Patatin-like Phospholipase Domain-containing 3 Rs738409 Research Articles

A nutrigenetic precision approach for the management of non-alcoholic fatty liver disease

The Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of non-alcoholic fatty liver disease (NAFLD) and is strongly regulated by changes in energy balance and dietary factors. We aimed to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity. PNPLA3-rs738409 SNP was genotyped in 181 patients with NAFLD who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530, Echosens). According to the established cut-off, a CAP value≥300dB/m was used to identify severe steatosis (S3). An independent group of 46 biopsy-proven NAFLD subjects was used as validation cohort. Overall, median age was 53 years (range 44; 62) and 60.2% of patients were male. Most subjects (56.3%) had S3 and showed increased liver stiffness (p<0.001), AST (p=0.003) and ALT levels (p<0.001) compared to those with CAP<300dB/m. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with S3 (p=0.001). The same result was confirmed in the validation cohort, were the interaction between high carbohydrate intake (48%) and PNPLA3 SNP was significantly associated with steatosis ≥33% (p=0.038). The intake of greater than or equal to 48% carbohydrate in NAFLD patients carriers of the CG/GG allele of PNPLA3 rs738409 may increase the risk of significant steatosis.

The variability of PNPLA3 gene as a potential marker of cold adaptation in Yakuts

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. It has been reported that specific variants of patatin-like phospholipase domain-containing 3 (PNPLA3) gene, notably SNPs rs738409 and rs2294918 are associated with high risks of liver disease. PNPLA3 rs738409 polymorphism is the main determinant of fatty liver and affects development and progression of NAFLD. rs2294918 is another SNP localised in PNPLA3 gene, it is associated with reduced expression of the PNPLA3 protein, lowering the effect of the rs738409:G variant on predisposition to steatosis and liver damage. The frequencies of alleles, genotypes, haplotypes and diplotypes (combinations of genotypes at two loci) of polymorphic variants of the PNPLA3 gene (rs2294918 and rs738409) were studied in the cohort of Yakuts (n = 150) living in the Republic of Sakha (Yakutia). Genotyping of PNPLA3 (rs738409 and rs2294918) was performed by PCR-PDRF method. The single nucleotide polymorphism rs738409 (I148M) of the PNPLA3 gene in the Yakut population is characterised by a high frequency of the risk allele G (72%). Analysis of the distribution frequency of the rs2294918 polymorphism genotypes showed that the allele G was predominant in 89.3% of individuals of the studied group of Yakuts. In this study, we identified two major diplotypes [GG][GG] and [CG][GG]. The high frequency of the mutant rs738409: G variant in Yakuts may be an adaptation of the organism to low temperatures. The study of the adiponutringene may be an important key to understanding the mechanisms of adaptation to low temperatures and metabolic processes in the indigenous population of the North.

Combined effect of PNPLA3 rs738409 and UGT1A1 rs10929303 gene polymorphisms on nonalcoholic fatty liver disease in children

Objective: To investigate the combined effects of patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (C > G) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) rs10929303 (C > T) on nonalcoholic fatty liver disease (NAFLD) in children and adolescents so as to provide scientific evidence for NAFLD genetic research. Methods: 1 027 children and adolescents aged 7-18 were selected as the research subjects. The general situation, past medical history, height and body weight measurements, and B- mode ultrasound test of the liver were investigated by dedicated full-time personnel. In addition, the morning fasting venous blood was collected to measure the blood biochemical indicators. DNA was extracted and genotyped for PNPLA3 rs738409 and UGT1A1 rs10929303. Logistic regression analysis was used to analyze the association and combined effect of the two gene polymorphisms and NAFLD. Statistical analysis was performed by t-test, Mann-Whitney U test, or c2 test according to different data. Results: The GG genotype of PNPLA3 rs738409 and the CC genotype of UGT1A1 rs10929303 were associated with an increased risk of developing NAFLD in children by 89% (OR = 1.89, 95% CI: 1.11-3.23, P = 0.019) and 96% (OR = 1.96, 95% CI: 1.21-3.17, P = 0.006), respectively, while the concurrent risk of NAFLD in those who carried the above two genotypes increased by 306% compared with those who did not carry both genotypes (OR = 4.06, 95% CI: 1.90 ~ 8.66, P < 0.001). Conclusion: The combined effect of PNPLA3 and UGT1A1 gene polymorphisms can significantly increase the risk of NAFLD in children, providing new evidence for elucidating the genetic susceptibility to NAFLD.

Association of PNPLA3 SNP With the Development of HBV-related Hepatocellular Carcinoma.

