Patatin-like Phospholipase Domain-containing Protein 3 Rs738409 Research Articles

PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic dysfunction-associated steatotic liver disease.

The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship. A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01. The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex.

PNPLA3 rs738409 polymorphism and kidney dysfunction: an association beyond nonalcoholic fatty liver disease?

This commentary is primarily devoted to a recent observational study by Mantovani and colleagues (Aliment Pharmacol Ther. 2023; 57: 1093-102) examining the adverse effect of the patatin-like phospholipase domain-containing protein-3 (PNPLA3 ) rs738409 G allele on the kidney function in a cohort of 1,144 middle-aged Italian individuals with metabolic dysfunction. In this study, the authors found that the PNPLA3 rs738409 G allele was significantly associated with lower levels of estimated glomerular filtrate rate (eGFR), even after adjusting for not only common anthropometric and cardiometabolic risk factors but also ethnicity, serum liver enzymes, use of drugs against dyslipidemia and chronic kidney disease polygenic risk score. Additionally, in a subgroup of 144 patients followed for a median of 17 months, the authors also found that the PNPLA3 rs738409 G allele was independently associated with a faster eGFR decline. Commenting on the cohort study by Mantovani et al ., we also summarized the rapidly expanding evidence linking the PNPLA3 rs738409 variant with the risk of kidney disease. Furthermore, we discussed the potential research implications of these findings.

PNPLA3 rs738409 Genetic Variant Inversely Correlates with Platelet Count, Thereby Affecting the Performance of Noninvasive Scores of Hepatic Fibrosis.

Noninvasive tests (NITs) including platelets (PLTs) have been proposed to replace hepatic biopsy for the diagnosis of nonalcoholic fatty liver disease (NAFLD), or as more recently redefined, metabolic dysfunction-associated steatotic liver disease (MASLD). There has been reported an inverse correlation between PLTs and progressive MASLD, which is also affected by the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C>G mutation. However, the correlation between low PLTs and PNPLA3 genotype has been poorly investigated. We stratified 1155 biopsy-proven MASLD patients according to PNPLA3 genotype. The hepatic expression of genes involved in megakaryopoiesis was investigated in n = 167 bariatric patients by RNAseq. PLT count progressively decreased according to the number of PNPLA3 at-risk alleles, irrespective of the presence of advanced fibrosis. The hepatic expression of genes involved in PLT biogenesis was associated with the PNPLA3 GG genotype. Finally, the presence of the PNPLA3 homozygosity flattened the accuracy of fibrosis-4 (FIB-4) in discriminating histological fibrosis stages. The PNPLA3 GG genotype may underpower the accuracy of NITs which include PLT count in identifying those patients with potentially reversible stages of fibrosis.

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis

Background and aimsLittle is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). Methods and resultsWe enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: −6.55; 95% CI −11.0 to −2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. ConclusionsThis pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.

The impact of polymorphism in PNPLA3 and TM6SF2 genes on the susceptibility and survival of hepatitis C-related hepatocellular carcinoma

BackgroundGenetic variants of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been reported with the development of hepatocellular carcinoma (HCC). This study aims to explore the role of The PNPLA3 rs738409 and TM6SF2 rs58542926 single-nucleotide polymorphisms (SNPs) on the incidence and survival of HCV-induced HCC in Egyptians.Methods and resultsThis case-control study included (120) HCC and (144) hepatitis C virus (HCV) patients. Baseline clinical, laboratory, tumor characteristics data, HCC recurrence, and overall survival were collected. PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphism were detected by TaqMan allelic discrimination assay. We found that HCC patients were significantly older with male predominance. A significant difference between the TT genotypes of TM6SF2 frequency was observed in HCC compared with HCV patients. Moreover, the T allele of TM6SF2 distributions revealed a significant contribution to the different stages of HCC (p=0.03). Both PNPLA3 rs738409 and TM6SF2 rs58542926 variants showed a significant relation with treatment response according to the modified RECIST criteria. Age and diabetes mellitus were the independent factors associated with the development of HCC by multivariate regression analysis.ConclusionsTM6SF2 rs58542926 polymorphism, not PNPLA3 rs738409, could be implicated in the development of HCV-induced HCC and its progression.

Higher Levels of Plasma Hyaluronic Acid and N-terminal Propeptide of Type III Procollagen Are Associated With Lower Kidney Function in Children With Non-alcoholic Fatty Liver Disease.

