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