PNPLA3 Polymorphisms Research Articles

Interaction Between PNPLA3 and SIRT5 Genetic Variants in Association with Liver Fibrosis Severity in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease.

This study evaluated the association between polymorphisms in the PNPLA3, TM6SF2, HSD17B13, and SIRT5 genes and the severity of fibrosis and steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Fibrosis and steatosis were assessed by MRE and MRI-PDFF, respectively. The polymorphisms were determined by allelic discrimination in blood samples. 204 patients aged 57.0 ± 13.5 years were included. Sixty-two (30.4%) patients had significant fibrosis (≥F2). Among F2-F4 fibrosis, the PNPLA3 rs738409 GG genotype was significantly higher than the CC + CG genotypes (44.9% vs. 21.4%, p = 0.001). The SIRT5 rs12216101 GG vs. TT + TG genotypes also exhibited a similar trend (64.3% vs. 27.9%, p = 0.012). In multivariate analysis, the PNPLA3 GG genotype (OR = 3.48, 95%CI: 1.50-8.06; p = 0.004) and SIRT5 rs12216101 GG genotype (OR = 5.43, 95%CI: 1.32-22.33; p = 0.019) were independently associated with F2-F4 fibrosis. Additionally, the proportion of patients with F2-F4 fibrosis significantly increased with the number of combined risk genotypes. Among S2-S3 steatosis, the prevalence of HSD17B13 AG + GG genotypes was higher than that of the AA genotype (37.5% vs. 23.9%, p = 0.048) and independently associated with moderate/severe steatosis in multivariate analysis (OR = 2.26, 95%CI: 1.14-4.49; p = 0.020). Our data indicate that the PNPLA3 and SIRT5 polymorphisms were independently and additively linked to significant fibrosis, while the HSD17B13 polymorphism was associated with increased steatosis in Thai populations. These data might emphasize the importance of genetic variants in progressive MASLD.

Role of patatin-like phospholipase domain-containing 3 gene for decreasing kidney function in recently diagnosed diabetes mellitus

AimsWe examined the association of the G allele in the single-nucleotide polymorphism (SNP) rs738409 in the third exon of patatin-like phospholipase domain-containing 3 gene (PNPLA3) gene, with chronic kidney disease in diabetes endotypes. MethodsParticipants with recent-onset diabetes (n = 707) from the prospective German Diabetes Study (GDS) underwent cluster assignment, detailed phenotyping, genotyping and magnetic resonance spectroscopy to quantify hepatocellular lipid content (HCL). ResultsSevere insulin-resistant diabetes (SIRD) had the lowest glomerular filtration rates (eGFR) and highest HCL compared to severe insulin-deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes endotypes (all p < 0.05). HCL was negatively associated with eGFR (r = −0.287, p < 0.01) across all groups. Stratification by G-allele carrier status did not reveal any association between HCL and eGFR among the endotypes. However, the proportion of G-allele carriers increased from 44 % for eGFR >60 ml/min to 52 % for eGFR <60 ml/min (p < 0.05). ConclusionsThe PNPLA3 polymorphism may contribute to declining kidney function independently of liver lipids.

Distinct Gut Microbial Signature and Host Genetic Variants in Association with Liver Fibrosis Severity in Patients with MASLD.

Gut microbiota might affect the severity and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to characterize gut dysbiosis and clinical parameters regarding fibrosis stages assessed by magnetic resonance elastography. This study included 156 patients with MASLD, stratified into no/mild fibrosis (F0-F1) and moderate/severe fibrosis (F2-F4). Fecal specimens were sequenced targeting the V4 region of the 16S rRNA gene and analyzed using bioinformatics. The genotyping of PNPLA3, TM6SF2, and HSD17B13 was assessed by allelic discrimination assays. Our data showed that gut microbial profiles between groups significantly differed in beta-diversity but not in alpha-diversity indices. Enriched Fusobacterium and Escherichia_Shigella, and depleted Lachnospira were found in the F2-F4 group versus the F0-F1 group. Compared to F0-F1, the F2-F4 group had elevated plasma surrogate markers of gut epithelial permeability and bacterial translocation. The bacterial genera, PNPLA3 polymorphisms, old age, and diabetes were independently associated with advanced fibrosis in multivariable analyses. Using the Random Forest classifier, the gut microbial signature of three genera could differentiate the groups with high diagnostic accuracy (AUC of 0.93). These results indicated that the imbalance of enriched pathogenic genera and decreased beneficial bacteria, in association with several clinical and genetic factors, were potential contributors to the pathogenesis and progression of MASLD.

