Common Genetic Variants and Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver disease associated with insulin resistance and obesity that ranges from simple triglyceride (TG) accumulation in hepatocytes (bland steatosis) to hepatic steatosis with inflammation (steatohepatitis), fibrosis, cirrhosis, and hepatocellular carcinoma.1Neuschwander-Tetri B. Caldwell S. Nonalcoholic steatohepatitis:summary of an AASLD single topic conference.Hepatology. 2003; 37: 1202-1219Crossref PubMed Scopus (1759) Google Scholar, 2White D.L. Kanwal F. El-Serag H.B. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.Clin Gastroenterol Hepatol. 2012; 10: 1342-1359Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar Data from the Dallas Heart Study indicate that NAFLD affects more than one-third of adults, suggesting that ∼78 million individuals in the U.S. population have NAFLD, defined as hepatic TG content ≥5.6%3Browning J.D. Szczepaniak L.S. Dobbins R. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2859) Google Scholar (2010 census). As with alcoholic liver disease, a minority of individuals with hepatic steatosis develop progressive liver disease.4Argo C.K. Northup P.G. Al-Osaimi A.M. et al.Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.J Hepatol. 2009; 51: 371-379Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar Although there are clinical and biochemical indicators that to some degree predict the presence of advanced fibrosis in NAFLD, noninvasively differentiating individuals who have bland steatosis from those with steatohepatitis is currently impossible.5Francque S.M. Verrijken A. Mertens I. et al.Noninvasive assessment of nonalcoholic fatty liver disease in obese or overweight patients.Clin Gastroenterol Hepatol. 2012; 10 (quiz e87): 1162-1168Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 6Torres D.M. Williams C.D. Harrison S.A. Features, diagnosis, and treatment of nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2012; 10: 837-858Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Unlike most other hepatitides, serum aminotransferase levels are not elevated in most individuals with NAFLD and do not predict the presence or absence of steatohepatitis.3Browning J.D. Szczepaniak L.S. Dobbins R. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2859) Google Scholar, 7Mofrad P. Contos M.J. Haque M. et al.Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.Hepatology. 2003; 37: 1286-1292Crossref PubMed Scopus (854) Google Scholar Because of the large number of individuals affected by NAFLD, this creates a dilemma for clinicians: how to identify those patients at greatest risk and most likely to benefit from aggressive therapy. Despite the high prevalence of NAFLD and the risk of progressive liver disease,4Argo C.K. Northup P.G. Al-Osaimi A.M. et al.Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.J Hepatol. 2009; 51: 371-379Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar we are just now beginning to understand the metabolic alterations in humans that lead to hepatic TG accumulation. By and large, lipid accrual in liver during insulin resistance is a consequence of increased fatty acid (FA) release from adipose tissue in conjunction with increased hepatic FA synthesis from carbohydrate precursors.8Diraison F. Moulin P. Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.Diabetes Metab. 2003; 29: 478-485Crossref PubMed Scopus (297) Google Scholar, 9Donnelly K.L. Smith C.I. Schwarzenberg S.J. et al.Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J Clin Invest. 2005; 115: 1343-1351Crossref PubMed Scopus (2283) Google Scholar Although mechanisms available for hepatic lipid export (oxidation and lipoprotein secretion) are increased in NAFLD,10Iozzo P. Bucci M. Roivainen A. et al.Fatty acid metabolism in the liver, measured by positron emission tomography, is increased in obese individuals.Gastroenterology. 2010; 139: 846-856Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 11Sunny N.E. Parks E.J. Browning J.D. et al.Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease.Cell Metab. 2011; 14: 804-810Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 12Fabbrini E. Mohammed B.S. Magkos F. et al.Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.Gastroenterology. 2008; 134: 424-431Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar these processes appear to be saturated, leading to the accumulation of TG within the cytosol of hepatocytes. Taken together, these data represent the basic paradigm for development of hepatic steatosis in humans. The consequences of increased cytosolic neutral lipids are less clear. The dogma that intrahepatic TG accumulation causes insulin resistance is questionable on the basis of human studies.13Tanoli T. Yue P. Yablonskiy D. et al.Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.J Lipid Res. 2004; 45: 941-947Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 14Hooper A.J. Adams L.A. Burnett J.R. Genetic determinants of hepatic steatosis in man.J Lipid Res. 2011; 52: 593-617Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 15Romeo S. Kozlitina J. Xing C. