Gamut of applications of GRS in NAFLD

Author, year [ref] Method Finding Conclusion
Vespasiani-Gentilucci, 2018 [26] 107 individuals with NASH-cirrhosis, 93 with non-cirrhotic NAFLD, and 90 controls were submitted to genotyping. Compared to a GRS = 0, a GRS of 1–2 was associated with a 4-fold increased risk, and a score of 3–4 was associated with a 20-fold increased risk of having non-cirrhotic NAFLD. A GRS = 3–4 was associated with a four-fold increased risk of NASH-cirrhosis. A dose-response relationship was found between increasing GRS and risk of severe liver disease.
A risk score based on SNPs for the PNPLA3, TM6SF2, and KLF6 variants was developed.
Kawaguchi-Suzuki, 2018 [29] 55 participants of an RCT on long-term pioglitazone treatment in NASH were enrolled. The genetic response score was significantly associated with achievement of the primary outcome. Genetic factors account for a fraction of the inter-individual variability in response to pioglitazone administration in NASH patients.
Primary outcome defined as ≥ 2-point reduction of NAS.
SNPs in putative candidate genes were evaluated.
A genetic response score was developed based on the sum of response alleles for selected genes.
Ma, 2018 [30] 1521 participants of the 3rd-generation cohort of the Framingham Heart Study were enrolled. Higher GRS were associated with increased steatosis in individuals who had decreased MDS or AHEI scores, but not in those with stable or improved diet scores. Dietary improvements are particularly recommendable to those who are at a high genetic risk for developing NAFLD.
Dietary intake was assessed with the self-administered semi-quantitative 126-item Harvard food frequency questionnaire. Diets were scored based on either the MDS or the AHEI.
The extent of steatosis was assessed using CT images.
Weighted GRS for NAFLD was determined based on multiple SNPs identified in GWAS of NAFLD.
Danford, 2018 [31] 177 individuals with biopsy-proven NAFLD were recruited. The combination of eLP-IR with the genetic score and age accurately predicted advanced stages of fibrosis (stages 3–4 liver) with an AUROC = 0.82. A study supporting the notion that genetic and metabolic drivers dictate the severity of NAFLD as well as indicating a novel risk stratification based on pathogenic determinants of disease.
The eLP-IR index was calculated based on serum biomarkers using MRS.
Genetic score - Individuals who had neither allele of PNPLA3 and TM6SF2 received a 0 score. 1 point was assigned for either heterozygotes or homozygotes of NPLA3 and TM6SF2 minor alleles. A score of 2 was assigned to those who had ≥ 1 allele of both PNPLA3 and TM6SF2 minor alleles.
Di Costanzo, 2019 [27] 230 obese Italian children underwent metabolic assessment and evaluation of gene polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7). HFF% was assessed with MR. HFF% was accounted for by anthropometric and metabolic variables (BMI, HOMA-IR, MetS, transaminases, GGT and albumin) for 8.7%. And by genetic factors for 16.1%. Genetic factors play a key role in the determinism of intra-hepatic fat content in obese Italian children.
A weighted-GRS (combining PNPLA3, GCKR, and TM6SF2 risk alleles) was associated with an approximately eight-fold increased NAFLD risk.
Zusi, 2019 [28] A GRS was developed taking into account the SNPs of GCKR, MBOAT7, GPR120, SOD2, PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP and KLF6 as well as clinical risk factors in a cohort of 514 obese children and adolescents. By adding a 11-polymorphism GRS, the accuracy of the statistical model for predicting the risk of NAFLD was significantly (albeit modestly) improved as compared to a model evaluating established clinical risk factors alone. NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326 and, more slightly, with ELOVL2 rs2236212, in obese children and adolescents.
NAFLD was diagnosed with US.

AHEI: alternative healthy eating index; AUROC: area under the receiver operating characteristic curve; BMI: body mass index; CT: computed tomography; ELOVL2: ELOVL fatty acid elongase 2; eLP-IR: enhanced lipoprotein IR index; FADS2: Fatty Acid Desaturase 2; GCKR: glucokinase regulator; GGT: gamma-glutamyl-transferase; GPR120: G-protein coupled receptor 120; GWAS: genome-wide association studies of NAFLD; HFF%: hepatic fat fraction; HOMA-IR: homeostasis model assessment of insulin resistance; KLF6: Kruppel like factor 6; LPIN1: Lipin 1; MBOAT7: Membrane Bound O-Acyltransferase Domain Containing 7; MDS: mediterranean-style diet score; MR: magnetic resonance; MRS: nuclear magnetic resonance spectroscopy; MTTP: microsomal triglyceride transfer protein; NAS: NAFLD activity score; PNPLA3: Patatin-like phospholipase domain-containing protein 3; RCT: randomized controlled trial; SNPs: single nucleotide polymorphisms; SOD2: superoxide dismutase 2; TM6SF2: Transmembrane 6 Superfamily Member 2; US: ultrasound