Are transmembrane 6 superfamily member 2 gene polymorphisms associated with steatohepatitis after pancreaticoduodenectomy?

After pancreaticoduodenectomy, 20-40% of patients develop steatotic liver disease (SLD), and steatohepatitis can be a problem. Although patatin-like phospholipase domain-containing 3 protein (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms are involved in SLD and steatohepatitis development, whether this is the case after pancreaticoduodenectomy is unclear. Forty-three patients with pancreatic cancer who underwent pancreaticoduodenectomy at our hospital between April 1, 2018, and March 31, 2021, were included. We extracted DNA from noncancerous areas of residual specimens after pancreaticoduodenectomy and determined PNPLA3 and TM6SF2 gene polymorphisms using real-time polymerase chain reaction. SLD was defined as a liver with an attenuation value of ≤40 HU or a liver-to-spleen ratio of ≤0.9 on computed tomography. We defined high hepatic fibrosis indexes (HFI) instead of steatohepatitis as a Fibrosis-4 index of ≥2.67 or nonalcoholic fatty liver disease fibrosis score of ≥0.675 in patients with SLD. The cumulative incidence of SLD (P = 0.299) and high HFI (P = 0.987) after pancreaticoduodenectomy were not significantly different between the PNPLA3 homozygous and minor allele groups. The incidences of high HFI at 1 year after pancreaticoduodenectomy were 16.8% and 27.0% in the TM6SF2 major homozygous and minor allele groups, respectively, with a significant difference in the cumulative incidence (P = 0.046). The TM6SF2 minor allele may contribute to steatohepatitis development after pancreaticoduodenectomy.

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus.

The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident. To evaluate the associations of gene-polymorphism-related MAFLD in PLWH. The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression. The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH. The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

High red meat consumption among PNPLA3 polymorphism carriers is associated with NAFLD in a multi-center cross-sectional study.

Patatin-like phospholipase domain-containing 3 gene (PNPLA3) polymorphism has been implicated in susceptibility to non-alcoholic fatty liver disease (NAFLD), with evidence for potential interaction with nutrition. However, the combination of meat consumption with genetic polymorphism has not been tested. Therefore, this study aims to test the association between the joint presence of PNPLA3 rs738409 G-allele with high meat consumption and NAFLD in populations with diverse meat consumption. A cross-sectional study among Israeli screening and Brazilian primary healthcare populations. Food consumption was assessed by a food-frequency questionnaire. PNPLA3 polymorphism was defined as homozygous (GG) or heterozygous (GC). Inconclusive/probable NAFLD was defined as a fatty liver index (FLI) ≥ 30 and probable NAFLD as FLI ≥ 60. The sample included 511 subjects from the screening and primary healthcare populations (n = 213 and n = 298, respectively). Genetic polymorphism (homozygous GG or heterozygous GC) combined with high consumption of total meat, red and/or processed meat, unprocessed red meat, and processed meat was associated with the highest odds for inconclusive/probable NAFLD (OR = 2.75, 95%CI 1.27-5.97, p = 0.011; OR = 3.24, 1.43-7.34, p = 0.005; OR = 2.92, 1.32-6.47, p = 0.008; OR = 3.16, 1.46-6.83, p = 0.003, respectively), adjusting for age, gender, BMI, alcohol consumption, carbohydrate, and saturated fat intake. In addition, genetic polymorphism combined with high processed meat consumption was associated with the highest odds for probable NAFLD (OR = 2.40, 95%CI 1.04-5.56, p = 0.040). High red meat intake may confer a greater risk for NAFLD among PNPLA3 polymorphism carriers. Prospective studies are needed to confirm these findings and consider minimizing red and processed meat consumption among PNPLA3 polymorphism carriers.

