Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

Table 1 List of genome/exome wide association studies and loci identified for non-alcoholic fatty liver disease

Ref.	Phenotype associated with	Ancestry of samples included	Genotyping platform	Discovery sample size	Replication sample size	Genes
Romeo et al[6], 2008	Increased hepatic fat levels and inflammation	Hispanic, African American and European American individuals	Perlegen Sciences Custom array (12138 NS variation)	2111 individuals with MRS measured hepatic steatosis	None	PNPLA3
Chalasani et al[15], 2010	Features of hepatic histology	Non-Hispanic white women	Illumina (324,623 SNPs)	236, non-Hispanic white women	None	FDFT1, rs343062 (Chr 7), COL13A1, rs6591182 (Chr 11), EFCAB4B, rs2499604 (chr 1), PZP, rs1421201 (Chr 18) rs2710833 (Chr 4)
Speliotes et al[16], 2011	CT measured hepatic steatosis	European american including Amish	Affymetrix, Illumina	7126 with CT measured hepatic steatosis	592/1405	PNPLA3, NCAN, PPP1R3B, GCKR, LYPLAL1
Kawaguchi et al[3], 2012	NAFLD	Japanese	Illumina	529 patients consisting of four NAFLD subgroups (Matteoni’s classification)	None	PNPLA3, SAMM50, PARVB, HS3ST1-HSP90AB2P, YIPF1
Kitamoto et al[66], 2013	NAFLD	Japanese	Illumina	392 NAFLD and 934 controls	172 NAFLD and 1012 controls	PNPLA3, SAMM50, PARVB gene
Kozlitina et al[19], 2014	MRS measured hepatic steatosis	Hispanic, African, American and European	Illumina	2,736	None	PNPLA3 and TM6SF2

NAFLD: Non-alcoholic fatty liver disease; CT: Computed tomography; SNPs: Single nucleotide polymorphisms; MRS: Magnetic resonance spectroscopy.

Table 2 Functional role of major genes associated with non-alcoholic fatty liver disease identified by genome/exome wide association studies

Gene	Protein	Cellular location1	Function1	Chromosome location2	No. of exons and size2	Pathway/biologic function1	Tissues expressed1
PNPLA3	Patatin-like phospholipase domain-containing protein 3	Lipid droplets	Triacyl glycerol lipase and acylglycerol O-cyltransferase activities	Chromosome 22: 43,923,739-43,964,488 (forward strand)	9 (2805 bp)	Triacyl glycerol degradation and in glycerol-lipid metabolism	Liver, gall bladder, kidney, exocrine pancreas, seminal vesicles, intestine and salivary glands
TM6SF2	Transmembrane 6 superfamily member 2	ER and the ER-golgi intermediate compartment	Regulation of fat in liver influencing triglyceride secretion and lipid droplet content	Chromosome 19: 19,264,364-19,273,391 (reverse strand)	10 (1505 bp)	Promotes very low density lipoprotein export	Liver and intestine
SAMM50	Sorting and assembly machinery component 50 homolog	Outer mitochondrial membrane	Assembly of beta-barrel proteins	Chromosome 22: 43,955,421-44,010,531 (forward strand)	15 (1717)	Transport to the Golgi and subsequent modification and mitochondrial protein import	Liver, muscle, skeletal, lung adipocyte, colon and other tissues
PARVB	Parvin, beta	Cytoplasm	Involved in the reorganization of the actin cytoskeleton and formation of lamellipodia	Chromosome 22: 44,024,277-44,172,949 (forward strand)	13 (5429 bp)	ERK signaling and focal adhesion	Liver, muscle, skeletal, lung adipocyte, colon and other tissues
NCAN	Neurocan	Extracellular, Golgi lumen	Modulates neuronal adhesion and neurite growth during development	Chromosome 19: 19,211,973-19,252,233 (forward strand)	15 (6387 bp)	Developmental	Liver, muscle, skeletal, lung adipocyte, colon and other tissues
PPP1R3B	Protein phosphatase 1, regulatory subunit 3B	Glycogen granule	Acts as glycogen targeting subunit for phosphatase PP1	Chromosome 8: 9,136,255-9,151,574 (reverse strand)	2 (5548 bp)	Regulating glycogen synthesis	Liver, skeletal muscle
GCKR	GCKR	Cytoplasm, nucleus	Inhibits glucokinase by forming an inactive complex with this enzyme. The affinity of GCKR for GK is modulated by fructose metabolites	Chromosome 2: 27,496,842-27,523,684 (forward strand)	19 (2186 bp)	Carbohydrate metabolism	Liver, pancreas, colon and other tissues
LYPLAL1	Lysophospholipase-like 1	Cytoplasm	Depalmitoylating activity	Chromosome 1: 219,173,844-219,212,865 (forward strand)	5 (1898 bp)	Negative regulation of golgi to plasma membrane protein transport	Liver, muscle, skeletal, lung adipocyte, colon and other tissues

¹Data extracted from http://www.genecards.org/;

²Data extracted from ENSEBL http://asia.ensembl.org/index.html; ER: Endoplasmic reticulum; PP1: Protein phosphatase 1; GCKR: Glucokinase (Hexokinase 4) regulator; GK: Glucokinase; ERK: Extracellular signal–regulated kinase.