Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction

被引：28

作者：

Palmer, Nicholette D. ^{[1
]}

Kahali, Bratati ^{[2
,3
,4
]}

Kuppa, Annapurna ^{[3
,4
]}

Chen, Yanhua ^{[3
,4
]}

Du, Xiaomeng ^{[3
,4
]}

Feitosa, Mary F. ^{[5
]}

Bielak, Lawrence F. ^{[6
]}

O'Connell, Jeffrey R. ^{[7
]}

Musani, Solomon K. ^{[8
]}

Guo, Xiuqing ^{[9
]}

Smith, Albert, V ^{[10
]}

Ryan, Kathleen A. ^{[7
]}

Eirksdottir, Gudny ^{[10
]}

Allison, Matthew A. ^{[11
]}

Bowden, Donald W. ^{[1
]}

Budoff, Matthew J. ^{[12
]}

Carr, J. Jeffrey ^{[13
]}

Chen, Yii-Der, I ^{[9
]}

Taylor, Kent D. ^{[9
]}

Correa, Adolfo ^{[8
]}

Crudup, Breland F. ^{[8
]}

Halligan, Brian ^{[3
,4
]}

Yang, Jian ^{[14
]}

Kardia, Sharon L. R. ^{[6
]}

Launer, Lenore J. ^{[15
]}

Fu, Yi-Ping ^{[16
,17
]}

Mosley, Thomas H., Jr. ^{[8
]}

Norris, Jill M. ^{[18
]}

Terry, James G. ^{[13
]}

O'Donnell, Christopher J. ^{[1
]}

Rotter, Jerome, I ^{[9
]}

Wagenknecht, Lynne E. ^{[19
]}

Gudnason, Vilmundur ^{[10
,20
]}

Province, Michael A. ^{[5
]}

Peyser, Patricia A. ^{[6
]}

Speliotes, Elizabeth K. ^{[3
,4
]}

机构：

[1] Wake Forest Sch Med, Dept Biochem, 1 Med Ctr Blvd, Winston Salem, NC 27157 USA

[2] Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India

[3] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[5] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[6] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[7] Univ Maryland, Dept Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[8] Univ Mississippi, Dept Med, Jackson, MS USA

[9] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[10] Iceland Heart Assoc, Kopavogur, Iceland

[11] Univ Calif San Diego, Dept Family Med & Publ Hlth, San Diego, CA 92103 USA

[12] Harbor UCLA Med Ctr, Dept Internal Med, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[13] Vanderbilt Univ, Dept Radiol, Sch Med, Nashville, TN USA

[14] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[15] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA

[16] NHLBI, Framingham Heart, NIH, Framingham, MA USA

[17] NHLBI, Off Biostat Res, NIH, Bethesda, MD USA

[18] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Anschutz Med Campus, Aurora, CO USA

[19] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27101 USA

[20] Univ Iceland, Dept Med, IS-101 Reykjavik, Iceland

来源：

HUMAN MOLECULAR GENETICS | 2021年 / 30卷 / 15期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; CONFERS SUSCEPTIBILITY; VARIANTS; LOCI; POLYMORPHISMS; METAANALYSIS; ADIPOSITY;

D O I：

10.1093/hmg/ddab096

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 x 10(-7)); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

引用

页码：1443 / 1456

页数：14

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