Association study of  PNPLA2  gene with histological parameters of NAFLD in an obese population

Zegers, Doreen; Verrijken, An; Beckers, Sigri; Francque, Sven; Camp, Jasmijn K. Van; Aerts, Evi; Ruppert, Martin; Hubens, Guy; Michielsen, P.; Hul, Wim Van; Gaal, Luc F. Van

doi:10.1016/j.clinre.2015.09.001

Cited by 7 publications

(11 citation statements)

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“…Thus, 16 genes could be associated with obesity in children. For instance, several of them have been identified in previous obesity studies including ACACB , ACSS , ADIPOQ , DGAT2 , HSL , FASN , PNPLA2 , PNPLA3 , PPAR-γ , SREBP1 SNP17 and TNF [ 25 – 37 ].…”

Section: Discussionmentioning

confidence: 99%

Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children

et al. 2017

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ObjectiveWe used targeted next-generation sequencing to investigate whether genetic variants of lipid metabolism-related genes are associated with increased susceptibility to nonalcoholic fatty liver disease (NAFLD) in obese children.MethodsA cohort of 100 obese children aged 6 to 18 years were divided into NAFLD and non-NAFLD groups and subjected to hepatic ultrasound, anthropometric, and biochemical analyses. We evaluated the association of genetic variants with NAFLD susceptibility by investigating the single nucleotide polymorphisms in each of 36 lipid-metabolism-related genes. The panel genes were assembled for target region sequencing. Correlations between single nucleotide variations, biochemical markers, and clinical phenotypes were analyzed.Results97 variants in the 36 target genes per child were uncovered. Twenty-six variants in 16 genes were more prevalent in NAFLD subjects than in in-house controls. The mutation rate of MTTP rs2306986 and SLC6A2 rs3743788 was significantly higher in NAFLD subjects than in non-NAFLD subjects (OR: 3.879; P = 0.004; OR: 6.667, P = 0.005). Logistic regression analysis indicated the MTTP variant rs2306986 was an independent risk factor for NAFLD (OR: 23.468, P = 0.044).ConclusionsThe results of this study, examining a cohort of obese children, suggest that the genetic variation at MTTP rs2306986 was associated with higher susceptibility to NAFLD. This may contribute to the altered lipid metabolism by disruption of assembly and secretion of lipoprotein, leading to reducing fat export from the involved hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children

et al. 2017

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“…Likewise, the enzyme adipose triglyceride lipase ATGL (PNPLA2 gene) is key in the initiation of TG lipolysis, hence, it is the leading protein involved in TG mobilization to free fatty acids (FFA) and glycerol. FFA mobilization is one of the main metabolic changes in obesity and its complications [11,12]. PNPLA2 is negatively regulated by insulin and positively regulated by beta-adrenergic receptors and its genetic defect manifests neutral lipid storage disease and myopathy associated with fatty liver [13].…”

Section: Introductionmentioning

confidence: 99%

Association of the PNPLA2, SCD1 and Leptin Expression with Fat Distribution in Liver and Adipose Tissue From Obese Subjects

Cruz-Color

Hernández‐Nazará

Maldonado-González

et al. 2019

Exp Clin Endocrinol Diabetes

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The expansion of adipose tissue is regulated by insulin and leptin through SREBP-1c, up-regulating lipogenesis in tissues by SCD1 enzyme, while ATGL enzyme is key in lipolysis. The research objective was to evaluate the expression of SREBF1, SCD1, PNPLA2, and LEP genes in hepatic-adipose tissue, and related them with the increment and distribution of fat depots of individuals without insulin resistance. Thirty-eight subjects undergoing elective cholecystectomy with liver and adipose tissue biopsies (subcutaneous-omental) are included. Tissue gene expression was assessed by qPCR and biochemical parameters determined. Individuals are classified according to the body mass index, classified as lean (control group, n=12), overweight (n=11) and obesity (n=15). Abdominal adiposity was determined by anthropometric and histopathological study of the liver. Increased SCD1 expression in omental adipose tissue (p=0.005) and PNPLA2 in liver (p=0.01) were found in the obesity group. PNPLA2 decreased expression in subcutaneous adipose tissue was significant in individuals with abdominal adiposity (p=0.017). Anthropometric parameters positively correlated with liver PNPLA2 and the expression of liver PNPLA2 with serum leptin. SCD1 increased levels may represent lipid storage activity in omental adipose tissue. Liver PNPLA2 increased expression could function as a primary compensatory event of visceral fat deposits associated to the leptin hormone related to the increase of adipose tissue.

