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Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Tertiary referral center.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49\u2005\u00b1\u20059 years, body mass index [BMI] 43.2\u2005\u00b1\u20056.8 kg\/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45\u2005\u00b1\u200514 years, BMI 29.7\u2005\u00b1\u20055.7 kg\/m2).<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcome Measures<\/jats:title><jats:p>Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgaa729","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T12:04:48Z","timestamp":1602849888000},"page":"e300-e315","source":"Crossref","is-referenced-by-count":43,"title":["The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-679X","authenticated-orcid":false,"given":"Panu K","family":"Luukkonen","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"Minerva Foundation Institute for Medical Research, Helsinki, Finland"},{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-9324","authenticated-orcid":false,"given":"Sami","family":"Qadri","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"Minerva Foundation Institute for Medical Research, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina E","family":"Lehtim\u00e4ki","sequence":"additional","affiliation":[{"name":"HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Juuti","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Abdominal 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