ObjectiveHyaluronic acid (HA) and N-terminal propeptide of type III procollagen (PIIINP) are two non-invasive biomarkers of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the relationships of plasma levels of HA and PIIINP with kidney function in children with NAFLD.MethodsPlasma HA and PIIINP levels were measured using two commercially available enzyme-linked immunosorbent assay kits in a cohort of 106 Caucasian overweight or obese children with biopsy-proven NAFLD. Glomerular filtration rate (eGFR) was estimated using the Bedside Schwartz equation. Genotyping for the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant was performed using an allelic discrimination assay.ResultsChildren with fibrosis F2 had significantly higher plasma PIIINP and HA levels than those with F0 or F1 fibrosis. Liver fibrosis was positively associated with plasma HA and PIIINP, as well as with the presence of the risk allele G of PNPLA3 rs738409 variant, and negatively with eGFR. Moreover, eGFR showed significant inverse associations with HA and PIIINP levels, as well as the presence of G of PNPLA3 rs738409, and liver fibrosis stage. Notably, our multivariable regression models showed that higher plasma PIIINP (standardized beta coefficient: −0.206, P = 0.011) and HA levels (standardized beta coefficient: −0.531, P < 0.0001) were associated with lower eGFR values, even after adjustment for age, sex, systolic blood pressure, PNPLA3 rs738409 genotype, and any stage of liver fibrosis.ConclusionsHigher levels of HA and PIIINP were associated with lower eGFR values in Caucasian children with biopsy-proven NAFLD, independently of PNPLA3 rs738409 genotype and other potential confounding factors.

Correlations between PNPLA3 Gene Polymorphisms and NAFLD in Type 2 Diabetic Patients.

Background and Objectives: Non-alcoholic fatty liver disease is a worldwide significant public health problem, particularly in patients with type 2 diabetes mellitus. Identifying possible risk factors for the disease is mandatory for a better understandingand management of this condition. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked to the development and evolution of fatty liver but not to insulin resistance. The aim of this study isto evaluate the relationships between PNPLA3 and fatty liver, metabolic syndrome and subclinical atherosclerosis. Materials and Methods: The study group consisted of patients with type 2 diabetes mellitus without insulin treatment. The degree of liver fat loading was assessed by ultrasonography, and subclinical atherosclerosis was assessed using carotid intima-media thickness (CIMT). PNPLA3 rs738409 genotype determination was performed by high-resolution melting analysis that allowed three standard genotypes: CC, CG, and GG. Results: Among the 92 patients, more than 90% showed various degrees of hepatic steatosis, almost 62% presented values over the normal limit for the CIMT. The majority of the included subjects met the criteria for metabolic syndrome. Genotyping of PNPLA3 in 68 patients showed that the difference between subjects without steatosis and subjects with hepatic steatosis was due to the higher frequency of genotype GG. The CC genotype was the most common in the group we studied and was significantly more frequent in the group of subjects with severe steatosis; the GG genotype was significantly more frequent in subjects with moderate steatosis; the frequency of the CG genotype was not significantly different among the groups.When we divided the group of subjects into two groups: those with no or mild steatosis and those with moderate or severe steatosis it was shown that the frequency of the GG genotype was significantly higher in the group of subjects with moderate or severe steatosis. PNPLA3 genotypes were not associated with metabolic syndrome, subclinical atherosclerosis, or insulin resistance. Conclusions: Our results suggest that PNPLA3 does not independently influence cardiovascular risk in patients with type 2 diabetes mellitus. The hypothesis that PNPLA3 may have a cardioprotective effect requires future confirmation.

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

BACKGROUNDThe 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. AIMTo investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis (NASH), and whether this polymorphism is associated with hepatic histological features. METHODSFifty-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.RESULTSThirty-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). CONCLUSIONThe 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.

Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis

Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. We found significant associations between AH risk and the risk alleles of rs738409 (p=0.0081) and HP (p=0.0371), but not rs72613567 (p=0.3132), rs58542926 (p=0.2180), or rs641738 (p=0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR=1.59 (95% CI: 1.15-2.22), p=0.0055] and HP*2 [OR=1.38 (95% CI: 1.04-1.82), p=0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p=0.0921). PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.

The PNPLA3 rs738409 Variant but not MBOAT7 rs641738 is a Risk Factor for Nonalcoholic Fatty Liver Disease in Obese U.S. Children of Hispanic Ethnicity.

