{"doi":"10.17615/b3ee-r077","title":"Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol","abstract":"Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r2 > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10−12). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT– haplotype] versus 16-fold [CC+ haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus.","journal":"UNC Libraries","year":2020,"id":141187,"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":0.9532,"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":11271,"name":"Karen L. Mohlke","orcid":"0000-0001-6721-153X","position":1,"is_corresponding":false},{"id":236714,"name":"Mete Civelek","orcid":"0000-0002-8141-0284","position":2,"is_corresponding":false},{"id":531594,"name":"Ying Wu","orcid":"0000-0002-5635-8090","position":3,"is_corresponding":false},{"id":548484,"name":"Marie P. Fogarty","orcid":"0000-0001-9011-5749","position":4,"is_corresponding":false},{"id":548235,"name":"Amanda F. Marvelle","orcid":null,"position":5,"is_corresponding":false},{"id":255376,"name":"Swarooparani Vadlamudi","orcid":"0000-0001-9650-768X","position":6,"is_corresponding":false},{"id":19624,"name":"Antti J. Kangas","orcid":"0000-0001-7492-1732","position":7,"is_corresponding":false},{"id":22013,"name":"Anne Jackson","orcid":"0000-0002-9672-2547","position":8,"is_corresponding":false},{"id":1035,"name":"Michael Boehnke","orcid":"0000-0002-6442-7754","position":9,"is_corresponding":false},{"id":21672,"name":"Martin L. Buchkovich","orcid":"0000-0002-4684-081X","position":10,"is_corresponding":false},{"id":275123,"name":"Tamara S. Roman","orcid":"0000-0003-1056-5294","position":11,"is_corresponding":false},{"id":607178,"name":"Arlene J. Gonzalez","orcid":null,"position":12,"is_corresponding":false},{"id":16068,"name":"Kyle J. Gaulton","orcid":"0000-0003-1318-7161","position":13,"is_corresponding":false},{"id":90056,"name":"Jeroen R. Huyghe","orcid":"0000-0001-6027-9806","position":14,"is_corresponding":false},{"id":277044,"name":"Markku Laakso","orcid":"0000-0002-3394-7749","position":15,"is_corresponding":false},{"id":16065,"name":"Christian Fuchsberger","orcid":"0000-0002-5918-8947","position":16,"is_corresponding":false},{"id":15457,"name":"Aldons J. Lusis","orcid":"0000-0001-9013-0228","position":17,"is_corresponding":false},{"id":460895,"name":"Praveen Sethupathy","orcid":"0000-0001-9887-8871","position":18,"is_corresponding":false},{"id":21907,"name":"Johanna Kuusisto","orcid":"0000-0001-6550-3176","position":19,"is_corresponding":false},{"id":19633,"name":"Mika Ala‐Korpela","orcid":"0000-0001-5905-1206","position":20,"is_corresponding":false},{"id":19625,"name":"Pasi Soininen","orcid":null,"position":21,"is_corresponding":false},{"id":19902,"name":"Francis S. Collins","orcid":"0000-0002-1023-7410","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:24.429854Z","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":[]}