PNPLA3 Polymorphisms Research Articles

Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study.

We studied for the first time among children differences in plasma alanine aminotransferase (ALT) among genotypes of the rs641738 polymorphism in the MBOAT7 gene that has been associated with increased risk of nonalcoholic fatty liver disease among adults. We also investigated the associations of a genetic risk score combining information from the MBOAT7, PNPLA3, and TM6SF2 polymorphisms with plasma ALT. We performed a 2-y follow-up study in 467 Caucasian children aged 6-9 y, genotyped the MBOAT7, PNPLA3, and TM6SF2 polymorphisms, calculated a genetic risk score from these polymorphisms (scored 0-3) and assessed plasma ALT. Children carrying the T allele of the MBOAT7 polymorphism had 7% higher plasma ALT at baseline (17.8 vs. 19.1 U/l, P = 0.022) and 10% higher plasma ALT at 2-y follow-up (18.0 vs. 19.7 U/l, P = 0.022) than the noncarriers. A higher genetic risk score was associated with higher plasma ALT at baseline (17.5, 18.5, 19.2, and 22.8 U/l, P = 0.008 for linear trend) and 2-y follow-up (18.2, 18.9, 18.9, and 32.8 U/l, P = 0.017 for linear trend). Children carrying the T allele of the MBOAT7 polymorphism had higher plasma ALT than the noncarriers. Children with the MBOAT7, PNPLA3, and TM6SF2 variants had the highest plasma ALT.

Concise Review: Current Status and Future Directions on Research Related to Nonalcoholic Fatty Liver Disease

Considered a feature of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), is associated with insulin resistance, type 2 diabetes, obesity and drug toxicity. Its prevalence is estimated at about 30% in western countries mainly due to sedentary life styles and high fat diets. Genome-wide association studies have identified polymorphisms in several genes, for example, PNPLA3, and TM6SF2 which confer susceptibility to NAFLD. Here, we review recent findings in the NAFLD field with a particular focus on published transcriptomics datasets which we subject to a meta-analysis. We reveal a common gene signature correlating with the progression of the disease from steatosis and steatohepatitis and reveal that lipogenic and cholesterol metabolic pathways are main actors in this signature. We propose the use of disease-in-a-dish models based on hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSC). These will enable investigations into the contribution of genetic background in the progression from NALFD to non-alcoholic steatohepatitis. Furthermore, an iPSC-based approach should aid in the elucidation of the function of new biomarkers, thus enabling better diagnostic tests and validation of potential drug targets. Stem Cells 2017;35:89-96.

Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy

Autophagy has been shown to be crucial in the regulation of the intracellular lipid stores in hepatocytes. We hypothesize that immunity-related GTPase family M (IRGM) gene (an autophagy-related gene) variants confer the susceptibility to non-alcoholic fatty liver disease (NAFLD) development. 832 obese children and adolescents aged 6-18years were recruited. NAFLD was determined by liver ultrasonography. We genotyped PNPLA3 rs738409, GCKR rs780094, TM6SF2 rs58542926, six IRGM single nucleotide polymorphisms (rs13361189, rs9637876, rs72553867, rs10065172, rs1000113, and rs11747270). To understand the molecular mechanism, we examined the effects of IRGM knockdown and overexpression on autophagic flux and lipid droplet metabolism in human hepatoma cells. 22.8% of recruited obese children and adolescents had NAFLD. Multiple logistic regression analysis revealed that after controlling for the effects of age- and gender-adjusted body mass index, gender, PNPLA3, GCKR, and TM6SF2 polymorphisms, variant IRGM rs10065172 TT genotype independently increased the odds ratio of NAFLD by 2.04 (95% confidence interval 1.22-3.42; p=0.007), as compared to the CC genotype. The predictive model was validated by means of 10-fold cross validation. Functional assay revealed that IRGM knockdown inhibited autophagic flux and increased lipid droplet content in HepG2 and PLC/PRF/5 cells, which were reversed by the autophagy inducer rapamycin administration. Similarly, wortmannin (an autophagy inhibitor) increased intracellular lipid droplet content. In contrast, overexpression of IRGM caused decreased lipid droplet content in HepG2 cells. Our findings suggest that IRGM may contribute to the development of human NAFLD by altering hepatic lipid metabolism through the autophagy pathway. Autophagy is involved in the process of lipid metabolism in hepatocytes. The mechanism of autophagy regulation by IRGM has just been unveiled. This study demonstrates that genetic variants in IRGM confer risk of human non-alcoholic fatty liver disease. The functional studies reveal how IRGM regulates hepatic lipid droplet content.