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“…Among them, the SNPs that change the binding affinity of transcription factors or miRNA and affect gene expression constitute an important class of regulatory SNPs [ 35 ]. In our study, SNP rs28633403, located at 5.6 kb upstream of PNPLA2 gene on chromosome 11, was found to be a tagSNP of PNPLA2 gene [ 13 ]. The effects of transcription factor binding and methylation levels might be involved in the underlying mechanism by which PNPLA2 rs28633403 leads to DKD susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…PNPLA2 is a susceptibility gene of nonalcoholic fatty liver disease (NAFLD) in an obese population [ 13 ]. Rs28633403 (A>G) and rs1138714 (A>G) are tagSNPs in PNPLA2 gene with the frequency of minor allele greater than 5%, and rs1138693 (T>C) is a missence polymorphism (L481P) in coding sequence.…”

Section: Introductionmentioning

confidence: 99%

“…Genetic studies in obese individuals have shown that rs1138714 was associated with fat mass percentage and volume of subcutaneous adipose tissue, and rs28633403 was related to fat mass percentage and subcutaneous adipose tissue. For SNP rs1138693, it is a risk factor for susceptibility to increased levels of Aminotransferase (AST) enzyme [ 13 ]. However, the association of the SNPs with DKD is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Association between PNPLA2 Gene Polymorphisms and the Risk of Diabetic Kidney Disease in a Chinese Han Population with Type 2 Diabetes

Zhao

Zhang

Wang

et al. 2020

Journal of Diabetes Research

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Diabetic kidney disease (DKD) is one of the most common complications of diabetes and the leading cause of end-stage renal disease. Here, we investigated the association of PNPLA2 gene variations with DKD susceptibility in a Chinese Han population. A total of 818 participants with type 2 diabetes were recruited in the case-control study, including 379 patients diagnosed with DKD. We observed that 2 tagSNPs, PNPLA2 rs28633403 (A>G) and rs1138714 (A>G), were associated with DKD (rs28633403: genotype, P=0.017; allele, P=0.015; rs1138714: genotype, P=0.029; allele, P=0.018). PNPLA2 rs1138693 (T>C), a missense SNP, showed no association with DKD (genotype, P=0.966; allele, P=0.845). Genetic model analysis revealed that minor allele G of PNPLA2 rs28633403 was a protective factor of DKD in a dominant model adjusted by confounders (AG+GG vs. AA: adjusted odds ratio (aOR), 0.619; 95% CI 0.447-0.857; P=0.004) and in an additive model (AG vs. AA: aOR, 0.633; 95% CI 0.447-0.895; P=0.010; GG vs. AA: aOR, 0.588; 95% CI 0.385-0.897; P=0.014). Minor allele G of PNPLA2 rs1138714 was associated with a higher risk of DKD in a dominant model adjusted by confounders (AG+GG vs. AA: adjusted odds ratio (aOR), 1.531; 95% CI 1.134-2.067; P=0.005) and in an additive model (AG vs. AA: aOR, 1.529; 95% CI 1.118-2.091; P=0.008). The combined effect of PNPLA2 rs28633403 AA+rs1138714 AG or GG genotype showed an association with DKD, adjusted by confounders (aOR, 2.194; 95% CI 1.378-3.492; P=0.001), which was considered statistically significant with a markedly increased risk of DKD after a Holm-Bonferroni correction for multiple tests (P<0.00125). Our results suggest that PNPLA2 rs28633403 and rs1138714 are significantly associated with the risk of DKD in a Chinese Han population with type 2 diabetes.

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Association study of PNPLA2 gene with histological parameters of NAFLD in an obese population

Abstract: Although we found evidence for moderate association between PNPLA2 tagSNPs and anthropometric and metabolic parameters in our cohort, no evidence for association between polymorphisms in the PNPLA2 gene and the presence and severity of NAFLD was identified.

Cited by 7 publications

References 36 publications

Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children

Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children

Association of the PNPLA2, SCD1 and Leptin Expression with Fat Distribution in Liver and Adipose Tissue From Obese Subjects

Association between PNPLA2 Gene Polymorphisms and the Risk of Diabetic Kidney Disease in a Chinese Han Population with Type 2 Diabetes

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