Browsing by Subject "PNPLA3"

Now showing 1 - 3 of 3
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    Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis
    (Wiley, 2019) Samala, Niharika; Gawrieh, Samer; Tang, Qing; Lourens, Spencer G.; Shah, Vijay H.; Sanyal, Arun J.; Liangpunsakul, Suthat; Chalasani, Naga; Medicine, School of Medicine
    Introduction & Aim Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalisation. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study, we investigated the risk factors, characteristics and outcomes of mild to moderate AH (M‐AH). Methods A total of 255 individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 was included. Participants were seen at enrollment, 6 and 12 months. M‐AH was defined as MELD ≤20 at presentation, whereas severe AH as MELD ≥21. Results In total, 100 individuals had M‐AH, whereas 155 had severe AH. Individuals with M‐AH were older (49 vs 44 years, P = 0.01), had lower BMI (27 vs 31 kg/m2, P = 0.0007) and more likely to be male (68% vs 55%, P = 0.046) compared to the severe AH group. A higher proportion in the M‐AH group consumed coffee in the last 5 years compared to the severe AH group (29% vs 18%, P = 0.03), and fewer had PNPLA3 risk allele G (P = 0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, P = 0.13) and total number of drinks in last 30‐day period (331 vs 280, P = 0.14) were not different between two groups. Compared to severe AH, patients with M‐AH had significantly lower mortality at 30 days (2% vs 13.6%), 90 days (3% vs 22.6%) and 12 months (10.4% vs 31.4%) (P < 0.001 for all). Conclusions Individuals with M‐AH were older, less obese, drank coffee more often and carried more favourable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. M‐AH had substantial mortality with one in ten dying by 12 months.
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    PNPLA3—A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease
    (Frontiers Media, 2019-12-17) Dong, Xiaocheng Charlie; Biochemistry and Molecular Biology, School of Medicine
    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.
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    Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans
    (Impact Journals, 2016-10-13) Liu, Wanqing; Anstee, Quentin M.; Wang, Xiaoliang; Gawrieh, Samer; Gamazon, Eric R.; Athinarayanan, Shaminie; Liu, Yang-Lin; Darlay, Rebecca; Cordell, Heather J.; Daly, Ann K.; Day, Chris P.; Chalasani, Naga; Department of Medicine, IU School of Medicine
    The increased expression of PNPLA3148M leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic PNPLA3 transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL (p = 6.6×10-8) influencing PNPLA3 transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate PNPLA3 transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of PNPLA3148M in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of PNPLA3 gene in human livers.