Concomitant nonalcoholic fatty liver disease (NAFLD)/hepatic steatosis (HS) is suggested to increase the risk of hepatocellular carcinoma (HCC) in hepatitis virus B (HBV)-infected patients. Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 gene single-nucleotide polymorphism (SNP) is well-known to be associated with the development of NAFLD/HS; however, it is still unclear whether this SNP is related to the development of HCC in HBV-infected patients. We investigated a total of 202 HBV-infected patients who received percutaneous liver biopsy, and simultaneously assessed biopsy-proven HS, insulin resistance, and the PNPLA3 SNP status. We further investigated the relationships of these factors with the development of HCC in HBV-infected patients. Most of the enrolled cases (196/202: 97.0%) were non-cirrhotic patients. One hundred seventy-three patients (85.6%) received antiviral therapy. A Kaplan-Meier analysis showed that the incidence of HCC development in patients with HS was higher than that in patients without HS (p<0.01). An increased homeostasis model assessment as an index of insulin resistance (HOMA-IR) value (≥1.6) was associated not only with the presence of HS (p<0.0001) but also with the development of HCC (p<0.01). The PNPLA3 rs738409 SNP was also associated with the presence of HS (p<0.01) and the development of HCC (p<0.05) in HBV-infected patients. In addition to HS and IR, PNPLA3 rs738409 SNP was suggested to be associated with the development of HCC in Japanese patients with HBV infection.

Profiling of cell-free DNA methylation and histone signatures in pediatric NAFLD: A pilot study.

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children and adolescents, increasing the risk of its progression toward nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. There is an urgent need for noninvasive early diagnostic and prognostic tools such as epigenetic marks (epimarks), which would replace liver biopsy in the future. We used plasma samples from 67 children with biopsy-proven NAFLD, and as controls we used samples from 20 children negative for steatosis by ultrasound. All patients were genotyped for patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O-acyltransferase domain containing 7 (MBOAT7), and klotho-β (KLB) gene variants, and data on anthropometric and biochemical parameters were collected. Furthermore, plasma cell-free DNA (cfDNA) methylation was quantified using a commercially available kit, and ImageStream(X) was used for the detection of free circulating histone complexes and variants. We found a significant enrichment of the levels of histone macroH2A1.2 in the plasma of children with NAFLD compared to controls, and a strong correlation between cfDNA methylation levels and NASH. Receiver operating characteristic curve analysis demonstrated that combination of cfDNA methylation, PNPLA3 rs738409 variant, coupled with either high-density lipoprotein cholesterol or alanine aminotransferase levels can strongly predict the progression of pediatric NAFLD to NASH with area under the curve >0.87. Conclusion: Our pilot study combined epimarks and genetic and metabolic markers for a robust risk assessment of NAFLD development and progression in children, offering a promising noninvasive tool for the consistent diagnosis and prognosis of pediatric NAFLD. Further studies are necessary to identify their pathogenic origin and function.

Genetic variants associated with metabolic dysfunction-associated fatty liver disease in western China.

IntroductionWe aimed to confirm the association between some single nucleotide polymorphisms (SNPs) and metabolic dysfunction‐associated fatty liver disease (MAFLD) in western China.MethodsA total of 286 cases and 250 healthy controls were enrolled in our study. All samples were genotyped for patatin‐like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, membrane‐bound O‐acyltransferase domain containing 7 (MBOAT7) rs641738, glucokinase regulator (GCKR) rs1260326 and rs780094, and GATA zinc finger domain containing 2A (GATAD2A) rs4808199. Using logistic regression analysis, we evaluated the association between MAFLD and each SNP under different models. Multiple linear regression was used to find the association between SNPs and laboratory characteristics. Multifactor dimensionality reduction was applied to test SNP–SNP interactions.ResultsThe recessive model and additive model of PNPLA3 rs738409 variant were related to MAFLD (odds ratio [OR] = 1.791 and 1.377, respectively, p = 0.038 and 0.027, respectively). However, after Benjamini‐Hochberg adjustment for multiple tests, all associations were no longer statistically significant. PNPLA3 rs738409 correlated with AST levels. GCKR rs780094 and rs1260326 negatively correlated with serum glucose but positively correlated with triglycerides in MAFLD. Based on MDR analysis, the best single‐locus and multilocus models for MAFLD risk were rs738409 and six‐locus models, respectively.ConclusionsIn the Han population in western China, no association was found between these SNPs and the risk of MAFLD. PNPLA3 rs738409 was associated with aspartate aminotransferase levels in MAFLD patients. GCKR variants were associated with increased triglyceride levels and reduced serum fasting glucose in patients with MAFLD.

Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans.

