Dataset Information

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.

ABSTRACT:

Introduction

This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD).

Methods

PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest.

Results

The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers.

Discussion

This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.

SUBMITTER: Vilar-Gomez E

PROVIDER: S-EPMC8087619 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.

Vilar-Gomez Eduardo E Pirola Carlos Jose CJ Sookoian Silvia S Wilson Laura A LA Belt Patricia P Liang Tiebing T Liu Wanqing W Chalasani Naga N

The American journal of gastroenterology 20210501 5

<h4>Introduction</h4>This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD).<h4>Methods</h4>PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of ...[more]

PMID: 33306506

Similar Datasets

Project description:The unclear link between intake of polyunsaturated fatty acids (PUFAs) and risk of cardiovascular disease (CVD) could depend on genetic differences between individuals. Minor alleles of single-nucleotide polymorphisms (SNPs) in the ∆5 fatty acid desaturase (FADS) 1 gene were associated with lower blood concentrations of long-chain ω-3 (n-3) and ω-6 (n-6) PUFAs, indicating an associated loss of function effect. We examined whether the SNP rs174546 in FADS1 modifies the association between PUFA intakes and CVD risk. We included 24,032 participants (62% women, aged 44-74 y) from the Malmö Diet and Cancer cohort without prevalent CVD and diabetes. During a mean follow-up of 14 y, 2648 CVD cases were identified. Diet was assessed by a modified diet history method. A borderline interaction was observed between the α-linolenic acid (ALA) (18:3n-3)-to-linoleic acid (LA) (18:2n-6) intake ratio and FADS1 genotype on CVD incidence (P = 0.06). The ALA-to-LA intake ratio was inversely associated with CVD risk only among participants homozygous for the minor T-allele (HR for quintile 5 vs. quintile 1 = 0.72; 95% CI: 0.50, 1.04; P-trend = 0.049). When excluding participants reporting unstable food habits in the past (35%), the interaction between the ALA-to-LA intake ratio and FADS1 genotype on CVD incidence was strengthened and statistically significant (P = 0.04). Additionally, we observed a significant interaction between ALA and FADS1 genotype on ischemic stroke incidence (P = 0.03). ALA was inversely associated with ischemic stroke only among TT genotype carriers (HR for quintile 5 vs. quintile 1 = 0.50; 95% CI: 0.27, 0.94; P-trend = 0.02). In this large cohort, we found some weak, but not convincing, evidence of effect modification by genetic variation in FADS1 on the associations between PUFA intakes and CVD risk. For the 11% of the population homozygous for the minor T-allele of rs174546 that associates with lower ∆5 FADS activity, high ALA intake and ALA-to-LA intake ratio may be preferable in the prevention of CVD and ischemic stroke.

Project description:Background and aimsIt is unclear whether rs738409 (p.I148M) missense variant in patatin-like phospholipase domain-containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy-proven NAFLD.Approach and resultsCausal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non-Hispanic White patients. Total effect of rs738409 on fibrosis was β = 0.19 (95% CI: 0.09-0.29). The direct effect of rs738409 on fibrosis after removing mediators' effects was β = 0.09 (95% CI: 0.01-0.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were β = 0.010 (95% CI: 0.04-0.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (β = 0.09, 95% CI: 0.05-0.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (β = 0.023, 95% CI: 0.011-0.037). Mediation analysis in a separate group of 404 individuals with biopsy-proven NAFLD from other races and ethnicity showed similar results.ConclusionsIn NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.

Project description:BackgroundThe fibrosis-4 (FIB-4) index is a non-invasive method to assess the severity of liver fibrosis. The development of liver fibrosis is influenced by genetic predisposition and dietary factors. However, the modulating effect of dietary factors on the genetic susceptibility of liver fibrosis remains unclear. The study aims to investigate the role of dietary factors in modulating the genetic susceptibility of liver fibrosis.MethodsHere, we conducted a genome-wide association study (GWAS) of FIB-4 index-directed liver fibrosis risk, adjusted with diet, lifestyle factors, and hepatitis serological markers. The high (N = 1,476) and low (N = 36,735) liver fibrosis risk groups were defined with a FIB-4 > 2.67 and < 1.3, respectively.ResultsThe age-related FIB-4 variation showed subjects with a FIB-4 > 2.67 (3.8%), indicating high fibrosis risk, occurred predominantly among individuals above 60 years old. The multivariable analysis showed that tea intake is significantly associated with a reduced risk of liver fibrosis. The GWAS adjusted for sex, age, age2, dietary factors (tea and coffee consumption, vegetarian preference), lifestyle (alcohol consumption, physical activity), hepatitis serological markers (anti-HCV, HBsAg, HBeAg), and the top ten principal components indicated 25 genome-wide significant signals (p < 5 × 10- 8). Two variants (rs56293029 and rs9389269) were previously associated with the FIB-4 index in alcohol-related cirrhosis, while the 23 SNPs remaining were novel. The rs9399136 (HBS1L) is a protective variant, and rs9274407 (HLA-DQB1) is a risk variant, both contributing to liver fibrosis development. Our results showed that genetic factors play a major role in liver fibrosis, while dietary factors have minor effects on disease progression. Pathway analysis suggested the potential of immune response and hematopoietic systems function in the pathogenesis of liver disease.ConclusionsThe studies not only revealed the protective role of rs9399136 (HBS1L) and the risk effect of rs9274407 (HLA-DQB1) toward liver fibrosis in a Taiwanese population, but also demonstrated that individual consumption patterns, such as tea uptake, have a minor impact on liver fibrosis prevention. The pathway analysis from GWAS variants further indicated the importance of immune responses in the pathogenesis of liver fibrosis.

Project description:IntroductionThe burden of non-alcoholic fatty liver disease (NAFLD) continues to disproportionately impact under-resourced communities in the U.S., particularly Mexican-origin populations. Genetic polymorphisms such as the rs738409 C/G variant in patatin-like phospholipase domain-containing 3 (PNPLA3) have been associated with higher prevalence of and progression along the NAFLD spectrum. This qualitative study conducted in the U.S. Southwest aimed to assess Mexican-origin men's experience receiving genetic testing for PNPLA3 risk carrier status.MethodsSemi-structured interviews were conducted with 17 Mexican-origin men whose NAFLD status and genetic predisposition were determined as part of a previous cross-sectional study. The interview guide included questions exploring participants' insights on how genetic risk status was delivered, how the information influenced their motivation for lifestyle modification to reduce NAFLD risk, and any knowledge sharing that occurred with family members after learning of their PNPLA3 risk status. Interviews were conducted and audio recorded in English (n = 6) and Spanish (n = 11) and uploaded into NVivo software for data analysis and interpretation. Guided by the Health Belief Model, a thematic analysis approach was used to identify primary themes.ResultsResults highlighted men's preference for receiving this type of genetic risk information through a letter sent to their homes. General comprehension of PNPLA3 risk status was deemed high and most men stated sharing their genetic predisposition to NAFLD with their immediate family members. Participants also indicated that family and awareness of this genetic risk acted as primary motivators for implementing behavior changes (e.g., diet, physical activity) toward the prevention of more severe liver conditions.DiscussionFindings from this qualitative study suggest the feasibility of communicating genetic risk for NAFLD among Mexican-origin men. Future strategies for the dissemination of genetic risk results among Mexican-origin individuals should consider familial and cultural appropriate strategies.

Project description:BackgroundReliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined.MethodsWe retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors.ResultsA score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%.ConclusionsOur results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients.

Dataset Information

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.

Introduction

Methods

Results

Discussion

Publications

Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets