{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:59:59Z","timestamp":1777323599807,"version":"3.51.4"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T00:00:00Z","timestamp":1541030400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin\u2010like phospholipase domain containing 3 (<jats:italic toggle=\"yes\">PNPLA3<\/jats:italic>) and transmembrane 6 superfamily member 2 (<jats:italic toggle=\"yes\">TM6SF2<\/jats:italic>) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy\u2010proven NAFLD were enrolled in this cross\u2010sectional study. <jats:italic toggle=\"yes\">PNPLA3 <\/jats:italic>I148M and <jats:italic toggle=\"yes\">TM6SF2 <\/jats:italic>E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP\u2010IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP\u2010IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (<jats:italic toggle=\"yes\">P<\/jats:italic> &lt; 0.001 to 0.02) after adjustment for potential confounders. <jats:italic toggle=\"yes\">PNPLA3<\/jats:italic> 148M and <jats:italic toggle=\"yes\">TM6SF2<\/jats:italic> E167K genotypes were significantly associated with steatosis (<jats:italic toggle=\"yes\">P<\/jats:italic> = 0.003 and <jats:italic toggle=\"yes\">P<\/jats:italic> = 0.02, respectively). A combination of the eLP\u2010IR and genetic score was able to predict the presence of NAS \u22653 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3\u20104 liver fibrosis with an AUROC of 0.82. <jats:italic toggle=\"yes\">Conclusion: <\/jats:italic>This proof\u2010of\u2010concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors.<\/jats:p>","DOI":"10.1002\/hep4.1267","type":"journal-article","created":{"date-parts":[[2018,11,1]],"date-time":"2018-11-01T13:41:14Z","timestamp":1541079674000},"page":"1467-1478","source":"Crossref","is-referenced-by-count":13,"title":["A Pathophysiologic Approach Combining Genetics and Insulin Resistance to Predict the Severity of Nonalcoholic Fatty Liver Disease"],"prefix":"10.1097","volume":"2","author":[{"given":"Christopher J.","family":"Danford","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margery A.","family":"Connelly","sequence":"additional","affiliation":[{"name":"Laboratory Corporation of America Holdings (LabCorp),Morrisville,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Shalaurova","sequence":"additional","affiliation":[{"name":"Laboratory Corporation of America Holdings (LabCorp),Morrisville,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Endocrinology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Herman","sequence":"additional","affiliation":[{"name":"Division of Endocrinology,Duke University Medical Center,Durham,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imad","family":"Nasser","sequence":"additional","affiliation":[{"name":"Department of Pathology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"Otvos","sequence":"additional","affiliation":[{"name":"Laboratory Corporation of America Holdings (LabCorp),Morrisville,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nezam H.","family":"Afdhal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z. Gordon","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2018,11,1]]},"reference":[{"key":"hep41267-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2010meta\u2010analytic assessment of prevalence, incidence, and outcomes","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep41267-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/hep.20466","article-title":"Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity","volume":"40","year":"2004","journal-title":"Hepatology"},{"key":"hep41267-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/aje\/kws448","article-title":"Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988\u20131994","volume":"178","year":"2013","journal-title":"Am J Epidemiol"},{"key":"hep41267-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1053\/j.gastro.2014.11.039","article-title":"Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States","volume":"148","year":"2015","journal-title":"Gastroenterology"},{"key":"hep41267-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1136\/gut.2003.019984","article-title":"Long term prognosis of fatty liver: risk of chronic liver disease and death","volume":"53","year":"2004","journal-title":"Gut"},{"key":"hep41267-bib-0006-20240114","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/hep.25739","article-title":"Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep41267-bib-0007-20240114","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cld.2015.10.007","article-title":"Nonalcoholic fatty liver disease: lipids and insulin resistance","volume":"20","year":"2016","journal-title":"Clin Liver Dis"},{"key":"hep41267-bib-0008-20240114","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","year":"2008","journal-title":"Nat Genet"},{"key":"hep41267-bib-0009-20240114","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/ng.2901","article-title":"Exome\u2010wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease","volume":"46","year":"2014","journal-title":"Nat Genet"},{"key":"hep41267-bib-0010-20240114","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1053\/j.gastro.2016.01.032","article-title":"The MBOAT7\u2010TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep41267-bib-0011-20240114","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.metabol.2016.01.013","article-title":"Noninvasive diagnosis of nonalcoholic fatty liver disease: are we there yet?","volume":"65","year":"2016","journal-title":"Metabolism"},{"key":"hep41267-bib-0012-20240114","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1007\/s00125-017-4340-1","article-title":"Use of HOMA\u2010IR to diagnose non\u2010alcoholic fatty liver disease: a population\u2010based and inter\u2010laboratory study","volume":"60","year":"2017","journal-title":"Diabetologia"},{"key":"hep41267-bib-0013-20240114","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1089\/met.2014.0050","article-title":"Lipoprotein insulin resistance index: a lipoprotein particle\u2010derived measure of insulin resistance","volume":"12","year":"2014","journal-title":"Metab Syndr Relat Disord"},{"key":"hep41267-bib-0014-20240114","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Nonalcoholic Steatohepatitis Clinical Research Network. 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