Non-alcoholic fatty liver disease with and without metabolic syndrome: Different long-term outcomes

BackgroundNon-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are both shown to increase the risk of cardiovascular diseases and type 2 diabetes. However, there is a great overlap between these two diseases. The present study was aimed to examine the cardiovascular and metabolic prognosis of non-alcoholic fatty liver disease with and without metabolic syndrome. MethodsMiddle-aged subjects (n=958) were divided into four subgroups, those with NAFLD and MetS, those with NAFLD or MetS, and healthy controls. The baseline characteristics of the subgroups were analyzed. The follow-up time for cardiovascular events was about 16years. After approximately 21years the cardiac ultrasound and laboratory parameters were re-analyzed and new type 2 diabetes cases were recorded. ResultsThose with both diseases were at the greatest risk for cardiovascular events (p<0.001). Compared to healthy controls, only those with MetS, with or without NAFLD, were at increased risk for the development of type 2 diabetes (p<0.001) and for an increase in left ventricular mass index (p=0.001 and p=0.005, respectively). The cardiovascular and metabolic risk in subjects with NAFLD only was quite similar to that in healthy controls. The I148M variant of the patatin-like phospholipase domain-containing 3 gene (PNPLA3 polymorphism) was most present in those with NAFLD only (p=0.008). ConclusionsNAFLD with MetS implies a considerable risk for cardiovascular diseases, type 2 diabetes and the increase of left ventricular mass index whereas NAFLD without MetS does not.

Association between PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease

Objective To develop a novel method for genotyping rs738409 (C>G) single nucleotide polymorphism(SNP), and explore the association between the rs738409 genotypes and non-alcoholic fatty liver disease (NAFLD). Methods Method establishment and analysis of genetic susceptibility. The principle of amplification refractory mutation system (ARMS) and combined a TaqMan fluorogenic probe as signal report were used, by monitoring the difference of cycle threshold (ΔCt=C allele-special primer Ct values minus G allele-special primer Ct values) between the two PCR reactions in a real-time PCR, the method for rs738409 genotyping was established (ARMS-TaqMan). 618 subjects (men: 401; women: 217), in an annual health check-up program from January 2011 to December 2014 in Aerospace Center Hospital, were performed for rs738409 genotyping by the ARMS-TaqMan assay. Fatty liver was diagnosed based on abdominal ultrasonography. The chi-square test and multiple logistic analyses were used to analyze the relationship of rs738409 genotypes and NAFLD. Results The ΔCt by ARMS-TaqMan for rs738409 genotyping were -13.1±1.4 of CC alleles (243 cases), 0.01±0.45 of CG alleles (282 cases), and 12.7±1.9 of GG alleles (93 cases), respectively. The GG alleles frequency of rs738409 were significantly higher in patients with NAFLD compared with subjects without NAFLD (21.5% vs 12.3%, χ2=8.677, P=0.003). In comparison to subjects with CC alleles, the OR (95% confidence interval) adjusted for age, gender, total cholesterol, triglyceride, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, fasting blood glucose and body mass index was 1.35 (0.91-2.00) in subjects with CG alleles and was 2.21 (1.32-3.71) in subjects with GG alleles (P=0.013). Variant rs738409 genotypes were associated with significant increased trend in alanine aminotransferase (ALT) level from CC alleles, CG alleles to GG alleles (F=8.980, P<0.001), and in aspartate aminotansferase (AST) between GG alleles and CC alleles (F=6.491, P<0.001). Conclusions The novel ARMS-TaqMan assay had the features of accuracy, one step and high-throughput for rs738409 genotyping. The G allele of rs738409 was a risk factor of NAFLD susceptibility and associated with higher level serum ALT and AST.(Chin J Lab Med, 2016, 39: 45-49) Key words: Polymorphism, Genetic; Non-alcoholic fatty liver disease; Real-time polymerase chain reaction

Reduction of Caloric Intake Might Override the Prosteatotic Effects of the PNPLA3 p.I148M and TM6SF2 p.E167K Variants in Patients with Fatty Liver: Ultrasound-Based Prospective Study

Background: The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent risk factors for non-alcoholic fatty liver disease (NAFLD). In this study, we assessed the effects of caloric restriction on liver phenotypes in NAFLD patients in relation to the PNPLA3 and TM6SF2 genotypes. Methods: We genotyped both variants in 143 individuals with NAFLD (55 females, age 18-74 years) and 180 controls (85 females, age 33-66 years). Liver steatosis was assessed using the ultrasound-based Hamaguchi score. A 4-month dietetic intervention, consisting of restriction of daily caloric intake without changes in physical activity, was performed. Results: Both PNPLA3 (p = 0.002) and TM6SF2 (p = 0.041) variants were associated with NAFLD before intervention. Overall, 88 patients completed the intervention, which led to a significant decrease of steatosis, ALT activities, body mass index, hip and waist circumferences, and waist-hip ratio (all p < 0.0001). Hepatic steatosis and anthropometric traits improved significantly (p < 0.05) in carriers of either PNPLA3 or TM6SF2 risk genotype. The improvement of phenotypic traits, apart from WHR (p = 0.02), was not modified by the presence of PNPLA3 or TM6SF2 variants. Conclusions: The PNPLA3 and TM6SF2 polymorphisms are associated with NAFLD assessed by the Hamaguchi score. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD.

