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

Table 2 Overview of the main studies testing combined genetic/clinical risk score in the assessment of non-alcoholic fatty liver disease patients

Ref.	Variables included	Risk score formula	Outcomes
Kotronen et al[46], 2009	Clinical and laboratory data (metabolic syndrome, type 2 diabetes, insulin, AST, AST/ALT ratio and PNPLA3 rs738409 GG)	NAFLD liver fat score: [-2.89 + 1.18 × metabolic syndrome (yes = 1/no = 0) + 0.45 × type 2 diabetes (yes = 2/no = 0) + 0.15 × fS-insulin (mU/L) + 0.04 × fS-AST (U/L) - 0.94 × AST/ALT] and PNPLA3 rs738409 GG	Independent predictor of NAFLD with AUROC of 0.872 ± 0.02 (95%CI: 0.84-0.91); Addition of rs738409 to the score improved the accuracy of the prediction by only < 1%.
Francque et al[47], 2012	ALT, fasting levels of C-peptide, ultrasound steatosis scores and PNPLA3 rs738409 genotypes	ND	Predictor of NASH with AUROC of 0.8 Rs738409 correlated with development of NASH but did not add value
Guichelaar et al[55], 2013	PNPLA3 rs738409 G allele, CK-18 > 145 IU/ L, Glucose > 100 mg/dL, C-reactive protein > 0.8 mg/dL	Sum of risk factors	82% probability of NASH (all four risk factors) vs 9% in their absence
Hyssalo et al[56], 2014	PNPLA3 genotype, AST, fasting insulin	NASH score: -3.05 + 0.562 × PNPLA3 genotype (CC = 1/GC = 2/GG = 3) - 0.0092 × fS-insulin (mU/L) + 0.0023 × AST (IU/L) + 0.0019 × (fS-insulin × AST)	Finnish cohort NPV 86%, PPV 53% for NASH Italian cohort NPV 74%, PPV 65% for NASH
Zhou et al[48], 2016	Glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6, AST, and fasting insulin and	NASH ClinLipMet score: -8.167 + 0.954 × PNPLA3 genotype (CC = 1/GC = 2/GG = 3) + 0.0451 × AST (IU/L) + 0.0667 × fS12 insulin (mU/L) - 3.151× log10(LysoPC(16:0)) (μmol/L) + 2.617 × log10(PE(40:6)) (μmol/L) + 2.357 × 13 log10(Glu) (μmol/L) + 7.813 × log10(Ile) (μmol/L) - 6.102 × log10(Gly) (μmol/L)	Identified patients with NASH with an AUROC of 0.866 (95%CI: 0.820-0.913)
Donati et al[28], 2017	PNPLA3rs738409 genotypes PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738, age, sex, obesity, type 2 diabetes, severe fibrosis	HCC risk score: 1/{1 + e-[(-12.588 + (0.162 × age) + (0.404 × sex: 1 if male, -1 if female) + (0.259 × obesity: 1 present, -1absent) + (0.587 × T2DM: 1 present,-1 absent) + (1.299 × severe fibrosis: 1 yes, -1 no) + (0.442 × number of risk alleles)]}	Identified patients with HCC with an AUROC of 0.96 ± 0.04 (96% sensitivity, 89% specificity)

PNPLA3: Patatin-like phospholipase domain-containing protein 3; AUROC: Area under the receiver operating characteristic curve; CI: Confidence interval; NASH: Non-alcoholic steatohepatitis; 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; HCC: Hepatocellular carcinoma; NPV: Negative predictive value; PPV: Positive predictive value.