Association between PPARGC1A single nucleotide polymorphisms and increased risk of nonalcoholic fatty liver disease among Iranian patients with type 2 diabetes mellitus

Saremi, Leila; Lotfıpanah, Shirin; Mohammadi, Masumeh; Hosseinzadeh, Hassan; Hosseini‐Khah, Zahra; Johari, Behrooz; Saltanatpour, Zohreh

doi:10.3906/sag-1808-138

Cited by 7 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because this polymorphism made the PPARGC1A structure more rigid, Gly482Ser polymorphism has a critical damaging impact on protein function and its structural orientation. This prediction is supported by the cited experimental data [ 26 , 27 ], and the results of this study will help wet lab researchers expand potent treatments against PPARGC1A.…”

Section: Discussionsupporting

confidence: 82%

“…In another study, Yongsakulchai et al suggested that the combination of PPAR- γ C1431T, PGC-1 α Gly482Ser, and LXR α −115G/A polymorphisms increase the risk of CAD and were predictive of the severity of coronary atherosclerosis [ 73 ]. We studied the in vitro effect of Gly482Ser polymorphism on NAFLD and CAD's pathogenesis in type 2 diabetic patients in two of our previous studies [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases

2021

Self Cite

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PPARGC1A) regulates the expression of energy metabolism’s genes and mitochondrial biogenesis. The essential roles of PPARGC1A encouraged the researchers to assess the relation between metabolism-related diseases and its variants. To study Gly482Ser (+1564G/A) single-nucleotide polymorphism (SNP) after PPARGC1A modeling, we substitute Gly482 for Ser482. Stability prediction tools showed that this substitution decreases the stability of PPARGC1A or has a destabilizing effect on this protein. We then utilized molecular dynamics simulation of both the Gly482Ser variant and wild type of the PPARGC1A protein to analyze the structural changes and to reveal the conformational flexibility of the PPARGC1A protein. We observed loss flexibility in the RMSD plot of the Gly482Ser variant, which was further supported by a decrease in the SASA value in the Gly482Ser variant structure of PPARGC1A and an increase of H-bond with the increase of β-sheet and coil and decrease of turn in the DSSP plot of the Gly482Ser variant. Such alterations may significantly impact the structural conformation of the PPARGC1A protein, and it might also affect its function. It showed that the Gly482Ser variant affects the PPARGC1A structure and makes the backbone less flexible to move. In general, molecular dynamics simulation (MDS) showed more flexibility in the native PPARGC1A structure. Essential dynamics (ED) also revealed that the range of eigenvectors in the conformational space has lower extension of motion in the Gly482Ser variant compared with WT. The Gly482Ser variant also disrupts PPARGC1A interaction. Due to this single-nucleotide polymorphism in PPARGC1A, it became more rigid and might disarray the structural conformation and catalytic function of the protein and might also induce type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). The results obtained from this study will assist wet lab research in expanding potent treatment on T2DM.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases

2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The A allele of rs8192678 SNP in PPARGC1A gene is a risk factor for NAFLD development in adult Iranian and Chinese Han populations [ 69 , 91 ] . However, the SNP was not associated with the biochemical and physiological parameters investigated in the study, including body mass index, fasting blood sugar, creatine, TGs, plasma lipid levels, HbA1c, and microalbumin levels.…”

Section: Resultsmentioning

confidence: 99%

“…However, the SNP was not associated with the biochemical and physiological parameters investigated in the study, including body mass index, fasting blood sugar, creatine, TGs, plasma lipid levels, HbA1c, and microalbumin levels. PPARGC1A is a transcriptional factor involved in lipid and energy metabolism [ 69 ] . The gene encodes peroxisome proliferator-activated receptor PGC-1α, which is highly expressed in the liver.…”

Section: Resultsmentioning

confidence: 99%

Update on Non-Alcoholic Fatty Liver Disease-Associated Single Nucleotide Polymorphisms and Their Involvement in Liver Steatosis, Inflammation, and Fibrosis: A Narrative Review