PNPLA3 polymorphism increases risk for and severity of chronic hepatitis C liver disease.

AIMTo examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum.METHODSLiterature was searched systematically from PubMed/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C (CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms.RESULTSOf 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic hepatitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214 (95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762 (95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002 (95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750 (95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613 (95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity.CONCLUSIONPNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients.

PNPLA3 and TNF-&amp;lt;i&amp;gt;α&amp;lt;/i&amp;gt; G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

Introduction: There is growing evidence that genetic and environmental factors play an important role in the development and progression of non-alcoholic fatty liver disease (NAFLD). We investigated the association of single nucleotide polymorphism (SNP) rs738409 in PNPLA3 gene and TNF-α G238A polymorphism with the development and severity of NAFLD in an overweight and obese Egyptian population. Material and Methods: 100 overweight and obese patients with NAFLD and 30 control subjects were enrolled. All NAFLD patients underwent a confirmatory biopsy. Laboratory investigations included fasting plasma glucose, kidney and liver function tests, liver enzymes, lipid profile and hepatitis markers. Abdominal ultrasound was performed and all subjects were genotyped for (rs738409) PNPLA3 and (rs361525) TNF-α gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results: The homozygous GG genotype of the PNPLA3 was most frequent among patients with NASH (26%) as compared to borderline NASH (20.5%) and simple steatosis (20%). Higher serum levels of transaminases were observed in NAFLD patients and controls who were carriers of the G allele of rs738409, but this was not statistically significant. Regarding the TNF-α G238A SNP; the frequency of the A allele was significantly higher in NAFLD patients (20%) compared to controls (5%) (p value = 0.006). The highest TNF G allele frequency was observed in the NASH group (88%) and this was statistically significant (p value = 0.009). Conclusion: Our study confirmed the association of the PNPLA3 (rs738409) and TNF-α promoter region G238A polymorphisms with susceptibility to NAFLD and its progression.

FRI-188 - The Association between Pnpla3 Polymorphisms and Fibrosis Progression and Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C

FRI-188 - The Association between Pnpla3 Polymorphisms and Fibrosis Progression and Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C

Intensive lifestyle treatment for non-alcoholic fatty liver disease in children with severe obesity: inpatient versus ambulatory treatment

Lifestyle intervention is the only established therapy for non-alcoholic fatty liver disease (NAFLD). The optimal treatment schedule and predictors of response of this treatment have not been established in children. We aimed to evaluate the 2-year efficacy of an inpatient versus ambulatory intensive lifestyle intervention for treating NAFLD in children with severe obesity. A cohort study of 51 severely obese non-diabetic children (mean age 14.7 (±2.4) years; BMI-z-score 3.5 (±0.5)) with liver steatosis were non-randomly allocated to inpatient treatment (2 or 6 months), ambulatory treatment or usual care. Proton Magnetic Resonance Spectroscopy determined liver steatosis and serum alanine aminotransferase (ALT) at 6 months were the primary outcome measures. Baseline variables were evaluated as predictors of treatment response. Liver steatosis had disappeared in 43, 29 and 22% and serum ALT normalized in 41, 33 and 6% at the end of 6 months in the inpatient, ambulatory or usual care treatment groups, respectively. Only the proportions of ALT normalization in inpatient and ambulatory treatment compared with usual care were significantly higher. Treatment effects of inpatient and ambulatory treatment were sustained at 1.5 years follow-up. No baseline characteristic, including PNPLA3 polymorphism or leptin, was consistently predictive for treatment response. A 6-month intensive inpatient and ambulatory lifestyle treatment in children with severe obesity reverses NAFLD in a minority of patients. This study suggests that inpatient compared with ambulatory intensive treatment does not importantly increase treatment success. Further efforts to optimize and individualize lifestyle interventions and additional treatments options are needed particular for children with severe obesity resistant to conventional lifestyle interventions.

Patatin-Like Phospholipase Domain-Containing 3 I148M Variant Is Associated with Liver Steatosis and Fat Distribution in Chronic Hepatitis B.

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C. The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB). Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped. PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score > 3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI). In our CHB patients, the PNPLA3 polymorphisms influenced the development of liver steatosis, but not fibrosis status. The association of PNPLA3 p.I148M with liver steatosis increased with the greater amount of abdominal fat, irrespective of BMI.

A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity

Background and aimsGenome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity. Methods130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions. ResultsAfter adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P<0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P=0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P=1.0×10−4 and 0.048, respectively), steatosis stage (P=0.029), and higher ALT levels (P=0.002). Subjects with GRS ≥6 showed a significantly increased risk of NASH (OR=2.55, P=0.045) compared to those with GRS ≤5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P=0.219). ConclusionNAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals.

Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B.

To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients.

Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents

Evidence relating dietary patterns to obesity and related disorders such as non-alcoholic fatty liver disease (NAFLD) is limited in pediatric age. Aim of this study was to analyze the association between dietary patterns, obesity and development of severe steatosis and the metabolic syndrome in a series of children and adolescents referred for suspected NAFLD, and the interaction with the rs738409 I148M PNPLA3 polymorphism. Two hundred patients (112 females) had completed a food frequency and demographic questionnaire. Nearly 58% were obese, and 32% were overweight. Mild, moderate, and severe fatty liver was present in 60 (30%), 87 (44%), and 51 (26%) participants, respectively. A great proportion of overweight/obese children and adolescents reported a correct dietary pattern. At multivariate ordinal regression analysis considering demographic, anthropometric, genetic, and behavioral determinants, the major determinant of steatosis severity was PNPLA3 I148M genotype (p<0.0001), followed by older age (p=0.017), higher waist circumference (p=0.016), and less time spent practising physical exercise (p=0.034). Furthermore, there was a significant interaction between PNPLA3 I148M and intake of sweetened beverages (p=0.033) and of vegetables (p=0.038). In conclusion, although dietary pattern was reportedly correct in at-risk overweight adolescents with NAFLD, we report a novel interaction between PNPLA3 I148M and dietary components with the severity of steatosis.

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Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.

Role of PNPLA3 polymorphism in pathogenesis of liver diseases

Role of PNPLA3 polymorphism in pathogenesis of liver diseases

The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls

BackgroundReduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls.MethodsTo this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery.ResultsAdiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features.ConclusionsThe I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.

PNPLA3 Polymorphisms and Liver Aminotransferase Levels in a Mexican American Population

This study examined genetic associations of patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and liver aminotransferases in an extensively documented, randomly recruited Mexican American population at high risk of liver disease. Two single nucleotide polymorphisms (SNP) in the PNPLA3 gene (i.e., rs738409 and rs2281135) were genotyped in 1532 individuals. Population stratification was corrected by the genotyping of 103 ancestry informative markers (AIMs) for Mexican Americans. Both PNPLA3 SNPs showed highly significant association with alanine aminotransferase (ALT) levels, but was also, in males, associated with aspartate aminotransferase (AST) levels. Haplotypic association test of the two SNPs suggested stronger genetic association with rs738409 than rs2281135. Obvious sex effects were observed: rs738409-sex interaction in ALT levels P = 8.37 x 10(-4); rs738409-sex interaction in AST levels P = 5.03 x 10(-3). This population study highlights a sex-specific association of PNPLA3 polymorphisms and elevated liver enzymes in a population-based study, independent of common pathological factors of the metabolic syndrome. The strong genetic association found in women ≤ 50 years old, but not in women > 50 years old, suggests that sex hormones may mediate the sex effect.

Noninvasive Assessment of Nonalcoholic Fatty Liver Disease in Obese or Overweight Patients

Reliable noninvasive tools are needed for staging nonalcoholic fatty liver disease (NAFLD). Published scoring systems have not been validated in prospective assessments of unselected patients. We aimed to identify factors that predicted development of nonalcoholic steatohepatitis (NASH) in a large group of overweight or obese patients and compared these with established factors. We performed a prospective analysis of factors associated with the development and severity of NAFLD in patients at a single obesity center. We evaluated liver involvement in 542 patients by a large set of routine and non-routine parameters, including ultrasound and genetic testing. Those suspected of having NAFLD underwent liver biopsy (57.7%). Patients were divided into design cohort (n = 200) and validation cohort (n = 113) to identify factors associated with the presence and severity of NAFLD and NASH. Factors independently associated with development of NASH included increased levels of alanine aminotransferase (ALT), fasting levels of C-peptide, and ultrasound steatosis scores (USSs), with area under the receiver operating curve (AUROC) values of 0.854 in the design cohort and 0.823 in the validation cohort. NASH activity scores also correlated with level of ALT, USS, and fasting level of C-peptide (R(2) = 0.491). Independent predictors of advanced fibrosis included waist circumference and level of aspartate aminotransferase (AUROC values of 0.839 and 0.846 for design and validation cohorts, respectively; negative predictive values of 98% and 97%, respectively, for a cutoff of -2.14). Previously published scoring systems had significantly lower AUROC values. Levels of CK18 and PNPLA3 polymorphisms correlated with development of NASH but did not add value. Parameters routinely analyzed in assessing obese patients can be used to determine the presence of NASH and advanced fibrosis. Non-routine tests do not increase diagnostic accuracy. Previously published scores are significantly less accurate.