Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables

Table 1 Overview of the main studies testing pure genetics risk score in the assessment of non-alcoholic fatty liver disease patients

Ref.	Variables included	Risk score formula	Outcomes
Petta et al[53], 2012	IL28B rs12979860 CC and PNPLA3 rs738409 GG	IL28B rs12979860 CC + PNPLA3 rs738409 GG	Higher prevalence of moderate-severe lobular inflammation (P < 0.001) and NASH > 5 (P = 0.02)
Nobili et al[42], 2014	PNPLA3 rs738409 C>G, SOD2 rs4880 C>T, KLF6 rs3750861 G>A and LPIN1 rs13412852 C>T	1/[1+e^ (-0.804-PNPLA3 GG × 1.923 + SOD2 TT × 0.564 + LPIN1 TT × 0.551 - KLF6 AG-AA × 0.324)]	AUROC 0.75 (CI: 0.67-0.82, P < 0.0001) per NASH, cutoff 0.42%-90% sensitivity/36% specificity for NASH
Leon-Mimila et al[43], 2015	PNPLA3 rs738409, LYPLAL1 rs12137855, GCKR rs1260326 and PPP1R3B rs4240624	GRS = Sum of at-risk alleles: 0 for homozygous for the non-risk allele, 1 for heterozygous and 2 for homozygous for the risk allele	GRS ≥ 6 increased risk of NAS (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5
Wang et al[40], 2016	PNPLA3 rs738409 and TM6SF2 rs58542926	Sum of at-risk alleles: 0, 1 or 2 according to the number of minor allele	OR for NAFLD increase of 1.52 per additional risk allele
Di Costanzo et al[54], 2017	PNPLA3 rs738409, GCKR rs1260326 and TM6SF2 rs58542926	Weighted sum of at-risk alleles	A 3 SNPs weighted genetic score > 0.32: five-fold increased risk of NAFLD
Krawczyk et al[38], 2017	PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738	Sum of at-risk alleles	Association with increasing hepatic fibrosis and steatosis; increase of serum AST activities (P < 0.0001), trends for increased ALT (P = 0.08) and GGT (P = 0.07)
Larrieta-Carrasco et al[39], 2018	PNPLA3 rs738409, PNPLA3 rs3810622, SAMM50 rs2143571, ADPOQ rs17366743, COL13A1 rs7101190 and COL13A1 rs12277556	Polygenic risk score = Sum of at-risk alleles 0 for homozygous for the non-risk allele, 1 for heterozygous and 2 for homozygous for the risk allele	9-12 vs 1-4 risk alleles: 65.8% and 48.5% higher ALT and AST levels
Vespasiani-Gentilucci et al[45], 2018	PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861	GRS: Sum of at-risk alleles PNPLA3 CC = 0, CG = 1, GG = 2; TM6SF2 CC = 0, CT and TT = 1; KLF6 CC = 0, CT and TT = 1	In healthy subjects: GRS 1-2 vs 0 increases 4-fold and GRS 3-4 vs 0 increases 20-fold the risk of non-cirrhotic NAFLD; in non-cirrhotic NAFLD: GRS 3-4 vs 0 increases 4-fold the risk of NASH cirrhosis
Di Costanzo et al[41], 2018	PNPLA3 rs738409, GCKR rs1260326, TM6SF2 rs58542926 and MBOAT7 rs641738	GRS: Sum of at-risk alleles (0-2); wGRS: Sum of at-risk alleles Beta coefficient	GRS 3 vs 2 higher in NAFLD (P = 0.001) wGRS > 0.28: three fold increased risk of NAFLD
Koo et al[44], 2018	PNPLA3 rs738409 and TM6SF2 rs58542926	Sum of at-risk alleles: PNPLA3 CC = 0, CG = 1, GG =2 TM6SF2 CC = 0, CT and TT = 1	Prevalence of NASH in NAFLD patients: 28.2% (0 allele), 41.8% (1 allele), 63.7% (2 alleles), 69.2% (3 alleles); risk of NASH: 2.04 OR per risk allele

GRS: Genetic risk score; wGRS: Weighted GRS; PNPLA3: Patatin-like phospholipase domain-containing protein 3; SOD2: Superoxide dismutase 2; KLF6: Krueppel-like factor 6; LPIN1: Lipin1; AUROC: Area under the receiver operating characteristic curve; CI: Confidence interval; NASH: Non-alcoholic steatohepatitis; GCKR: Glucokinase regulatory gene; TM6SF2: Transmembrane 6 superfamily member 2; ALT: Alanine aminotransferase; GGT: γ-glutamyl transferase; NAFLD: Non-alcoholic fatty liver disease; AST: Aspartate aminotransferase; MBOAT7: Membrane bound O-acyltransferase domain containing 7; SAMM50: Sorting and assembly machinery component 50 homolog; COL13A1: Collagen, type XIII, alpha 1.