title: Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).
abstract: Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant association analysis and trans-ethnic meta-analysis of 6201 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low-frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity-specific gene-level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low-frequency/rare variants, while meta-analysis of gene-level results identified a significant association for HGFAC. However, identified single-variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate that genetic factors influencing circulating HGF levels may be complex and ethnically diverse.
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Larson
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Department of Internal Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Berardi
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.affiliation: Department of Epidemiology, University of Pittsburgh, PA, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Wassel
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Kirsch
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Sale
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.affiliation: Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Naomi Q
authors.initials: NQ
authors.lastname: Hanson
authors.affiliation: Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
mesh_terms: D050197:Atherosclerosis / Q000208:ethnology* / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics; D015331:Cohort Studies; D017228:Hepatocyte Growth Factor / Q000097:blood* / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012697:Serine Endopeptidases / Q000235:genetics*; D014481:United States
chemical_list: D017228:Hepatocyte Growth Factor; C081092:HGF activator; D012697:Serine Endopeptidases
keywords: Protein; circulation; genetic association; genome-wide analysis