Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

Nature Genetics

Volumn 46, Issue 4, 2014, Pages 352-356

  Kozlitina, Julia ^a   Smagris, Eriks ^a   Stender, Stefan ^b   Nordestgaard, Børge G ^b   Zhou, Heather H ^c   Tybjærg Hansen, Anne ^b   Vogt, Thomas F ^c   Hobbs, Helen H ^a   Cohen, Jonathan C ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; GLUTAMIC ACID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LYSINE; RECOMBINANT PROTEIN; SHORT HAIRPIN RNA; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN;

ADENO ASSOCIATED VIRUS; ARTICLE; CONTROLLED STUDY; DISEASE MARKER; EXOME; GENE; GENE IDENTIFICATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; HUMAN CELL; HUMAN TISSUE; LIVER INJURY; NONALCOHOLIC FATTY LIVER; NUCLEOTIDE SEQUENCE; PNPLA3 GENE; PRIORITY JOURNAL; PROTEIN EXPRESSION; TM6SF2 GENE; WILD TYPE;

ADENO-ASSOCIATED VIRUS; MUS;

ADIPOSE TISSUE; ALANINE TRANSAMINASE; AMINO ACID SEQUENCE; ANIMALS; BASE SEQUENCE; CHROMATOGRAPHY, LIQUID; DEPENDOVIRUS; EXOME; FATTY LIVER; GENE KNOCKDOWN TECHNIQUES; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; HEPATOCYTES; HUMANS; LIPOPROTEINS, VLDL; LIVER; MEMBRANE PROTEINS; MICE; MOLECULAR SEQUENCE DATA; MUTATION, MISSENSE; REAL-TIME POLYMERASE CHAIN REACTION; RECOMBINANT PROTEINS; SEQUENCE ALIGNMENT; SEQUENCE ANALYSIS, DNA; TRIGLYCERIDES;

EID: 84898058711     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.2901     Document Type: Article

References (22)

1. Tiniakos, D.G., Vos, M.B. & Brunt, E.M. Nonalcoholic fatty liver disease: Pathology and pathogenesis. Annu. Rev. Pathol. 5, 145-171 (2010
2. Browning, J.D. et al. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 40, 1387-1395 (2004
3. McCullough, A.J. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8, 521-533, viii (2004
4. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008
5. Speliotes, E.K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011
6. Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520-528 (2008
7. Chambers, J.C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131-1138 (2011
8. Victor, R.G. et al. The Dallas Heart Study: A population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473-1480 (2004
9. Gorden, A. et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum. Hered. 75, 34-43 (2013
10. Hernaez, R. 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. 11, 1183-1190 e2 (2013
11. Stender, S., Frikke-Schmidt, R., Nordestgaard, B.G. & Tybjaerg-Hansen, A. Extreme bilirubin levels as a causal risk factor for symptomatic gallstone disease. JAMA Intern. Med. 173, 1222-1228 (2013
12. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707-713 (2010
13. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189-197 (2008
14. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56-65 (2009
15. Krogh, A., Larsson, B., von Heijne, G. & Sonnhammer, E.L. Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J. Mol. Biol. 305, 567-580 (2001
16. Marchler-Bauer, A. et al. CDD: A Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res. 39, D225-D229 (2011
17. Kaliannan, K. et al. Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Proc. Natl. Acad. Sci. USA 110, 7003-7008 (2013
18. Friedewald, W.T., Levy, R.I. & Fredrickson, D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative centrifuge. Clin. Chem. 18, 499-502 (1972
19. Szczepaniak, L.S. et al. Measurement of intracellular triglyceride stores by H spectroscopy: Validation in vivo. Am. J. Physiol. 276, E977-E989 (1999
20. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909 (2006
21. Folch, J., Lees, M. & Sloane Stanley, G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497-509 (1957
22. Chen, Z. et al. AAV8-mediated long-term expression of human LCAT significantly improves lipid profiles in hCETP;Ldlr+/ mice. J. Cardiovasc. Transl. Res. 4, 801-810 (2011