Cryptogenic non-cirrhotic HCC: Clinical, prognostic and immunologic aspects of an emerging HCC etiology

The incidence of hepatocellular carcinoma (HCC) in non-cirrhotic livers is rising significantly, but clear risk factors for screening remain elusive. This study sought to characterize non-cirrhotic HCC etiologies. HCC cases from 2009 to 2020 in a Dutch referral center were examined, revealing 371 out of 1654 cases (22%) as non-cirrhotic. Notably, the incidence of non-cirrhotic HCC increased by 61% in the time frame between 2009 and 2020. Interestingly 39% of non-cirrhotic HCC cases had cryptogenic origins. Cryptogenic non-cirrhotic HCC exhibited similarities with non-cirrhotic NAFLD HCC, but displayed advanced tumor stages, lower surgical rates, and a more frequent presence of symptoms, which substantiated in poor survival rates. Advanced cryptogenic non-cirrhotic HCC stages exhibited elevated serum interleukin-6 levels compared to non-cirrhotic HCC with defined etiologies. Comparative analysis encompassing cryptogenic and NAFLD non-cirrhotic HCC cohorts and controls unveiled comparable circulating immune biomarker profiles and PNPLA3 polymorphisms. To conclude, the primary etiology of non-cirrhotic HCC in our cohort has not defined risk factors. This cryptogenic variant exhibits distinct traits, such as advanced tumors and increased symptoms, and most resemble burned-out NAFLD. Understanding this HCC variant is crucial for improving screening and management strategies.

Psoriasis and steatotic liver disease: Are PNPLA3 and TM6SF2 polymorphisms suitable for the hepato-dermal axis hypothesis?

Introduction and ObjectivesA high prevalence of steatotic liver disease has been described in psoriasis. However, the influence of genetic polymorphisms has yet to be investigated in this scenario. This study aims to determine the frequency of steatosis, advanced liver fibrosis and PNPLA3/TM6SF2 genotypes in individuals with psoriasis and to evaluate the impact of genetic polymorphisms, metabolic parameters and cumulative methotrexate dose on steatosis and fibrosis. Materials and MethodsCross-sectional study that prospectively included psoriasis outpatients, submitted to clinical and laboratory analysis, transient elastography (FibroScan®, Fr) and PNPLA3/TM6SF2 genotyping. Steatosis was defined by CAP ≥275 dB/m and advanced liver fibrosis as transient elastography ≥10 kPa. Logistic regression analysis evaluated the independent variables related to steatosis and fibrosis; p-value< 0.05 was considered significant. ResultsOne hundred and ninety-nine patients were enrolled (age 54.6 ± 12.6 years, 57.3% female). Metabolic syndrome (MetS), steatosis and advanced liver fibrosis prevalence were 55.8%, 54.8% and 9%, respectively. PNPLA3 and TM6SF2 genotypes frequencies were CC 42.3%/CG 49.5%/GG 8.2% and CC 88.7%/ CT 11.3%/ TT 0%. MetS (OR3.01 95%CI 1.51-5.98; p = 0.002) and body mass index (OR1.17 95%CI 1.08-1.26; p < 0.01) were independently associated with steatosis. Diabetes Mellitus (T2DM) (OR10.76 95%CI 2.42-47.87; p = 0.002) and harboring at least one PNPLA3 G allele (OR5.66 95%CI 1.08-29.52; p = 0.039) were associated with advanced fibrosis, but not TM6SF2 polymorphism or cumulative MTX dose. ConclusionsMetS and T2DM confer higher odds for steatosis and advanced fibrosis in individuals with psoriasis. PNPLA3 G allele, but not TM6SF2 polymorphism, impacts a 5-fold odds of advanced liver fibrosis.

Impact of PNPLA3 and TM6SF2 polymorphisms on the prognosis of patients with MASLD and type 2 diabetes mellitus.

Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and extrahepatic outcomes in T2DM-MASLD individuals. Patients' polymorphisms were analysed as follows: PNPLA3 CC, CG and GG; TM6SF2 CC and CT + TT; combined comparing no mutant allele, one allele G or T or ≥2 alleles G or T. Hierarchical models were built to assess associations between polymorphisms and outcomes, independently of confounding factors. Multivariate logistic regression was used for cirrhosis and its complications and extrahepatic cancer, and Cox regression for cardiovascular events (CVEs) and all-cause mortality. In total, 407 T2DM-MASLD patients (62.1 ± 10.5 years, 67.6% women) were followed for 11 (6-13) years. Having at least one G or T allele independently increased the risk of cirrhosis in the separate analysis of PNPLA3 and TM6SF2. Combined polymorphism analysis demonstrated an even higher risk of cirrhosis if two or more risk alleles were present (OR 18.48; 95% CI 6.15-55.58; p < .001). Regarding cirrhosis complications, the risk was higher in PNPLA3 GG and TM6SF2 CT + TT, also with an even higher risk when two or more risk alleles were present in the combined evaluation (OR 27.20; 95% CI 5.26-140.62; p < .001). There were no associations with CVEs or mortality outcomes. In T2DM, PNPLA3 and TM6SF2 polymorphisms, individually and additively, impact MASLD severity, with an increased risk of cirrhosis and its complications.