In nonalcoholic fatty liver disease (NAFLD) the patatin‐like phospholipase domain‐containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well‐characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2–4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.

Low skeletal muscle mass is associated with more severe histological features of non-alcoholic fatty liver disease in male.

Although low skeletal muscle mass is associated with non-alcoholic fatty liver disease (NAFLD), it is currently uncertain whether there are associations between weight-adjusted appendicular skeletal muscle (ASM%), severity of histological features of NAFLD, and the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. Our aim was to test for a possible influence of the PNPLA3 rs738409 variant on the association between ASM% and severity of NAFLD histological features. We enrolled 401 Chinese male with biopsy-proven NAFLD. Using a bioelectrical-impedance body composition analyzer (BIA, Inbody 720, Japan Inc., Tokyo), we calculated the ASM% as the percentage of total appendicular skeletal muscle mass (ASM, kg)/total body mass (kg) × 100. Compared to those with high ASM%, patients with low ASM% (≤ 30.6, i.e., the median value of distribution of the whole sample) had a greater severity of individual histological features of NAFLD. These patients also had a higher risk of severe steatosis and non-alcoholic steatohepatitis (NASH) (adjusted-odds ratio [OR] 2.34, 95% CI 1.39-3.93, and adjusted-OR 2.22, 95% CI 1.30-3.77) even after adjusting for age, body mass index, diabetes, and serum creatinine levels. Carriage of the G allele of PNPLA3 rs738409 plus low ASM% was associated with a higher risk of severe steatosis and presence of liver fibrosis (OR 3.02, 95% CI 1.46-6.26, p = 0.003 and OR 2.18, 95% CI 1.03-4.60, p = 0.041 respectively), and there was a non-significant but borderline increased risk of NASH (OR 2.00, 95% CI 0.98-4.06, p = 0.056). Low ASM% and the presence of a G allele within PNPLA3 rs738409 is associated with more severe histological features of NAFLD.

Evaluation of the association of a variant in PNPLA3 and TM6SF2 with fibrosis progression in patients with chronic hepatitis C infection after eradication: A retrospective study.

The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI]=1.096-5.794, p=0.03). The G and GG alleles were predictive of advanced fibrosis (OR=1.98, 95% CI=1.021-4.196, p=0.015; OR=3.12, 95% CI=1.572-6.536, p=0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI=1.081-6.29, p=0.033). T and TT alleles were predictive of advanced fibrosis (OR=2.3, 95% CI=1.005-5.98, p=0.007; OR=3.05, 95% CI=1.32-6.87, p=0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI=0.707-2.959, p=0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR=2.47, 95% CI=1.125-5.89, p=0.003). The GG alleles were predictive of fibrosis progression (OR=2.95, 95% CI=1.35-6.35, p=0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI=1.006-5.373, p=0.045; 95% CI=1.18-5.75, p=0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR=2.218, 95% CI=1.095-5.631, p=0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR=2.558, 95% CI=1.252-5.15, p=0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI=1.013-5.592, p=0.038; 95% CI=1.25-5.956, p=0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI=1.02-2.575, p=0.017; and HR2.109, 95% CI=1.36-3.271, p=0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR=1.322, 95% CI=1.003-1.857, p=0.045; and HR=1.855, 95% CI=1.35-2.765, p=0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.

Protective association of Klotho rs495392 gene polymorphism against hepatic steatosis in non-alcoholic fatty liver disease patients.

Background/AimsNon-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD.MethodsWe evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed.ResultsCarriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42–0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45–0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis.ConclusionsThe KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.

The Risk of Cirrhosis and Its Complications Based on PNPLA3 rs738409 G Allele Frequency

Background: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. Objective: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. Methods: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC was composed of the presence and absence of complications, such as variceal bleeding, hepatic ascites, and hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort and (ii) the presence and absence of complications in the patients with LC. Results: There was a significant difference among the patients without LC and those with alcohol, NAFLD-related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD-related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol-related cirrhosis unless there was a presence of G alleles. Conclusion: The PNPLA3 polymorphism was associated with the risk of NAFLD-related LC and its complications.

PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsy-proven Nonalcoholic Fatty Liver Disease.

Background and AimsIntra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease (NAFLD). We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.MethodsThe variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD. Visceral fat area (VFA) was measured by bioelectrical impedance. Significant liver fibrosis (SF), defined as stage F ≥2 on histology, was the outcome measure of interest.ResultsThe distribution of PNPLA3 genotypes was CC: 27.5%, CG: 48.2%, and GG: 24.3%. Higher VFA was associated with greater risk of having SF (adjusted-odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.02–1.04, p<0.05), independent of potential confounders. Among subjects with the same VFA level, the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not. Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF. VFA remained significantly associated with SF only among the rs738409 G-allele carriers (adjusted-OR: 1.05; 95% CI: 1.03–1.08 for the GG group; and adjusted-OR:1.03; 95% CI: 1.01–1.04 for the GC group). There was a significant interaction between VFA and PNPLA3 rs738409 genotype (Pinteraction=0.004).ConclusionsPNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD. Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF.