PurposeThe rs641738 C>T in membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) is implicated, along with the rs738409 C>G polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3), in nonalcoholic fatty liver disease (NAFLD). The association of these polymorphisms and NAFLD are investigated in Hispanic children with obesity.MethodsObese children with and without NAFLD were enrolled at a pediatric tertiary care health system and genotyped for MBOAT7 rs641738 C>T and PNPLA3 rs738409 C>G. NAFLD was characterized by the ultrasonographic presence of hepatic steatosis along with persistently elevated liver enzymes. Genetic variants and demographic and biochemical data were analyzed for the effects on NAFLD.ResultsAmong 126 enrolled subjects, 84 in the case group had NAFLD and 42 in the control group did not. The two groups had similar demographic distribution. NAFLD was associated with abnormal liver enzymes and elevated triglycerides and cholesterol (p<0.05). Children with NAFLD had higher percentage of PNPLA3 GG genotype at 70.2% versus 31.0% in non-NAFLD, and lower MBOAT7 TT genotype at 4.8% versus 16.7% in non-NAFLD (p<0.05). PNPLA3 rs738409 C>G had an additive effect in NAFLD; however, MBOAT7 rs641738 C>T had no effects alone or synergistically with PNPLA3 polymorphism. NAFLD risk increased 3.7-fold in subjects carrying PNPLA3 GG genotype and decreased in MBOAT7 TT genotype.ConclusionIn Hispanic children with obesity, PNPLA3 rs738409 C>G polymorphism increased the risk for NAFLD. The role of MBOAT7 rs641738 variant in NAFLD is less evident.

Genetic variant rs72613567 of HSD17B13 gene reduces alcohol-related liver disease risk in Chinese Han population.

Background & AimsRecently, the variant rs72613567:TA in the 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been associated with reduced levels of ALT and AST and a reduced risk of alcohol‐related liver disease (ALD) in the European population. Therefore, the aim of this study was to investigate the association between the polymorphisms of HSD17B13 and ALD, liver serum markers and patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) p.I148M in the Chinese Han population.MethodsA case‐control study was performed from five centres and included 769 ALD patients and 767 healthy controls. Two SNPs (rs72613567 and rs6834314) in HSD17B13 were genotyped using the Sequenom MassArray system and allele association analysis was performed using PLINK 1.90 software.Results HSD17B13 rs72613567:TA allele was associated with a reduced risk of ALD by 19% (95% confidence interval [CI]: 0.05‐0.31, P = .01), uniformly, the G allele in the rs6834314 reduced the risk of ALD by 19% (95% CI: 0.05‐0.31, P = 8.28 × 10−3). And the genotypes of two SNPs were associated with reducing the risk of ALD in three genetic model analysis. In addition, we found that TA allele was associated with lower levels of serum ALT, AST and GGT (P = .005, .007 and .02, respectively), higher level of serum ALB (P = .02), but not associated with ALP. In this cohort, the interaction between HSD17B13 rs72613567 and the steatogenic allele PNPLA3 rs738409 was not validated.ConclusionThe present study revealed that HSD17B13 rs72613567 was significantly associated with a reduced risk of ALD in Chinese Han population.

The effect of PNPLA3 polymorphism as gain in function mutation in the pathogenesis of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is often associated withmetabolic syndrome (type 2 diabetes, hypertension, hypertriglyceridemia, insulin resistance, and obesity). NAFLD is multi-factorial in pathogenesis with some genetic predisposition. The variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) is known to be an independent risk factor for hepatocellular cancer (HCC). The aim of this study was to investigate the role of PNPLA3 polymorphism as the risk factor for NAFLD. Patients had histological, ultrasonographic, biopsy evidence of NAFLD (n=248) and 81 controls were studied forPNPLA3 polymorphism. PNPLA3 genotyping was done from peripheral blood DNA by real-time polymerase chain reaction (RT-PCR). PNPLA3 genotyping of the groups NAFLD (CC [n = 76], CG [n = 83], GG [n = 89]) and control (CC [n= 42], CG [n = 22], GG [n = 17]) was determined. In the patient group, the G allele was 261 (52.63%) and the C allele was 235 (47.37%), whereas in the control group, the G allele was 56 (34.54%) and the C allele was 106 (65.43%). In our study, 53 out of 174 women had GG allele and 54 out of 155 men had GG allele. The findings suggest that there is a predominant relationship between men with PNPLA3 I148M variant with NAFLD in women. Patients with NAFLD carrying PNPLA3 rs738409 G>C variant are at higher risk of NAFLD.

PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease.

Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.

PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels.

Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P<.001), higher albuminuria (P=.039) and greater prevalence of chronic kidney disease (CKD; P=.046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (β-coefficient: 22.29, 95% CI: 0.99-43.60, P=.041). Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI.

Relationship Between PNPLA3 rs738409 Polymorphism and Decreased Kidney Function in Children With NAFLD.