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2097) Google Scholar As a result, the role of TG in the development of progressive liver disease may not be straightforward either. Is TG causative or simply a marker of a more sinister underlying metabolic abnormality? Thirty-three years have elapsed since NAFLD was first described,16Ludwig J. Viggiano T.R. McGill D.B. et al.Nonalcoholic steatohepatitis: Mayo clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar and it appears we may just now be on the threshold of answering this question as a result of recent advances from genome analysis. The ability to rapidly and cost-effectively genotype an individual’s DNA now allows for population-based assessment of the relationship between a disease and a multitude of single nucleotide polymorphisms (SNPs), the most common form of genomic variation.17Manolio T.A. Genomewide association studies and assessment of the risk of disease.N Engl J Med. 2010; 363: 166-176Crossref PubMed Scopus (1089) Google Scholar A genome-wide association study was carried out in 2008 in the Dallas Heart Study and identified a strong association between NAFLD and a missense mutation [Ile148→Met148 (I148M)] in patatin-like phospholipase domain-containing (PNPLA) 3 gene PNPLA3.15Romeo S. Kozlitina J. Xing C. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2097) Google Scholar Multiple subsequent studies have confirmed the association of PNPLA3-I148M with hepatic steatosis (odds ratio, 3.26) as well as steatohepatitis (odds ratio, 3.26) and hepatic fibrosis (odds ratio, 3.27).18Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (644) Google Scholar A subsequent study from the GOLD Consortium19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar also identified additional genomic regions in a population of European ancestry associated with hepatic steatosis alone (glycogen binding subunit of protein phosphatase 1 gene PPP1R3B) or in combination with steatohepatitis (neurocan gene NCAN, glucokinase regulatory protein gene GCKR, and lysophospholipase-like 1 gene LYPLAL1; odds ratios of 1.65, 1.45, and 1.37, respectively). In the current issue of Clinical Gastroenterology and Hepatology, Hernaez et al20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar have attempted to replicate the findings of the GOLD Consortium19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar in a multi-ethnic cohort (N = 4804) from the Third National Health and Nutrition Examination Survey (NHANES III). Unexpectedly, the PNPLA3 variant was associated with hepatic steatosis only among Mexican Americans in this cohort. The minor allele frequencies reported by the authors indicate that variants of NCAN and PPP1R3B associated with NAFLD are much more common among non-Hispanic whites than the other major U.S. ethnic/racial groups. As anticipated, NCAN and PPP1R3B regions were both associated with hepatic steatosis (defined by ultrasound), but only in non-Hispanic whites; no associations were found between these genomic regions and steatosis in non-Hispanic blacks or Mexican Americans. Unlike the initial report,19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar both LYPLAL1 and GCKR were not associated with hepatic steatosis in the NHANES III study population.20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar The authors also reported the relationship between the 5 NAFLD-associated genomic regions19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar and hepatic steatosis with “high” alanine aminotransferase (ALT) levels (>19 IU/L in women and >30 IU/L in men), which the authors claimed to be a surrogate for more severe NAFLD. In this analysis, only the associations with PNPLA3 and GCKR were significant and only in non-Hispanic whites. Variants of NCAN and LYPLAL1, both previously associated with steatohepatitis,19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar were not associated with hepatic steatosis with high ALT in any group. The data of Hernaez et al20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar must be interpreted with consideration given to several caveats. The prevalence of hepatic steatosis for this population-based study was quite high (37%). This is somewhat troubling because ultrasound is not as sensitive or specific for hepatic steatosis as other imaging modalities; sonography fails to detect liver TG when content is just above the upper limit of normal (5.6%–10.0%).21Browning J.D. New imaging techniques for non-alcoholic steatohepatitis.Clin Liver Dis. 2009; 13: 607-619Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This would suggest that the true prevalence of fatty liver in the study population was higher than reported and/or that some individuals were mistakenly classified as having NAFLD. In addition, the study appears to be underpowered to examine associations across ethnic/racial