Parental History of Type 2 Diabetes Mellitus and PNPLA3 Polymorphism Increase the Risk of Severe Stages of Nonalcoholic Fatty Liver Disease.

In non-alcoholic fatty liver disease (NAFLD), the influence of parental history of type 2 diabetes (T2D) allied to single nucleotide polymorphisms (SNPs) in the offspring is not known. We aimed to investigate the impact of the parental history of T2D, PNPLA3 and TM6SF2 polymorphisms in liver steatosis and fibrosis. This was a case-control study involving the offspring of T2D patients and controls without a parental history of T2D. Participants underwent clinical and laboratory evaluation, transient elastography (TE) by Fibroscan® (Echosens, Fr) and genotyping for PNPLA3 and TM6SF2. Multivariate logistic regression evaluated the influence of parental history of T2D on liver steatosis and fibrosis, controlled for age, gender, metabolic traits and SNPs. 161 T2D offspring and 78 controls, 10-46years old, were included. The offspring of T2D had higher prevalences of obesity, T2D, arterial hypertension and sedentarism. Parental history of T2D was associated with fibrosis ≥ F2 (OR 8.89, CI 95% 1.09-72.01, p = 0.041) after adjustment for age, gender, metabolic traits and SNPs. PNPLA3 GG genotype was independently associated with steatosis ≥ S1 (OR 8.15, CI 95% 1.93-34.38, p = 0.004) and fibrosis ≥ F2 (OR 4.31, CI 95% 1.11-16.61, p = 0.034). The offspring of T2D patients present a worse metabolic profile and the parental history of T2D confers an increased likelihood of hepatic fibrosis, independent of metabolic factors. PNPLA3 homozygous GG, but not TM6SF2 genotypes, also impacts on this phenotype.

Association between PNPLA3 and TM6SF2 gene polymorphisms and non-alcoholic fatty liver disease patients in Kazakhstan

&lt;b&gt;Background:&lt;/b&gt; Non-alcoholic fatty liver disease (NAFLD) is a growing burden on a global scale and considered as the most common liver disease of the 21&lt;sup&gt;st&lt;/sup&gt; century, affecting both adults and children. Genome-wide association studies (GWAS) in the field of liver diseases have made a significant contribution to the understanding of genetic background for NAFLD development. Targeted genes like PNPLA3 and TM6SF2 showed some relationship with the steatosis and hepatocellular carcinoma within NAFLD patients. In this study, we tried to analyze the frequency of PNPLA3 and TM6SF2 gene polymorphisms and their relationship to changes in instrumental and laboratory markers, the composition of the gut microbiome, the development and progression of NAFLD stage in Kazakhstan.&lt;br /&gt; &lt;b&gt;Materials and methods:&lt;/b&gt; 39 individuals were involved in this study, including 18 men and 21 women: patients with a history of heavy alcohol consumption (&amp;gt;20 g/day) and other specific diseases such as hepatitis B and C virus infection, etc. were excluded. The diagnosis was established based on the results of clinical assessment and laboratory-instrumental results. The microbiome composition of the large intestine was studied by semiconductor sequencing of the bacterial genome using biochips. The degree of steatosis and liver fibrosis were evaluated by fibroscanning on fibroscan touch 502. Genotyping of PNPLA3 and TM6SF2 were carried out by PCR.&lt;br /&gt; &lt;b&gt;Results:&lt;/b&gt; According to PNPLA3 genotyping: 21 patients (53.85%) were C/G, 7 (17.95%) were C/C and 11 (28.20%) were G/G. Within analyzed variables, GGT showed statistically significant difference among nucleotide variability with p-value of 0.012. Other parameters within metabolic panel also showed statistically significant difference between groups, namely, total cholesterol (p=0.036) and LDL (p=0.006). Genotyping of TM6SF2 includes 24 patients (61.54%) with C/C, 15 (38.46%) with C/T and 0 with T/T. The relationship between TM6SF2 liver function test results showed no statistically significant differences between groups. All other parameters including gut microbiome analysis are not statistically significant.&lt;br /&gt; &lt;b&gt;Conclusions:&lt;/b&gt; In this study, C/G genotype possesses the highest risk and GGT along with LDL were the statistically significant parameter between them in PNPLA3 gene. TM6SF2 and gut microbiome analysis did not reveal any statistically significant differences. Additional studies with larger sample size are recommended to obtain for more detailed and sensitive results.