Emerging evidence suggests that patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 genotype (the major genetic variant associated with susceptibility to nonalcoholic fatty liver disease [NAFLD]) is associated with decreased kidney function in adults. Currently, it is uncertain whether this association also occurs in children/adolescents and whether any association is independent of liver disease severity. We enrolled a sample of 142 Caucasian children and adolescents with biopsy-proven NAFLD, presenting to the Liver Unit of the "Bambino Gesù" Children's Hospital. The glomerular filtration rate (e-GFR) was estimated using the Bedside Schwartz equation, whereas 24-hour proteinuria was measured using a radioimmunoassay method. Genotyping for the PNPLA3 rs738409 genotype was undertaken using the single-nucleotide polymorphism genotyping allelic discrimination method. Overall, 45 children had G/G, 56 had G/C, and 41 had C/C PNPLA3 rs738409 genotype, respectively. Children with G/G genotype had significantly lower e-GFR (107.5±20 versus 112.8±18 versus 125.3±23 mL/min/1.73 m2 , P=0.002) and higher 24-hour proteinuria (58.5±21 versus 53.9±22 versus 42.9±20 mg/day, P=0.012) compared with those with either G/C or C/C genotypes. After adjustment for age, sex, systolic blood pressure, measures of adiposity, homeostasis model assessment-estimated insulin resistance and biopsy-confirmed nonalcoholic steatohepatitis and stage of liver fibrosis, the presence of rs738409 G/G genotype was independently associated with both lower e-GFR (β coefficient: -23.6; 95% confidence interval [CI]: -36.3 to -10.8; P<0.001) and higher 24-hour proteinuria (β coefficient: 15.3; 95% CI: 1.12 to 30.5; P=0.046). Conclusion: Regardless of established renal risk factors and the histological severity of NAFLD, the PNPLA3 G/G genotype was strongly associated with decreasing kidney function and increasing 24-hour proteinuria in children/adolescents with histologically confirmed NAFLD.

Correlation between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma: a meta-analysis of 10,330 subjects.

The correlation between patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism and hepatocellular carcinoma was investigated by several pilot studies, but the results of these studies were controversial. Therefore, we performed this study to better assess the relationship between PNPLA3 rs738409 polymorphism and the likelihood of hepatocellular carcinoma. Eligible studies were searched in PubMed, Medline, EMBASE, and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma. A total of 17 studies with 10,330 participants were analyzed. A significant association with the likelihood of hepatocellular carcinoma was detected for the PNPLA3 rs738409 polymorphism in dominant (P = 0.0001; OR 0.66; 95% CI 0.53, 0.82), recessive (P < 0.0001; OR 2.32; 95% CI 1.76, 3.06) and allele (P < 0.0001; OR 0.64; 95% CI 0.53, 0.77) comparisons. Further subgroup analyses revealed that the PNPLA3 rs738409 polymorphism was significantly associated with the likelihood of hepatocellular carcinoma in Caucasians (dominant model: P < 0.0001, OR 0.57, 95% CI 0.45, 0.71; recessive model: P < 0.0001, OR 2.74, 95% CI 2.02, 3.71; allele model: P < 0.0001, OR 0.56, 95% CI 0.46, 0.67). However, no positive results were detected in Asians. Our findings indicated that the PNPLA3 rs738409 polymorphism may serve as a potential biological marker of hepatocellular carcinoma in Caucasians.

GG Genotype of Pnpla3 Rs738409 Polymorphism Associated with Nash in Patients of Uzbek Nationality