groups, especially for SNPs with a low allelic frequency. Unlike the study from Hernaez et al, a significant association between PNPLA3 and hepatic steatosis has been observed in Hispanics, African Americans, and European Americans in the Dallas Heart Study (Table 1) and multiple other studies.18Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (644) Google Scholar If underpowered, the analysis would be prone to false-negative results, demonstrable for the lack of association of both PNPLA3 and GCKR with hepatic steatosis19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar, 22Palmer N.D. Musani S.K. Yerges-Armstrong L.M. et al.Characterization of European-ancestry NAFLD-associated variants in individuals of African and Hispanic descent.Hepatology. 2013; (April 8. Epub ahead of print)Google Scholar (Table 2).Table 1Odds Ratios (95% Confidence Intervals) of Hepatic Steatosis per PNPLA3-I148M AlleleDHS (n = 2287)NHANES III20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar (n = 4804)All1.59 (1.35–1.89)1.14 (0.97–1.35)Hispanic2.01 (1.46–2.76)1.25 (1.06–1.47)African American1.47 (1.10–1.97)1.05 (0.84–1.31)European American1.48 (1.08–2.01)1.10 (0.91–1.34)NOTE. Odds ratio per allele estimated assuming an additive (multiplicative) model for genotype-relative risk. The odds ratio for 2 alleles (MM genotype) is the square of the corresponding ratio per 1 allele.DHS, Dallas Heart Study. Open table in a new tab Table 2Common Variants Found in Genome-wide Association Studies of NAFLDSteatosisSteatohepatitisDHS (MRS)GOLD Consortium19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar (CT)Palmer et al22Palmer N.D. Musani S.K. Yerges-Armstrong L.M. et al.Characterization of European-ancestry NAFLD-associated variants in individuals of African and Hispanic descent.Hepatology. 2013; (April 8. Epub ahead of print)Google Scholar (CT)NHANES III20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar (US)GOLD Consortium19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar (histology)Odds ratio (95% CI)PNPLA3++++/–aAssociation only significant in Mexican Americans, not entire population.+3.26 (2.11–7.21)PPP1R3B–+++–0.93 (0.68–1.18)NCAN+++++1.65 (1.15–2.87)GCKR+++–+1.45 (1.19–1.86)LYPLAL1–++–+1.37 (1.17–1.57)NOTE. Odds ratio per allele estimated assuming an additive (multiplicative) model for genotype-relative risk. The odds ratio for 2 alleles is the square of the corresponding ratio per 1 allele.CI, confidence interval; CT, computed tomography; DHS, Dallas Heart Study; GOLD, Genetics of Obesity-related Liver Disease; MRS, magnetic resonance spectroscopy; US, ultrasound.a Association only significant in Mexican Americans, not entire population. Open table in a new tab NOTE. Odds ratio per allele estimated assuming an additive (multiplicative) model for genotype-relative risk. The odds ratio for 2 alleles (MM genotype) is the square of the corresponding ratio per 1 allele. DHS, Dallas Heart Study. NOTE. Odds ratio per allele estimated assuming an additive (multiplicative) model for genotype-relative risk. The odds ratio for 2 alleles is the square of the corresponding ratio per 1 allele. CI, confidence interval; CT, computed tomography; DHS, Dallas Heart Study; GOLD, Genetics of Obesity-related Liver Disease; MRS, magnetic resonance spectroscopy; US, ultrasound. Despite these shortcomings, the totality of the data compiled on PNPLA3 and the additional steatosis-associated SNPs have the potential to provide insight into the pathogenesis and progression of NAFLD. Current data from 4 population-based genome-wide association studies supporting the relationship between these 5 common variants and NAFLD are summarized in Table 2. Including the data from Hernaez et al,20Hernaez R. McLean J. Lazo M. et al.Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the Third National Health and Nutrition Examination Survey.Clin Gastroenterol Hepatol. 2013; 11: 1183-1190Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar there is a discrepancy between the studies regarding PPP1R3B, LYPAL1, and GCKR. The risk locus with the strongest association with hepatic steatosis, steatohepatitis, and fibrosis is PNPLA3, with an odds ratio twice that of the other common variants. When examining genome-wide association studies, odds ratios reflect the increased risk associated with having a single copy of the risk allele compared with the wild-type allele. In general, odds ratios below 3.00 are considered to be of modest effect size17Manolio T.A. Genomewide association studies and assessment of the risk of disease.N Engl J Med. 2010; 363: 166-176Crossref PubMed Scopus (1089) Google Scholar; however, each of these genomic regions has the potential to unravel the pathophysiology underlying NAFLD. The rub is that the trait-associated SNP may not be the causative genetic variant but simply a tag representing a larger body of SNPs. As a result, additional work is required to define how these variants alter normal physiology and/or identify the functional genetic variant in the haplotype block represented by the SNP. This process involves fine mapping to determine whether another SNP in the haplotype block has a stronger association with NAFLD than the tag SNP as well as functional studies in animal models that use techniques to knock-out and knock-in the allele of interest. To date, the mechanism whereby PNPLA3-I148M leads to hepatic steatosis remains unclear. PNPLA3 has both lipolytic and lipogenic activity, is expressed in adipose tissue and liver under transcriptional regulation by insulin, and localizes to cytosolic lipid droplets within hepatocytes.23Cohen J.C. Horton J.D. Hobbs H.H. Human fatty liver disease: old questions and new insights.Science. 