The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population

Abstract

Background: Accumulated studies have pointed out the striking association between variants in or near APOC3 , GCKR , PNPLA3 , and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear. Objectives: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. Methods: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3 , GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R. Results: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P =0.004, P corr =0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P =0.005, P corr =0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (β =0.01, 95% CI: 0.01–0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels. Conclusions: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.

Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD

“…Hernaez et al 33 showed a correlation between patients with simple steatosis with higher ALT and rs780094-T. Tan et al 34 demonstrated that NAFLD patients with rs1260326 and rs780094 allele T were prone to progress to NASH with significant fibrosis, which would be developed from lean NAFLD 4 . In addition, Yuan et al 16 explored the mediation effect of TG on the association between rs1260326-T in GCKR and the risk of NAFLD in the elderly Chinese Han population. Yet, in our study, the association between rs1260326-C and the odds of lean NAFLD was mediated by waist circumference.…”

“…Accumulating evidence indicated that genetic variants have contributed to the occurrence and development of NAFLD 10,11 . Genome-wide association studies (GWASs) have shown several single nucleotide polymorphisms (SNPs), e.g., rs738409-G in patatin-like phospholipase domain containing 3 (PNPLA3) 11 , rs58542926-T in transmembrane 6 superfamily member 2 (TM6SF2) 12 , rs13107325-T in solute carrier family 39 member 8 (SLC39A8) 13 , rs6834314-A in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) 14 and rs1260326-T in glucokinase regulator (GCKR) 15,16 associated with NAFLD-related comorbidities. Amongst the SNPs identified in GCKR, e.g., rs780093 and rs780094 were also identified as potential risk loci in metabolic syndrome 17 .…”

Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches

“…The GCKR rs1260326-T is associated with metabolism-related mechanisms, such as glycolysis, fatty acid circulation, and saturation. Yuan et al observed an increase in TG levels of rs1260326-T carriers and demonstrated an association between GCKR rs1260326-T and fatty liver by studying the elderly Chinese Han population [ 72 ]. Furthermore, Nahass et al confirmed that GCKR rs1260326 allele T was associated with susceptibility to NAFLD [ 83 ].…”

Advances in genetic variation in metabolism-related fatty liver disease

“…GCKR P446L is a functionally deficient variant that increases fat production by inducing glycolysis ( Carlsson et al, 2020 ). The variation of GCKR is associated with a variety of lipid metabolism disorders ( Fernandes Silva et al, 2019 ), significantly affected the MAFLD ( Yuan et al, 2022 ). A meta-analysis showed that both the GCKR rs780094 and rs1260326 polymorphisms were significantly associated with an increased risk of MAFLD ( Li et al, 2021 ).…”