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and has an estimated incidence of 20%-30% in the general population and 67%-75% in the obese population. Genetic predisposition can play an important role in development of this disease. No synonymous coding SNP rs738409 C/G (Ile148Met) in Patatin-like phospholipase domain-containing protein 3 (PNPLA3) genes has been found associated with the presence of NAFLD in a genome-wide association study. This association has been replicated in several cohorts of different ethnicity, but to date the assessment of this association has not been performed in the Central Asia populations. Aim: The purpose of our research is to investigate the association between polymorphic variant of PNPLA3 gene (rs738409) and susceptibility to non-alcoholic fatty liver disease (NAFLD) in Uzbekistan. Materials and Methods: In this case-control study, 73 patients a mean age of 55.1 diagnosed with NAFLD (48 patients with simple steatosis and 25 patients with non-alcoholic steatohepatitis (NASH)) and the age, gender and ethnically matched controls (n=37) were recruited. The diagnosis of NAFLD was verified on the basis of anamnesis, clinical and laboratory tests, and liver ultrasound. Genomic DNA was isolated and SNP genotyping was performed by using polymerase chain reaction with specific primers followed by restriction fragment length polymorphism analysis. Result: Showed significant association between GG genotype of the PNPLA3 rs738409 polymorphisms and NAFLD (p=0.03, OR = 2.99; 95% CI 1.21–7.42 for the additive model, Cochran-Armitage trend test; p=0.02, OR = 2.99; 95% CI 1.21–7.42 for the recessive model, Pearson’s χ2 test). Genotype frequencies of PNPLA3 rs738409 polymorphisms in a subset of patients with simple steatosis and NASH compare to the control group. Comparative analysis of resulting genotypes showed a slight increase of CG and GG genotypes among patient with simple steatosis, then among subjects of the control group, but this did not reach statistical significance. However, statistical analysis of genotype distribution between patients with NASH and controls showed a significant association between GG genotype and NASH assuming an additive model (p&lt;0, 0001, Cochran-Armitage trend test) and recessive model (p&lt;0, 0001, Pearson’s χ2 test). Conclusion: The present study, we confirm the association of PNPLA3 rs738409 GG genotype with susceptibility to NAFLD. After stratification into the two main subtypes of NAFLD, the risk genotype GG was found to be significantly associated with susceptibility to NASH. We also found that the GG genotype is not associated with simple steatosis in Uzbek population.

PNPLA3 rs738409 Polymorphism Predicts Development and Severity of Hepatic Steatosis but Not Metabolic Syndrome in Celiac Disease.

Metabolic syndrome (MS) and hepatic steatosis (HS) have been described in patients with celiac disease (CD) after starting a gluten-free diet (GFD), but data on predictive factors for these conditions are scarce. Recently, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 has been identified as a key factor for HS development in the general population. The aim of the study was to evaluate the role of PNPLA3 rs738409 in the development of MS and HS in CD patients after starting GFD. Between June 2014 and September 2016, we consecutively enrolled CD patients with HS, while those without steatosis served as a control group. All patients underwent anthropometric and serologic investigations, ultrasonography (US) to assess the degree and severity of HS, and genotyping of the PNPLA3 rs738409 polymorphism. Finally, 370 subjects were enrolled (136 with and 234 without HS). At genotyping assays, the CC genotype was found in 194 subjects (52.4%), the CG genotype in 138 subjects (37.3%), and the GG genotype in 38 subjects (10.2%). At binary logistic regression, only CG and GG alleles were predictive for the development of HS (odds ratio (OR) 1.97; p < 0.01 for CG and OR 6.9; p < 0.001 for GG). Body mass index (BMI) (OR 3.8; p < 0.001) and waist circumference (OR 2.8; p = 0.03) at CD diagnosis were the only independent factors for the development of MS. Intergroup comparisons showed that the severe grade of HS was more frequently observed in GG than in CC carriers (74% vs. 11.3%, p < 0.001, OR 21.8). PNPLA3 CG and GG carriers with CD have a higher susceptibility to hepatic steatosis, but not to metabolic syndrome. Moreover, patients with GG alleles display more severe forms of HS based on ultrasound.

PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.

High frequency of the PNPLA3 rs738409 [G] single-nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease.

An exploratory study was performed to determine the prevalence of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs78409 [G] allele among the Hmong as a risk factor for nonalcoholic fatty liver disease (NAFLD). NAFLD/nonalcoholic steatohepatitis is the world's most common chronic liver disease and is expected to replace viral hepatitis as the leading cause of cirrhosis and potential precursor to hepatocellular carcinoma (HCC). Of all populations in California, the Hmong experience the highest risk of death from HCC and the highest prevalence of metabolic syndrome risk factors among Asians that predispose them to NAFLD. Here a genetic explanation was sought for the high rates of chronic liver disease among the Hmong. The literature pointed to the PNPLA3 rs738409 [G] allele as a potential genetic culprit. Cell-free DNA was isolated from 26 serum samples previously collected in community settings. Quantitative polymerase chain reaction-based single-nucleotide polymorphism (SNP) genotyping was performed with a validated TaqMan SNP genotyping assay, and results were analyzed with TaqMan Genotyper software. The PNPLA3 rs738409 [C>G] variant occurred at a frequency of 0.46 (12 of 26; 95% confidence interval, 0.27-0.67). This carrier rate would rank the Hmong as the third highest population in the 1000 Genomes Project. Although this small sample size limits the generalizability, the high frequency rates of this allele along with the presence of metabolic syndrome risk factors warrant further studies into the etiology of NAFLD among the Hmong. Cancer 2018;124:1583-9. © 2018 American Cancer Society.