The influence of RS738409 I148M polymorphism of patatin-like phospholipase domain containing 3 gene on the susceptibility of non-alcoholic fatty liver disease

We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as mean ± standard deviation. Significant statistical level was chosen as p = 0.05.Our results demonstrate in a cohort from Turkey that rs738409 C > G polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.

A PNPLA3 Polymorphism Confers Lower Susceptibility to Incident Diabetes Mellitus in Subjects With Nonalcoholic Fatty Liver Disease

We investigated the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genotype and the risk of diabetes mellitus (DM) using a biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) cohort and a longitudinal observational cohort. Associations between genotypes and the prevalence of DM were evaluated with stratification according to the histological severity of NAFLD in the Boramae cohort (n= 706). A longitudinal cohort consisting of nondiabetic individuals with ≥2 health checkups was then selected to investigate the risk of incident DM according to the genotype (the GENIE cohort; n= 4998). Among subjects with NAFLD in the Boramae cohort, the G allele was independently associated with a lower prevalence of DM in both NAFL (odds ratio [OR] per 1 allele, 0.66; 95% confidence interval [CI], 0.46-0.97) and nonalcoholic steatohepatitis (OR per 1 allele, 0.59; 95% CI, 0.38-0.92). This result was replicated in the longitudinal GENIE cohort. The G allele was associated with a lower risk of incident DM during the median follow-up of 60 months in subjects with NAFLD (hazard ratio, 0.65; 95% CI, 0.45-0.93). In contrast, G allele carriers without NAFLD showed higher odds for DM in the context of the Boramae cohort (OR, 2.44; 95% CI, 1.00-5.95). These findings clarify conflicting results regarding the association between the PNPLA3 rs738409 genotype and the risk of DM, demonstrating a clear difference between subjects with and without NAFLD; this difference might be explained by the low metabolic risk in genetic NAFLD.

Correlation between PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphism and primary liver cancer in the Han Population of China's Northeast region

Objective: To investigate the correlation between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 gene polymorphisms and the incidence of primary liver cancer in the Han population of China's Northeast region. Methods: A case-control study was used to enroll 521 patients with primary liver cancer as the case group and 164 healthy people as the control group. The case group was divided into groups with and without liver cirrhosis according to etiology. The polymerase chain reaction (PCR) method was used to detect the genetic polymorphisms of PNPLA3 rs738409 and TM6SF2 rs58542926, respectively. Results: Compared with the control group, the frequency distribution of PNPLA3 rs738409 G allele in the case group was significantly different (OR = 1.583, P = 0.001). Further grouping showed that there was no statistically significant difference between the control and hepatitis C-related liver cancer group (P = 0.161), but there were significant differences in other groups (P < 0.05). Compared with the control group, the frequency of TM6SF2 rs58542926 T allele in the case group was significantly higher than that in the control group (OR = 1.759, P = 0.048). After grouping, the frequency of CT/TT genotype in the liver cancer group combined with liver cirrhosis and the T allele frequency in the alcohol-related liver cancer group had statistically significant difference (P = 0.045 and 0.032, respectively) when compared with control group. The patients were divided into CG/GG group and CC group, and CT/TT group and CC group according to whether they carried PNPLA3 rs738409 G allele, and TM6SF2 rs58542926 T allele. Results showed that there were no statistically significant differences in liver enzyme indexes, albumin (ALB), total bilirubin (TBIL), alpha-fetoprotein (AFP) and fasting blood glucose between CG/GG group and CC group, and CT/TT group and CC group. The patients with liver cirrhosis in the case group were divided into≥7 groups and < 7 groups according to the Child-Pugh score. Results showed that there were no statistically significant difference in the Child-Pugh score between PNPLA3 rs738409 CG/GG group and CC group patients and TM6SF2 rs58542926 CT/TT group and CC group patients (P > 0.05). Conclusion: PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphisms are correlated with the occurrence of primary liver cancer in the Han population of China's Northeast region. PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphisms have no effect on indexes' such as liver enzymes, ALB, TBIL, AFP and FBS in primary liver cancer..

