Journal ArticleDOI
The genetics of NAFLD.
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TLDR
The current status of the field is described, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3, influence disease progression.Abstract:
NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3, influence disease progression.read more
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Journal ArticleDOI
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
Zobair M. Younossi,Quentin M. Anstee,Milena Marietti,Timothy Hardy,Timothy Hardy,Linda Henry,Mohammed Eslam,Jacob George,Elisabetta Bugianesi +8 more
TL;DR: The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy.
Journal ArticleDOI
The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)
TL;DR: The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD, and the "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induceNAFLD and provides a more accurate explanation of NAFLd pathogenesis.
Journal ArticleDOI
The global NAFLD epidemic
Rohit Loomba,Arun J. Sanyal +1 more
TL;DR: The similarities and differences in the epidemiology of NAFLD in different regions of the world are discussed and the potential role of genetics and insulin resistance in disease progression is also presented.
Journal ArticleDOI
Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome
TL;DR: NAFLD might be a more direct predictor of type 2 diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma than metabolic syndrome because it is associated with high liver fat content.
Journal ArticleDOI
Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management
Stuart McPherson,Stuart McPherson,Timothy Hardy,E Henderson,Alastair D. Burt,Alastair D. Burt,Christopher P. Day,Christopher P. Day,Quentin M. Anstee,Quentin M. Anstee +9 more
TL;DR: Contrary to current dogma, this study suggests that steatosis can progress to NASH and clinically significant fibrosis.
References
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Journal ArticleDOI
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Eric S. Lander,Lauren Linton,Bruce W. Birren,Chad Nusbaum,Michael C. Zody,Jennifer Baldwin,Keri Devon,Ken Dewar,Michael Doyle,William Fitzhugh,Roel Funke,Diane Gage,Katrina Harris,Andrew Heaford,John Howland,Lisa Kann,Jessica A. Lehoczky,Rosie Levine,Paul A. McEwan,Kevin McKernan,James Meldrim,Jill P. Mesirov,Cher Miranda,William Morris,Jerome Naylor,Christina Raymond,Mark Rosetti,Ralph Santos,Andrew Sheridan,Carrie Sougnez,Nicole Stange-Thomann,Nikola Stojanovic,Aravind Subramanian,Dudley Wyman,Jane Rogers,John Sulston,R Ainscough,Stephan Beck,David Bentley,John Burton,C M Clee,Nigel P. Carter,Alan Coulson,Rebecca Deadman,Panos Deloukas,Andrew Dunham,Ian Dunham,Richard Durbin,Lisa French,Darren Grafham,Simon G. Gregory,Tim Hubbard,Sean Humphray,Adrienne Hunt,Matthew Jones,Christine Lloyd,Amanda McMurray,Lucy Matthews,Simon Mercer,Sarah Milne,James C. Mullikin,Andrew J. Mungall,Robert W. Plumb,Mark T. Ross,Ratna Shownkeen,Sarah Sims,Robert H. Waterston,Richard K. Wilson,LaDeana W. Hillier,John Douglas Mcpherson,Marco A. Marra,Elaine R. Mardis,Lucinda Fulton,Asif T. Chinwalla,Kymberlie H. Pepin,Warren Gish,Stephanie L. Chissoe,Michael C. Wendl,Kim D. Delehaunty,Tracie L. Miner,Andrew