{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:26:29Z","timestamp":1772994389667,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Large\u2010scale gene\u2013environment interaction (GxE) discovery efforts often involve analytical compromises for the sake of data harmonization and statistical power. Refinement of exposures, covariates, outcomes, and population subsets may be helpful to establish often\u2010elusive replication and evaluate potential clinical utility. Here, we used additional datasets, an expanded set of statistical models, and interrogation of lipoprotein metabolism via nuclear magnetic resonance (NMR)\u2010based lipoprotein subfractions to refine a previously discovered GxE modifying the relationship between physical activity (PA) and HDL\u2010cholesterol (HDL\u2010C). We explored this GxE in the Women's Genome Health Study (WGHS;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200923,294; the strongest cohort\u2010specific signal in the original meta\u2010analysis), the UK Biobank (UKB;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009281,380), and the Multi\u2010Ethnic Study of Atherosclerosis (MESA;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20094587), using self\u2010reported PA (MET\u2010min\/wk) and genotypes at rs295849 (nearest gene:\n                    <jats:italic>LHX1<\/jats:italic>\n                    ). As originally reported, minor allele carriers of rs295849 in WGHS had a stronger positive association between PA and HDL\u2010C (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>int<\/jats:sub>\n                    \u2009=\u20090.002). When testing available NMR metabolites to refine the HDL\u2010C outcome, we found a stronger interaction effect on medium\u2010sized HDL particle concentrations (M\u2010HDL\u2010P;\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>int<\/jats:sub>\n                    \u2009=\u20091.0\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ) than HDL\u2010C. Meta\u2010regression revealed a systematically larger interaction effect in cohorts from the original meta\u2010analysis with a greater fraction of women (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.018). In the UKB, GxE effects were stronger in women and using M\u2010HDL\u2010P as the outcome. In MESA, the primary interaction for HDL\u2010C showed nominal significance (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>int<\/jats:sub>\n                    \u2009=\u20090.013), but without clear sex differences and with a greater magnitude for large HDL\u2010P. Our work provides additional insights into a known gene\u2010PA interaction while illustrating the importance of phenotype and model refinement toward understanding and replicating GxEs.\n                  <\/jats:p>","DOI":"10.1002\/gepi.22607","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T05:28:46Z","timestamp":1736227726000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Refinement of a Published Gene\u2010Physical Activity Interaction Impacting HDL\u2010Cholesterol: Role of Sex and Lipoprotein Subfractions"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-1868","authenticated-orcid":false,"given":"Kenneth E.","family":"Westerman","sequence":"first","affiliation":[{"name":"Clinical and Translational Epidemiology Unit Massachusetts General Hospital Boston Massachusetts USA"},{"name":"Department of Medicine Harvard Medical School Boston Massachusetts USA"},{"name":"Programs in Metabolism and Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuomas O.","family":"Kilpel\u00e4inen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"},{"name":"Novo Nordisk Foundation Center for Genomic Mechanisms of Disease Broad Institute of MIT and Harvard Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Sevilla\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"Clinical and Translational Epidemiology Unit Massachusetts General Hospital Boston Massachusetts USA"},{"name":"Department of Medicine Harvard Medical School Boston Massachusetts USA"},{"name":"Programs in Metabolism and Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margery A.","family":"Connelly","sequence":"additional","affiliation":[{"name":"LabCorp Diagnostics Morrisville North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis C.","family":"Wood","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children's Nutrition Center Baylor College of Medicine Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Y.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Minnesota Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kent D.","family":"Taylor","sequence":"additional","affiliation":[{"name":"The Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center Torrance California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3872-7793","authenticated-orcid":false,"given":"Stephen S.","family":"Rich","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics University of Virginia Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerome I.","family":"Rotter","sequence":"additional","affiliation":[{"name":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics The Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center Torrance California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"Otvos","sequence":"additional","affiliation":[{"name":"Lipoprotein Metabolism Laboratory Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy R.","family":"Bentley","sequence":"additional","affiliation":[{"name":"Center for Research on Genomics and Global Health National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samia","family":"Mora","sequence":"additional","affiliation":[{"name":"Center for Lipid Metabolomics Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Division of Preventive Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Cardiovascular Division Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7554-6783","authenticated-orcid":false,"given":"Hugues","family":"Aschard","sequence":"additional","affiliation":[{"name":"Department of Computational Biology Institut Pasteur, Universit\u00e9 de Paris Paris France"},{"name":"Program in Genetic Epidemiology and Statistical Genetics Harvard T.H. Chan School of Public Health Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8538-2141","authenticated-orcid":false,"given":"D. C.","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Washington University St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Biostatistics Washington University St. Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel I.","family":"Chasman","sequence":"additional","affiliation":[{"name":"Division of Preventive Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Division of Genetics Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Department of Epidemiology Harvard T.H. 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