Astarini

Ratnasari

Wasityastuti

2022

IBJ

View full text Add to dashboard Cite

Genetic factors are involved in the development, progression, and severity of NAFLD. Polymorphisms in genes regulating liver functions may increase liver susceptibility to NAFLD. Therefore, we conducted this literature study to present recent findings on NAFLD-associated polymorphisms from published articles in PubMed from 2016 to 2021. From 69 selected research articles, 20 genes and 34 SNPs were reported to be associated with NAFLD. These mutated genes affect NAFLD by promoting liver steatosis (PNPLA3, MBOAT7, TM2SF6, PTPRD, FNDC5, IL-1B, PPARGC1A, UCP2, TCF7L2, SAMM50, IL-6, AGTR1, and NNMT), inflammation (PNPLA3, TNF-α, AGTR1, IL-17A, IL-1B, PTPRD, and GATAD2A), and fibrosis (IL-1B, PNPLA3, MBOAT7, TCF7L2, GATAD2A, IL-6, NNMT, UCP, AGTR1, and TM2SF6). The identification of these genetic factors helps to better understand the pathogenesis pathways of NAFLD

show abstract

“…However, Tai et al [ 8 ] reported that the PPARGC1A variant rs8192678 was associated with liver biopsy-proven NASH in severely obese Taiwanese patients[ 8 ]. Saremi et al [ 32 ] also indicated that the AA genotype and A allele of PPARGC1A increased in Iranian patients with liver biopsy-proven NAFLD[ 32 ]. The frequency of the PPARGC1A rs8192678 A allele was 0.453 in Han Chinese, 0.350 in Europeans, and 0.040 in Africans according to the National Center for Biotechnology Information human SNP database, which inferred that the PPARGC1A rs8192678 risk A allele conferred a higher genetic susceptibility to NAFLD in Asians than in Europeans and Africans[ 7 ].…”

Section: Discussionmentioning

confidence: 99%

PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease

Zhang¹,

Shen²,

Pan³

et al. 2021

WJG

View full text Add to dashboard Cite

BACKGROUND The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease (NAFLD) requires further confirmation. In addition, it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population. AIM To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis (NASH), and whether this polymorphism is associated with hepatic histological features. METHODS Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population. The SAF (steatosis, activity, and fibrosis) scoring system was used for hepatic histopathological evaluation. The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 were genotyped. The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction. RESULTS Thirty-seven patients with NAFLD had NASH, of which 12 were nonobese. The PPARGC1A rs8192678 risk A allele (carrying GA and AA genotypes) had the lowest P value in the dominant model; the odds ratio (OR) for NAFLD was 2.321 [95% confidence interval (CI): 1.121-4.806]. After adjusting for age, sex, and the PNPLA3 rs738409 risk G allele, the PPARGC1A rs8192678 A allele was a risk factor for NAFLD (OR 2.202, 95%CI: 1.030-4.705, P = 0.042). The genetic analysis showed that patients with NAFLD, moderate-to-severe steatosis (S2-3), and Activity 2-4 (A ≥ 2) were more likely to carry A in PPARGC1A rs8192678 (OR 5.000, 95%CI: 1.343-18.620, P = 0.012; and OR 4.071, 95%CI: 1.076-15.402, P = 0.031). The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3, A ≥ 2, and NASH (OR 6.190, 95%CI: 1.508-25.410, P = 0.011; OR 4.506, 95%CI 1.070-18.978, P = 0.040; and OR 6.337, 95%CI: 1.135-35.392, P = 0.035, respectively) after adjusting for age, sex, body mass index, and PNPLA3 rs738409 risk G allele. The results also showed that this polymorphism was associated with nonobese NASH (OR 22.000, 95%CI: 1.540-314.292, P = 0.021). The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele ( P = 0.014). CONCLUSION The PPARGC1A rs8192678 risk A allele is associated with NAFLD, and with S2-3, A ≥ 2 and NASH in NAFLD patients, independent of PNPLA3 rs738409, and may be associated with nonobese NASH.

show abstract

Association between PPARGC1A single nucleotide polymorphisms and increased risk of nonalcoholic fatty liver disease among Iranian patients with type 2 diabetes mellitus

Cited by 7 publications

References 21 publications

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases

Computational Analysis of Gly482Ser Single-Nucleotide Polymorphism in PPARGC1A Gene Associated with CAD, NAFLD, T2DM, Obesity, Hypertension, and Metabolic Diseases

Update on Non-Alcoholic Fatty Liver Disease-Associated Single Nucleotide Polymorphisms and Their Involvement in Liver Steatosis, Inflammation, and Fibrosis: A Narrative Review

PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease

Contact Info

Product

Resources

About