{"doi":"10.17615/e9ag-te86","title":"Association of protein function-altering variants with cardiometabolic traits: the strong heart study","abstract":"Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10–9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10–6; TRPM3, rs760461668, p = 5 × 10–8; SPTY2D1, rs756851199, p = 1.6 × 10–8; and TSPO, rs566547284, p = 2.4 × 10–6). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.","journal":"UNC Libraries","year":2024,"id":498971,"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":0.9134,"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":21821,"name":"Serena Sanna","orcid":"0000-0002-3768-1749","position":1,"is_corresponding":false},{"id":836525,"name":"R.L. Hanson","orcid":null,"position":2,"is_corresponding":false},{"id":605460,"name":"Ying Shan","orcid":"0000-0001-7673-8325","position":3,"is_corresponding":false},{"id":1346633,"name":"Kenneth R. Haack","orcid":null,"position":4,"is_corresponding":false},{"id":605452,"name":"Yun Li","orcid":"0000-0002-8426-565X","position":5,"is_corresponding":false},{"id":6475,"name":"Chris Bizon","orcid":"0000-0002-9491-7674","position":6,"is_corresponding":false},{"id":439829,"name":"Leslie J. Baier","orcid":"0000-0002-8773-9670","position":7,"is_corresponding":false},{"id":529783,"name":"N. Franceschini","orcid":null,"position":8,"is_corresponding":false},{"id":836512,"name":"S. Kobes","orcid":null,"position":9,"is_corresponding":false},{"id":246476,"name":"Shelley A. Cole","orcid":"0000-0002-2651-0127","position":10,"is_corresponding":false},{"id":263009,"name":"Phillip E. Melton","orcid":"0000-0003-4026-2964","position":11,"is_corresponding":false},{"id":1346634,"name":"L.G. Best","orcid":null,"position":12,"is_corresponding":false},{"id":522441,"name":"Çiğdem Köroğlu","orcid":"0000-0002-6778-4773","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:09:45.971055Z","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":[]}