Association of PNPLA3 rs738409 G/C gene polymorphism with nonalcoholic fatty liver disease in children: a meta-analysis

BackgroundNonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. Current studies have shown that PNPLA3 (Patatin-like phospholipase domain containing 3) rs738409 G/C gene polymorphism is associated with adult nonalcoholic fatty liver disease [1, 2].But there is no consensus on the relationship between PNPLA3 rs738409 G/C gene polymorphism and children NAFLD due to differences in population samples. To this end, a meta-analysis of published research is conducted to comprehensively assess the relationship between PNPLA3 gene polymorphism and NAFLD in children.MethodsWe searched MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to May 2019. Case-control studies assessing the relationship between PNPLA3 rs738409 G/C gene polymorphism with non-alcoholic fatty liver disease in children were selected according to inclusion and exclusion criteria. Random effects model was used to quantify the association between the PNPLA3 rs738409 G/C gene polymorphism and the susceptibility of children’s NAFLD. Fixed effects model was used to quantify the relationship between the PNPLA3 rs738409 G/C gene polymorphism and the severity of NAFLD in children. The Stata 12.0 software was employed for data analysis.ResultsA total of nine case-control studies were included in this meta-analysis containing data of 1173 children with NAFLD and 1792 healthy controls. Five studies compared NAFLD children and non-NAFLD healthy populations. Statistical analysis showed that PNPLA3 gene polymorphism was significantly associated with children’s NAFLD in the allele contrast, dominant, recessive and over dominant models (G vs C,OR = 3.343, 95% CI = 1.524–7.334; GG + GC vs CC,OR = 3.157, 95% CI = 1.446–6.892;GG vs GC + CC,OR = 5.692, 95% CI = 1.941–16.689; GG + CC vs GC,OR = 2.756, 95% CI = 1.729–4.392). Four case-control studies compared Children with nonalcoholic fatty liver (NAFL) and children with nonalcoholic steatohepatitis (NASH). The results showed that the PNPLA3 gene polymorphism was also significantly associated with the severity of NAFLD in children in recessive gene model (GG vs GC + CC,OR = 14.43, 95% CI = 5.985–34.997); The Egger’s test revealed no significant publication bias.ConclusionsMeta-analysis showed that PNPLA3 gene polymorphism was significantly associated with susceptibility and severity of NAFLD in children.

Genome-Wide Association Study of Liver Fat: The Multiethnic Cohort Adiposity Phenotype Study.

The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population‐specific genetic variants associated with liver fat. We conducted a genome‐wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population‐based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin‐like phospholipase domain containing 3 (PNPLA3) at 22q13 was confirmed to be associated with percent liver fat (P = 3.52 × 10−15) but more strongly in women than men (P heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA‐IR) (beta = 0.028; P = 0.009) and circulating levels of insulin (beta = 0.022; P = 0.020) and alanine aminotransferase (beta = 0.016; P = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [LMBRD1] and collagen type XIX alpha 1 chain [COL19A1] (P = 1.42 × 10−8) was also observed. Rs7724941 was associated with HOMA‐IR (beta = 0.12; P = 0.0005), insulin (beta = 0.11; P = 0.0003), triglycerides (beta = 0.059; P = 0.01), high‐density lipoprotein (beta = −0.046; P = 0.04), and sex hormone binding globulin (beta = −0.084; P = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). Conclusion: We replicated the PNPLA3 rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.

APOC3rs2854116, PNPLA3rs738409, and TM6SF2rs58542926 polymorphisms might influence predisposition of NAFLD: A meta-analysis.

It is plausible that apolipoprotein C3 (APOC3), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms may affect predisposition of nonalcoholic fatty liver disease (NAFLD), but the results of so far published studies remain controversial. The authors conducted this meta-analysis to clarify relationships between APOC3/PNPLA3/TM6SF2 polymorphisms and predisposition of NAFLD by pooling the findings of eligible studies. A comprehensive search of PubMed, Embase, Web of Science, and CNKI was endorsed by the authors to identify already published studies. Forty-nine studies were found to be eligible for meta-analyses. The pooled meta-analyses results showed that genotypic frequencies of APOC3 rs2854116, PNPLA3 rs738409, and TM6SF2 rs58542926 polymorphisms among patients and controls differed significantly. Moreover, genotypic frequencies of PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms among patients and controls from both Caucasians and Asians also differed significantly. But However, no such differences in genotypic frequencies were observed for the APOC3 rs2854117 polymorphism. This meta-analysis suggested that APOC3 rs2854116, PNPLA3 rs738409, and TM6SF2 rs58542926 polymorphisms might affect predisposition of NAFLD.

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P=8.13×10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P=2.27×10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P=1.52×10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P=2.31×10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P=1.72×10-4 ). Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

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