Familial clustering of nonalcoholic fatty liver disease in first-degree relatives of adults with lean nonalcoholic fatty liver disease.

The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD. This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.

Research of &lt;i&gt;PNPLA3&lt;/i&gt; I148M Gene Polymorphism in Patients with Non-Alcoholic Fatty Liver Disease, with Liver Cirrhosis and with Hepatocellular Carcinoma

Aim: to determine the frequency of PNPLA3 rs738409 C&gt;G gene polymorphism, leading to p.I148M substitution, in patients with non-alcoholic fatty liver disease (NAFLD), and to reveal the association between polymorphism and probable NAFLD outcomes: liver cirrhosis (LC) and hepatocellular carcinoma (HCC).Materials and methods. The study was conducted according to the “case-control” design, three main groups were formed: a group with NAFLD (n = 46), a group with LC (n = 61), a group with HCC (n = 50), as well as a control group (n = 70), for all groups we performed genotyping of the rs738409 polymorphism of the PNPLA3 gene. The relationship between the occurrence of different genotype variants and the diagnosis of patients was evaluated, the odds ratio (OR) of progression of NAFLD and the reliability of intergroup differences were determined.Results. NAFLD patients with PNPLA3 I148M polymorphism have a significantly higher chance of developing LC and HCC. The odds ratio for the GG genotype was 7.94 (95 % Cl: 2.19–28.84; p = 0.030) for LC and 6.51 (95 % Cl: 1.15–4.08; p = 0.039) — for HCC with concomitant LC. The presence of the minor G allele also increases the likelhood of transition from NAFLD to LC (OR = 2.38; 95 % Cl: 1.41–4.02; p = 0.010) and HCC in the presence of cirrhosis (OR = 2.17; 95 % Cl: 1.15–4.08; p = 0.039). Differences in the frequency of PNPLA3 polymorphism between the NAFLD and HCC groups were not significant. Additional risk factors for HCC associated with NAFLD are overweight (OR = 5.14; 95 % Cl: 1.94–13.67; p &lt; 0.001), arterial hypertension (OR = 8.49; 95 % Cl: 3.05–23,62; p &lt; 0.001) and diabetes mellitus (OR = 8.57; 95 % Cl: 1.03–71.48; p = 0.032).Conclusion. The frequency of single nucleotide polymorphism PNPLA3 significantly differs in patients with NAFLD, cirrhosis and HCC compared with the control group of healthy volunteers. The PNPLA3 I148M polymorphism increases the incidence of NAFLD progression to cirrhosis and HCC, but only with concomitant cirrhosis.

Analysis of genetic factors associated with fatty liver disease-related hepatocellular carcinoma.

Single-nucleotide polymorphisms (SNPs) in PNPLA3 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) genes are associated with fatty liver disease (FLD) progression and carcinogenesis. In the present study, we evaluated the characteristics of Japanese FLD patients according to HSD17B13 polymorphisms. We enrolled 402 patients who were clinically and pathologically diagnosed with FLD (alcoholic: 63 cases, nonalcoholic: 339 cases) at our hospital in 1990-2018 (228 males; median age: 54.9 [14.6-83.6] years). FLD patients with HSD17B13 A/A (212 cases) and others (A/AA or AA/AA; 190 cases) were compared. Compared to patients with HSD17B13 A/A and others, those with the A/A genotype showed increased incidence of hepatocellular carcinoma (HCC) (A/A vs. others; 18.4% vs. 9.5%, p = 0.01), cardiovascular diseases (14.2% vs. 4.2%, p < 0.01), and hypertension (56.6% vs. 47.4%, p = 0.06). In patients without A/A, the HCC incidence was significantly reduced in those with alcohol-related FLD, fibrosis-4 index <2.67, and the PNPLA3 CC genotype; however, there was no significant difference in nonalcoholic-FLD. Patients without HSD17B13 A/A showed severe steatosis (77% vs. 88.6%, p < 0.01). New HCC developed in 11 cases and the 5-year incidence rate of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 A/A, which was significantly higher than the rate for those with other SNP profiles (0.6%, p = 0.03). Inhibiting HSD17B13 activity may prevent HCC development, particularly in alcohol-related FLD and low-risk patients. Therefore, combinations of SNPs and other risk factors can be used for screening FLD-HCC.

