"Benjamin F. Voight","orcid":"0000-0002-6205-9994","position":8,"is_corresponding":false},{"id":607705,"name":"Fariba Vaziri‐Sani","orcid":"0000-0002-9953-2829","position":9,"is_corresponding":false},{"id":16064,"name":"Tanya M. Teslovich","orcid":null,"position":10,"is_corresponding":false},{"id":1063,"name":"Leif Groop","orcid":"0000-0002-0187-3263","position":11,"is_corresponding":false},{"id":1089,"name":"Mark I. McCarthy","orcid":"0000-0002-4393-0510","position":12,"is_corresponding":false},{"id":418874,"name":"E Shyong Tai","orcid":null,"position":13,"is_corresponding":false},{"id":608141,"name":"Tuomi, Tiinamaija","orcid":null,"position":14,"is_corresponding":false},{"id":7012,"name":"Patrick Sulem","orcid":"0000-0001-7123-6123","position":15,"is_corresponding":false},{"id":235848,"name":"James G. Wilson","orcid":"0000-0002-2676-8793","position":16,"is_corresponding":false},{"id":1035,"name":"Michael Boehnke","orcid":"0000-0002-6442-7754","position":17,"is_corresponding":false},{"id":16113,"name":"David Altshuler","orcid":"0000-0002-7250-4107","position":18,"is_corresponding":false},{"id":16755,"name":"Oluf Pedersen","orcid":"0000-0002-3321-3972","position":19,"is_corresponding":false},{"id":1165,"name":"Jaakko Tuomilehto","orcid":"0000-0002-8306-6202","position":20,"is_corresponding":false},{"id":426941,"name":"Suzanne B.R. Jacobs","orcid":"0000-0002-8103-1700","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:27.861239Z","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":[]}