2011; 332: 1519-1523Crossref PubMed Scopus (1508) Google Scholar In mice, adenoviral-mediated overexpression of PNPLA3-I148M leads to hepatic steatosis,24He S. McPhaul C. Li J.Z. et al.A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J Biol Chem. 2010; 285: 6706-6715Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar whereas inactivation of PNPLA3 does not yield a fatty liver phenotype.25Chen W. Chang B. Li L. et al.Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease.Hepatology. 2010; 16: 16Google Scholar In addition, recent data suggest that the I148M isoform leads to aberrant cytosolic lipid droplet metabolism.26Chamoun Z. Vacca F. Parton R.G. et al.PNPLA3/adiponutrin functions in lipid droplet formation.Biol Cell. 2013; 8: 201200036Google Scholar Taken together, these data provide strong evidence that PNPLA3-I148M is the variant responsible for susceptibility to hepatic steatosis and steatohepatitis in humans; however, additional functional studies are needed to define how the mutation alters hepatic metabolism and potentially provide targets for therapeutic intervention. The precise role of the other common variants in NAFLD susceptibility is less clear. To date, functional studies have not been performed. Both PPP1R3B and GCKR are involved in hepatic glucose metabolism, and a loss-of-function mutation would be anticipated to enhance hepatic FA synthesis.23Cohen J.C. Horton J.D. Hobbs H.H. Human fatty liver disease: old questions and new insights.Science. 2011; 332: 1519-1523Crossref PubMed Scopus (1508) Google Scholar The mechanism by which NCAN and LYPAL1 increase susceptibility to NAFLD and steatohepatitis is unknown. It should also be noted that the association between LYPAL1 and steatohepatitis has yet to be replicated in other cohorts. It is interesting that PPP1R3B, unlike the other variants, does not appear to increase the risk of steatohepatitis.19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar This suggests that the traditional view of NAFLD as a continuum may be incorrect. Likewise, none of these variants impair glycemia or insulin sensitivity, and 2 of them (PPP1R3B and GCKR) appear to be associated with improved glycemia.19Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (662) Google Scholar This further indicates that hepatic TG accumulation is not the cause of insulin resistance. In conclusion, additional work is required to better define the functional consequences of these SNPs and how metabolism is altered in a manner that promotes hepatic TG accumulation and, in most cases, inflammation and fibrosis. Genome-wide association studies of NAFLD have eliminated a priori assumptions and stand poised to yield novel (and perhaps unexpected) insights into the metabolic underpinnings of a highly prevalent and morbid disease. In addition, the abundance of data indicating that PNPLA3-I148M markedly increases susceptibility to steatohepatitis and advanced liver disease suggests that knowledge of this genotype in NAFLD patients for clinical decision-making is important, especially because of the ease and rapidity with which genetic sequencing can currently be carried out. In the immediate future, the association between the other common variants and NAFLD needs to be replicated in other populations to validate the genetic association, especially for those SNPs associated with steatohepatitis. The not-too-distant future holds the promise of individualized NAFLD risk assessment and treatment that are strongly influenced by genotypic (as opposed to phenotypic) factors. However, prospective studies will first be required to validate these SNPs as a useful and cost-effective screening tool, a tool that could enable clinicians to identify those patients with NAFLD at greatest risk for disease progression for the first time. The author thanks Julia Kozlitina for assembling the PNPLA3-I148M allelic odds ratios for hepatic steatosis from the Dallas Heart Study as well as Helen Hobbs and Jay Horton for thoughtful discussions. Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-Defined Steatosis Based on Data From the Third National Health and Nutrition Examination SurveyClinical Gastroenterology and HepatologyVol. 11Issue 9PreviewA genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. Full-Text PDF