THU-451 - Effect of PNPLA3 (rs738409 C > G) and TM6SF2 (rs58542926 C > T) polymorphisms on the prognosis of non-alcoholic fatty liver disease (NAFLD) in patients with type-2 Diabetes Mellitus

THU-451 - Effect of PNPLA3 (rs738409 C > G) and TM6SF2 (rs58542926 C > T) polymorphisms on the prognosis of non-alcoholic fatty liver disease (NAFLD) in patients with type-2 Diabetes Mellitus

THU-433 - Impact of PNPLA3 polymorphism on non-alcoholic fatty liver disease in Japan: a multicenter cohort study

THU-433 - Impact of PNPLA3 polymorphism on non-alcoholic fatty liver disease in Japan: a multicenter cohort study

WED-402 - Modelling the biological mechanisms of a PNPLA3 polymorphism in a 3D human liver spheroid for NASH progression and drug efficacy

WED-402 - Modelling the biological mechanisms of a PNPLA3 polymorphism in a 3D human liver spheroid for NASH progression and drug efficacy

Association of PNPLA3 and TM6SF2 Polymorphisms with NAFLD in Greek People with Type 2 Diabetes Mellitus

Association of PNPLA3 and TM6SF2 Polymorphisms with NAFLD in Greek People with Type 2 Diabetes Mellitus

No association of NAFLD-related polymorphisms in PNPLA3 and TM6SF2 with all-cause and cardiovascular mortality in an Austrian population study.

Single-nucleotide-polymorphisms in PNPLA3-rs738409 and the TM6SF2-rs58542926, associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), have been discussed as potentially protective for cardiovascular diseases. Therefore, we aimed to study the associations of PNPLA3/TM6SF2 variants with MAFLD and cardiovascular risk in apopulation-based sample of asymptomatic patients. The study cohort comprised 1742patients of European decent aged 45-80years from aregistry study undergoing screening colonoscopy for colorectal cancer between 2010 and 2014. SCORE2 and Framingham risk score calculated to assess cardiovascular risk. Data on survival were obtained from the national death registry RESULTS: Half of included patients were male (52%, 59 ± 10years), 819 (47%) carried PNPLA3‑G and 278 (16%) TM6SF2-T-alleles. MAFLD (PNPLA3‑G-allele: 46% vs. 41%, p = 0.041; TM6SF2‑T-allele: 54% vs. 42%, p < 0.001) was more frequent in patients harbouring risk alleles with both showing independent associations with MAFLD on multivariable binary logistic regression analysis. While median Framingham risk score was lower in PNPLA3‑G-allele carriers (10vs. 8, p = 0.011), SCORE2 and established cardiovascular diseases were similar across carriers vs. non-carriers of the respective risk-alleles. During amedian follow-up of 9.1years, neither PNPLA3‑G-allele nor TM6SF2‑T-allele was associated with overall nor with cardiovascular mortality. Carriage of PNPLA3/TM6SF2 risk alleles could not be identified as significant factor for all-cause or cardiovascular mortality in asymptomatic middle-aged individuals undergoing screening colonoscopy.

Investigation of Gene Variation Among Non-Alcoholic Fatty Liver Disease Patients in Gaza Strip: A Preliminary Study

The prevalent hepatic presentation of the metabolic syndrome is a non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver illnesses. Patients with NAFLD may develop liver damage depending on their genetic heritage. In this preliminary study, our main aim was to detect the genetic association of p85α (Met326Ile), PNPLA3 (C&gt;G), IL28B275 (A&gt;G), and IL28B860 (C&gt;T) single nucleotide polymorphisms (SNPs) with steatosis and NASH in patients from Gaza Strip. We performed an SNP analysis by RFLP-PCR in 33 cases of steatosis and 28 cases of non-alcoholic steatohepatitis (NASH), in addition to 29 age- and sex-matched controls. We found that only the mutant T allele of IL28B860 was significantly associated with an increased risk of steatosis (P = 0.04). The other studied alleles and genotypes were not significantly associated with increased or decreased risk of steatosis, NASH, or combined steatosis or NASH groups. Among all of the studied variables (age, sex, diabetes, and BMI), only BMI was significantly associated with an increased risk of steatosis as well as NASH. A linkage disequilibrium analysis showed that the association between the two SNPs of IL28B860 and IL28B275 was significant. Having the TG haplotype increased the risk of steatosis by 2.97 fold and the risk of combined steatosis or NASH by 2.44 fold. This haplotype increased the risk of NASH, but the effect was not significant.