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Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.
Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P; Vadlamudi, Swarooparani; Gonzalez, Arlene J; Buchkovich, Martin L; Huyghe, Jeroen R; Fuchsberger, Christian; Jackson, Anne U; Wu, Ying; Civelek, Mete; Lusis, Aldons J; Gaulton, Kyle J; Sethupathy, Praveen; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L.
  • Roman TS; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Marvelle AF; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Fogarty MP; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Vadlamudi S; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Gonzalez AJ; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Buchkovich ML; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Huyghe JR; Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • Fuchsberger C; Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • Jackson AU; Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wu Y; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Civelek M; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biomedical Engineering, Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
  • Lusis AJ; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Deparment of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of
  • Gaulton KJ; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • Sethupathy P; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Kangas AJ; Computational Medicine, Institute of Health Sciences, University of Oulu, 90014 Oulu, Finland.
  • Soininen P; Computational Medicine, Institute of Health Sciences, University of Oulu, 90014 Oulu, Finland; Nuclear Magnetic Resonance Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
  • Ala-Korpela M; Computational Medicine, Institute of Health Sciences, University of Oulu, 90014 Oulu, Finland; Nuclear Magnetic Resonance Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland; Oulu University Hospital, 90220 Oulu, Finland; Computational Medicine, School o
  • Kuusisto J; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland.
  • Collins FS; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Laakso M; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland.
  • Boehnke M; Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  • Mohlke KL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: mohlke@med.unc.edu.
Am J Hum Genet ; 97(6): 801-15, 2015 Dec 03.
Article en En | MEDLINE | ID: mdl-26637976
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 (r(2) > 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Genoma Humano / N-Acetilgalactosaminiltransferasas / Proteína beta Potenciadora de Unión a CCAAT / Sitios de Carácter Cuantitativo / HDL-Colesterol Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2015 Tipo del documento: Article
Texto completo
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PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Genoma Humano / N-Acetilgalactosaminiltransferasas / Proteína beta Potenciadora de Unión a CCAAT / Sitios de Carácter Cuantitativo / HDL-Colesterol Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Año: 2015 Tipo del documento: Article