Delehaunty,Jason B. Kramer,Lisa Cook,Robert S. Fulton,Douglas L. Johnson,Patrick Minx,Sandra W. Clifton,Trevor Hawkins,Elbert Branscomb,Paul Predki,Paul G. Richardson,Sarah Wenning,Tom Slezak,Norman A. Doggett,Jan Fang Cheng,Anne S. Olsen,Susan Lucas,Christopher J. Elkin,Edward Uberbacher,Marvin Frazier,Richard A. Gibbs,Donna M. Muzny,Steven E. Scherer,John Bouck,Erica Sodergren,Kim C. Worley,Catherine M. Rives,James H. Gorrell,Michael L. Metzker,Susan L. Naylor,Raju Kucherlapati,David L. Nelson,George M. Weinstock,Yoshiyuki Sakaki,Asao Fujiyama,Masahira Hattori,Tetsushi Yada,Atsushi Toyoda,Takehiko Itoh,Chiharu Kawagoe,Hidemi Watanabe,Yasushi Totoki,Todd D. Taylor,Jean Weissenbach,Roland Heilig,William Saurin,François Artiguenave,Philippe Brottier,Thomas Brüls,Eric Pelletier,Catherine Robert,Patrick Wincker,André Rosenthal,Matthias Platzer,Gerald Nyakatura,Stefan Taudien,Andreas Rump,Douglas R. Smith,Lynn Doucette-Stamm,Marc Rubenfield,Keith Weinstock,Mei Lee Hong,Joann Dubois,Huanming Yang,Jun Yu,Jian Wang,Guyang Huang,Jun Gu,Leroy Hood,Lee Rowen,Anup Madan,Shizen Qin,Ronald W. Davis,Nancy A. Federspiel,A. Pia Abola,Michael Proctor,Bruce A. Roe,Feng Chen,Huaqin Pan,Juliane Ramser,Hans Lehrach,Richard Reinhardt,W. Richard McCombie,Melissa De La Bastide,Neilay Dedhia,H. Blöcker,K. Hornischer,Gabriele Nordsiek,Richa Agarwala,L. Aravind,Jeffrey A. Bailey,Alex Bateman,Serafim Batzoglou,Ewan Birney,Peer Bork,Daniel G. Brown,Christopher B. Burge,Lorenzo Cerutti,Hsiu Chuan Chen,Deanna M. Church,Michele Clamp,Richard R. Copley,Tobias Doerks,Sean R. Eddy,Evan E. Eichler,Terrence S. Furey,James E. Galagan,James G. R. Gilbert,Cyrus L. Harmon,Yoshihide Hayashizaki,David Haussler,Henning Hermjakob,Karsten Hokamp,Wonhee Jang,L. Steven Johnson,Thomas A. Jones,Simon Kasif,Arek Kaspryzk,Scot Kennedy,W. James Kent,Paul Kitts,Eugene V. Koonin,Ian F Korf,David Kulp,Doron Lancet,Todd M. Lowe,Aoife McLysaght,Tarjei S. Mikkelsen,John V. Moran,Nicola Mulder,Victor J. Pollara,Chris P. Ponting,Greg Schuler,Jörg Schultz,Guy Slater,Arian F.A. Smit,Elia Stupka,Joseph Szustakowki,Danielle Thierry-Mieg,Jean Thierry-Mieg,Lukas Wagner,John W. Wallis,Raymond Wheeler,Alan Williams,Yuri I. Wolf,Kenneth H. Wolfe,Shiaw Pyng Yang,Ru Fang Yeh,Francis S. Collins,Mark S. Guyer,Jane Peterson,Adam Felsenfeld,Kris A. Wetterstrand,Richard M. Myers,Jeremy Schmutz,Mark Dickson,Jane Grimwood,David R. Cox,Maynard V. Olson,Rajinder Kaul,Christopher K. Raymond,Nobuyoshi Shimizu,Kazuhiko Kawasaki,Shinsei Minoshima,Glen A. Evans,Maria Athanasiou,Roger A. Schultz,Aristides Patrinos,Michael J. Morgan +248 more
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Journal ArticleDOI
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul Burton,David Clayton,Lon R. Cardon,Nicholas John Craddock,Panos Deloukas,Audrey Duncanson,Dominic P. Kwiatkowski,Mark I. McCarthy,Willem H. Ouwehand,Nilesh J. Samani,John A. Todd,Peter Donnelly,Jeffrey C. Barrett,Dan Davison,Doug Easton,David M. Evans,H. T. Leung,Jonathan Marchini,Andrew P. Morris,Chris C. A. Spencer,Martin D. Tobin,Antony P. Attwood,James P. Boorman,Barbara Cant,Ursula Everson,Judith M. Hussey,Jennifer Jolley,Alexandra S. Knight,Kerstin Koch,Elizabeth Meech,Sarah Nutland,Christopher Prowse,Helen