Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

English version České info

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10⁻⁸) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Vyšlo v časopise: Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits. PLoS Genet 7(3): e32767. doi:10.1371/journal.pgen.1001324
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001324

Souhrn

Zdroje

1. ClarkJM

2006 The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40 S5 10

2. KleinerDE

BruntEM

Van NattaM

BehlingC

ContosMJ

2005 Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41 1313 1321

3. HarrisonSA

Neuschwander-TetriBA

2004 Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin Liver Dis 8 861 879

4. FanJG

ZhuJ

LiXJ

ChenL

LuYS

2005 Fatty liver and the metabolic syndrome among Shanghai adults. J Gastroenterol Hepatol 20 1825 1832

5. StrubenVM

HespenheideEE

CaldwellSH

2000 Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 108 9 13

6. WillnerIR

WatersB

PatilSR

ReubenA

MorelliJ

2001 Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 96 2957 2961

7. SchwimmerJB

CeledonMA

LavineJE

SalemR

CampbellN

2009 Heritability of nonalcoholic fatty liver disease. Gastroenterology 136 1585 1592

8. RomeoS

KozlitinaJ

XingC

PertsemlidisA

CoxD

2008 Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40 1461 1465

9. KotronenA

JohanssonLE

JohanssonLM

RoosC

WesterbackaJ

2009 A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 52 1056 1060

10. IwasakiM

TakadaY

HayashiM

MinamiguchiS

HagaH

2004 Noninvasive evaluation of graft steatosis in living donor liver transplantation. Transplantation 78 1501 1505

11. SaadehS

YounossiZM

RemerEM

GramlichT

OngJP

2002 The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123 745 750

12. LimanondP

RamanSS

LassmanC

SayreJ

GhobrialRM

2004 Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings. Radiology 230 276 280

13. TeslovichTM

MusunuruK

SmithAV

EdmondsonAC

StylianouIM

2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 707 713

14. SpeliotesEK

WillerCJ

BerndtSI

MondaKL

ThorleifssonG

2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42 937 948

15. VoightBF

ScottLJ

SteinthorsdottirV

MorrisAP

DinaC

2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42 579 589

16. DupuisJ

LangenbergC

ProkopenkoI

SaxenaR

SoranzoN

2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42 105 116

17. ZhongH

YangX

KaplanLM

MolonyC

SchadtEE

2010 Integrating pathway analysis and genetics of gene expression for genome-wide association studies. Am J Hum Genet 86 581 591

18. YuanX

WaterworthD

PerryJR

LimN

SongK

2008 Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 83 520 528

19. PetersenKF

DufourS

HaririA

Nelson-WilliamsC

FooJN

2010 Apoliporpotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 362 1082 1089

20. PriceAL

ButlerJ

PattersonN

CapelliC

PascaliVL

2008 Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 4 e236 doi:10.1371/journal.pgen.0030236

21. SpeliotesEK

ButlerJL

PalmerCD

VoightBF

ConsortiumtG

2010 PNPLA3 variants specifically confer increased risk for histologic NAFLD but not metabolic disease. Hepatology 52 904 912

22. KathiresanS

VoightBF

PurcellS

MusunuruK

ArdissinoD

2009 Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 41 334 341

23. ValentiL

Al-SerriA

DalyAK

GalmozziE

RamettaR

Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51 1209 1217

24. SpeliotesEK

MassaroJM

HoffmannU

RamachandranV

MeigsJB

2010 Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: The Framingham Heart Study. Hepatology 51 1979 1987

25. SaxenaR

VoightBF

LyssenkoV

BurttNP

de BakkerPI

2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316 1331 1336

26. WillerCJ

SannaS

JacksonAU

ScuteriA

BonnycastleLL

2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40 161 169

27. KathiresanS

WillerCJ

PelosoGM

DemissieS

MusunuruK

2009 Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41 56 65

28. KathiresanS

MelanderO

GuiducciC

SurtiA

BurttNP

2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40 189 197

29. LindgrenCM

HeidIM

RandallJC

LaminaC

SteinthorsdottirV

2009 Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5 e1000508 doi:10.1371/journal.pgen.1000508

30. BeerNL

TribbleND

McCullochLJ

RoosC

JohnsonPR

2009 The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 18 4081 4088

31. BurkeJE

DennisEA

2009 Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50 Suppl S237 242

32. BurkeJE

DennisEA

2009 Phospholipase A2 biochemistry. Cardiovasc Drugs Ther 23 49 59

33. HeS

McPhaulC

LiJZ

GarutiR

KinchLN

2009 A sequence variation (I148M) in PNPlA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 285 6706 6715

34. RauchU

FengK

ZhouXH

2001 Neurocan: a brain chondroitin sulfate proteoglycan. Cell Mol Life Sci 58 1842 1856

35. AgiusL

2008 Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J 414 1 18

36. AulchenkoYS

RipkeS

IsaacsA

van DuijnCM

2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 1296

37. RampersaudE

BielakLF

ParsaA

ShenH

PostW

2008 The association of coronary artery calcification and carotid artery intima-media thickness with distinct, traditional coronary artery disease risk factors in asymptomatic adults. Am J Epidemiol 168 1016 1023

38. SorkinJ

PostW

PollinTI

O'ConnellJR

MitchellBD

2005 Exploring the genetics of longevity in the Old Order Amish. Mech Ageing Dev 126 347 350

39. HigginsM

ProvinceM

HeissG

EckfeldtJ

EllisonRC

1996 NHLBI Family Heart Study: objectives and design. Am J Epidemiol 143 1219 1228

40. CarrJJ

NelsonJC

WongND

McNitt-GrayM

AradY

2005 Calcified coronary artery plaque measurement with cardiac CT in population-based studies: standardized protocol of Multi-Ethnic Study of Atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults (CARDIA) study. Radiology 234 35 43

41. DawberT

1980 The Framingham Study: The Epidemiology of Atherosclerotic Disease. Cambridge, MA Harvard University Press

42. KannelWB

FeinleibM

McNamaraPM

GarrisonRJ

CastelliWP

1979 An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol 110 281 290

43. SplanskyGL

CoreyD

YangQ

AtwoodLD

CupplesLA

2007 The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am J Epidemiol 165 1328 1335

44. SpeliotesEK

MassaroJM

HoffmannU

FosterMC

SahaniDV

2008 Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study. J Gastroenterol Hepatol 23 894 899

45. ChenMH

LarsonMG

HsuYH

PelosoGM

GuoCY

2010 A three-stage approach for genome-wide association studies with family data for quantitative traits. BMC Genet 11 40

46. PriceAL

PattersonNJ

PlengeRM

WeinblattME

ShadickNA

2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909

47. AlmasyL

BlangeroJ

1998 Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62 1198 1211

48. ThorleifssonG

WaltersGB

GudbjartssonDF

SteinthorsdottirV

SulemP

2009 Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41 18 24

49. ChalasaniNP

SanyalAJ

KowdleyKV

RobuckPR

HoofnagleJ

2009 Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials 30 88 96

50. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575