{"doi":"10.17615/yerb-fr65","title":"Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk","abstract":"Background: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. Objectives: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. Methods: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. Results: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). Conclusions: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.","journal":"UNC Libraries","year":2024,"id":499009,"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":0.9373,"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":601165,"name":"Tapani Ebeling","orcid":"0000-0003-0323-8893","position":1,"is_corresponding":false},{"id":529785,"name":"E. Selvin","orcid":null,"position":2,"is_corresponding":false},{"id":240595,"name":"Elena V. Feofanova","orcid":"0000-0003-1428-7199","position":3,"is_corresponding":false},{"id":122478,"name":"J. Coresh","orcid":null,"position":4,"is_corresponding":false},{"id":1112,"name":"Veikko Salomaa","orcid":"0000-0001-7563-5324","position":5,"is_corresponding":false},{"id":626757,"name":"Sara B. Seidelmann","orcid":null,"position":6,"is_corresponding":false},{"id":982700,"name":"B Claggett","orcid":null,"position":7,"is_corresponding":false},{"id":27970,"name":"Scott D. Solomon","orcid":"0000-0003-3698-9597","position":8,"is_corresponding":false},{"id":41149,"name":"S. Cheng","orcid":"0000-0001-5079-402X","position":9,"is_corresponding":false},{"id":262832,"name":"Amil M. Shah","orcid":"0000-0003-1056-4451","position":10,"is_corresponding":false},{"id":431554,"name":"E. Boerwinkle","orcid":null,"position":11,"is_corresponding":false},{"id":529783,"name":"N. Franceschini","orcid":null,"position":12,"is_corresponding":false},{"id":1346723,"name":"Hannu Puolijoki","orcid":null,"position":13,"is_corresponding":false},{"id":56931,"name":"Calum A. MacRae","orcid":"0000-0001-5181-2664","position":14,"is_corresponding":false},{"id":588762,"name":"Bing Yu","orcid":"0000-0001-6013-5220","position":15,"is_corresponding":false},{"id":889693,"name":"Mikko Kuokkanen","orcid":"0000-0003-4375-9327","position":16,"is_corresponding":false},{"id":1247576,"name":"M. Perola","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"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":[]}