Stevens,Niall C. Taylor,Graham R. Walters,Neil Walker,Nicholas A. Watkins,Thilo Winzer,Richard Jones,Wendy L. McArdle,Susan M. Ring,David P. Strachan,Marcus Pembrey,Gerome Breen,David St Clair,Sian Caesar,Katherine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K. Green,Detelina Grozeva,Marian L. Hamshere,Peter Holmans,Ian Jones,George Kirov,Valentina Moskvina,Ivan Nikolov,Michael Conlon O'Donovan,Michael John Owen,David A. Collier,Amanda Elkin,Anne Farmer,Richard Williamson,Peter McGuffin,Allan H. Young,I. Nicol Ferrier,Stephen G. Ball,Anthony J. Balmforth,Jennifer H. Barrett,D. Timothy Bishop,Mark M. Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair S. Hall,Peter S. Braund,Richard J. Dixon,Massimo Mangino,Suzanne Stevens,John R. Thompson,Francesca Bredin,Mark Tremelling,Miles Parkes,Hazel E. Drummond,Charlie W. Lees,Elaine R. Nimmo,Jack Satsangi,Sheila A. Fisher,Alastair Forbes,Cathryn M. Lewis,Clive M. Onnie,Natalie J. Prescott,Jeremy D. Sanderson,Christopher G. Mathew,Jamie Barbour,M. Khalid Mohiuddin,Catherine E. Todhunter,John C. Mansfield,Tariq Ahmad,Fraser Cummings,Derek P. Jewell,John Webster,Morris J. Brown,G. Mark Lathrop,John M. C. Connell,Anna F. Dominiczak,Carolina A. Braga Marcano,Beverley Burke,Richard Dobson,Johannie Gungadoo,Kate L. Lee,Patricia B. Munroe,Stephen Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark J. Caulfield,Martin Farrall,Anne Barton,Ian N. Bruce,Hannah Donovan,Steve Eyre,Paul D. Gilbert,Samantha L. Hider,Anne Hinks,Sally John,Catherine Potter,Alan J. Silman,Deborah P M Symmons,Wendy Thomson,Jane Worthington,David B. Dunger,Barry Widmer,Timothy M. Frayling,Rachel M. Freathy,Hana Lango,John R. B. Perry,Beverley M. Shields,Michael N. Weedon,Andrew T. Hattersley,Graham A. Hitman,Mark Walker,Kate S. Elliott,Christopher J. Groves,Cecilia M. Lindgren,Nigel W. Rayner,Nicholas J. Timpson,Eleftheria Zeggini,Melanie J. Newport,Giorgio Sirugo,Emily J. Lyons,Fredrik O. Vannberg,Adrian V. S. Hill,Linda A. Bradbury,C Farrar,J J Pointon,Paul Wordsworth,Matthew A. Brown,Jayne A. Franklyn,Joanne M. Heward,Matthew J. Simmonds,Stephen C. L. Gough,Sheila Seal,Michael R. Stratton,Nazneen Rahman,Maria Ban,An Goris,Stephen Sawcer,Alastair Compston,David J. Conway,Muminatou Jallow,Kirk A. Rockett,Suzannah Bumpstead,Amy Chaney,Kate Downes,Mohammed J. R. Ghori,Rhian Gwilliam,Sarah E. Hunt,Michael Inouye,Andrew Keniry,Emma King,Ralph McGinnis,Simon C. Potter,Rathi Ravindrarajah,Pamela Whittaker,Claire Widden,David Withers,Niall Cardin,Teresa Ferreira,Joanne Pereira-Gale,Ingileif B. Hallgrímsdóttir,Bryan Howie,Zhan Su,Yik Ying Teo,Damjan Vukcevic,David Bentley,A Compston +195 more
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Journal ArticleDOI
Design and validation of a histological scoring system for nonalcoholic fatty liver disease
David E. Kleiner,Elizabeth M. Brunt,Mark L. Van Natta,Cynthia Behling,Melissa J. Contos,Oscar W. Cummings,Linda D. Ferrell,Yao Chang Liu,Michael Torbenson,Aynur Unalp-Arida,Matthew M. Yeh,Arthur J. McCullough,Arun J. Sanyal +12 more
TL;DR: A strong scoring system and NAS for NAFLD and NASH with reasonable inter‐rater reproducibility that should be useful for studies of both adults and children with any degree ofNAFLD are presented.
