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      Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

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          Abstract

          Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10 −10) and with hepatic inflammation (P=3.7×10 −4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

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          Most cited references 22

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          The natural history of nonalcoholic fatty liver disease: a population-based cohort study.

          The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1-23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003-1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7-2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3-5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2-7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low.
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            Whole-genome patterns of common DNA variation in three human populations.

             D A Hinds (2005)
            Individual differences in DNA sequence are the genetic basis of human variability. We have characterized whole-genome patterns of common human DNA variation by genotyping 1,586,383 single-nucleotide polymorphisms (SNPs) in 71 Americans of European, African, and Asian ancestry. Our results indicate that these SNPs capture most common genetic variation as a result of linkage disequilibrium, the correlation among common SNP alleles. We observe a strong correlation between extended regions of linkage disequilibrium and functional genomic elements. Our data provide a tool for exploring many questions that remain regarding the causal role of common human DNA variation in complex human traits and for investigating the nature of genetic variation within and between human populations.
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              Molecular mediators of hepatic steatosis and liver injury.

              Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nature genetics
                1061-4036
                1546-1718
                30 September 2008
                25 September 2008
                December 2008
                1 June 2009
                : 40
                : 12
                : 1461-1465
                Affiliations
                [1 ] Donald W. Reynolds Cardiovascular Clinical Research Center, Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA
                [2 ] Department of Clinical Sciences, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA
                [3 ] Department of Statistical Science, Southern Methodist University, Dallas, Texas 75275-0332, USA
                [4 ] Perlegen Sciences, Mountain View, California, 94043, USA
                [5 ] Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA
                [6 ] Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA
                [7 ] Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, Texas 75390-8591, USA
                Author notes
                Correspondence should be addressed to H.H.H. ( helen.hobbs@ 123456utsouthwestern.edu ) or J.C.C. ( jonathan.cohen@ 123456utsouthwestern.edu )
                [*]

                These authors contributed equally to this work.

                Article
                nihpa70399
                10.1038/ng.257
                2597056
                18820647
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: RL1 HL092550-02 ||HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL020948-317281 ||HL
                Categories
                Article

                Genetics

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