Journal ArticleDOI
Finding the missing heritability of complex diseases
Teri A. Manolio,Francis S. Collins,Nancy J. Cox,David Goldstein,Lucia A. Hindorff,David J. Hunter,Mark I. McCarthy,Erin M. Ramos,Lon R. Cardon,Aravinda Chakravarti,Judy H. Cho,Alan E. Guttmacher,Augustine Kong,Leonid Kruglyak,Leonid Kruglyak,Elaine R. Mardis,Charles N. Rotimi,Montgomery Slatkin,David Valle,Alice S. Whittemore,Michael Boehnke,Andrew G. Clark,Evan E. Eichler,Greg Gibson,Jonathan L. Haines,Trudy F. C. Mackay,Steven A. McCarroll,Peter M. Visscher +27 more
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Journal ArticleDOI
The International HapMap Project
John W. Belmont,Paul Hardenbol,Thomas D. Willis,Fuli Yu,Huanming Yang,Lan Yang Ch'Ang,Wei Huang,Bin Liu,Yan Shen,Paul K.H. Tam,Lap-Chee Tsui,Mary M.Y. Waye,Jeffrey Tze Fei Wong,Changqing Zeng,Qingrun Zhang,Mark S. Chee,Luana Galver,Semyon Kruglyak,Sarah S. Murray,Arnold Oliphant,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Michael S. Phillips,Andrei Verner,Shenghui Duan,Denise L. Lind,Raymond D. Miller,John P. Rice,Nancy L. Saccone,Patricia Taillon-Miller,Ming Xiao,Akihiro Sekine,Koki Sorimachi,Yoichi Tanaka,Tatsuhiko Tsunoda,Eiji Yoshino,David R. Bentley,Sarah E. Hunt,Don Powell,Houcan Zhang,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Toyin Aniagwu,Patricia A. Marshall,Olayemi Matthew,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Fiona Cunningham,Ardavan Kanani,Gudmundur A. Thorisson,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Peter Donnelly,Jonathan Marchini,Gilean McVean,Simon Myers,Lon R. Cardon,Andrew P. Morris,Bruce S. Weir,James C. Mullikin,Michael Feolo,Mark J. Daly,Renzong Qiu,Alastair Kent,Georgia M. Dunston,Kazuto Kato,Norio Niikawa,Jessica Watkin,Richard A. Gibbs,Erica Sodergren,George M. Weinstock,Richard K. Wilson,Lucinda Fulton,Jane Rogers,Bruce W. Birren,Hua Han,Hongguang Wang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Kazuo Todani,Takashi Fujita,Satoshi Tanaka,Arthur L. Holden,Francis S. Collins,Lisa D. Brooks,Jean E. McEwen,Mark S. Guyer,Elke Jordan,Jane Peterson,Jack Spiegel,Lawrence M. Sung,Lynn F. Zacharia,Karen Kennedy,Michael Dunn,Richard Seabrook,Mark Shillito,Barbara Skene,John Stewart,David Valle,Ellen Wright Clayton,Lynn B. Jorde,Aravinda Chakravarti,Mildred K. Cho,Troy Duster,Troy Duster,Morris W. Foster,Maria Jasperse,Bartha Maria Knoppers,Pui-Yan Kwok,Julio Licinio,Jeffrey C. Long,Pilar N. Ossorio,Vivian Ota Wang,Charles N. Rotimi,Patricia Spallone,Patricia Spallone,Sharon F. Terry,Eric S. Lander,Eric H. Lai,Deborah A. Nickerson,Gonçalo R. Abecasis,David Altshuler,Michael Boehnke,Panos Deloukas,Julie A. Douglas,Stacey Gabriel,Richard R. Hudson,Thomas J. Hudson,Leonid Kruglyak,Yusuke Nakamura,Robert L. Nussbaum,Stephen F. Schaffner,Stephen T. Sherry,Lincoln Stein,Toshihiro Tanaka +145 more
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.