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      PNPLA3 Single Nucleotide Polymorphism Prevalence and Association with Liver Disease in a Diverse Cohort of Persons Living with HIV

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          Abstract

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          In this pilot study, we determined the prevalence of single nucleotide polymorphisms (SNPs) in the PNPLA3 gene among persons living with HIV (PLWH). Overall, approximately 40% of the population carries at least one “G” allele that is associated with development of fatty liver and progressive liver disease. The highest rates were observed in those with Hispanic ethnicity. However, rates of steatosis (fatty liver) and liver fibrosis were relatively low when evaluated by magnetic resonance elastography with proton-density fat fraction measurement (MRE with PDFF). When putative NAFLD/NASH was present it was associated with the presence of the “G” allele.

          Abstract

          In persons living with HIV (PLWH), there are multiple sources of liver injury. Gene polymorphisms of PNPLA3 (patatin-like phospholipase domain-containing protein 3) have been identified as an important cofactor for increased disease severity in both alcoholic and non-alcoholic steatohepatitis (NASH). We utilized a well-characterized cohort of ethnically and racially diverse patients with HIV to define the prevalence of PNPLA3 SNPs (single nucleotide polymorphism) (rs738409), and to determine the relationship to hepatic steatosis and liver fibrosis. Steatosis was determined using MRI-PDFF (magnetic resonance imaging-determined proton density fat fraction) and fibrosis was estimated using MR Elastography (MRE). From the Miami Area HIV Study (MASH) cohort, 100 HIV positive participants and 40 controls (HCV/HIV = 20; HCV and HIV negative = 20) were evaluated. Nearly 40% of all participants carried the variant G allele associated with increased liver disease severity and 5% were homozygotic GG. The variant SNP occurred most frequently in those self-identified as Hispanic compared to white or Black participants. Hepatic steatosis (>5% fat) was present significantly more often in those without HIV vs. those with ( p < 0.001). Putative NAFLD/NASH was found to be present in 6% of tested subjects, who were HIV monoinfected. BMI was lower in those that carried the G allele for PNPLA3. This finding suggests that PNPLA3 may be an independent component to NAFLD (non-alcoholic fatty liver disease)/NASH development and longitudinal follow-up of the cohort is warranted.

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          The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD.

          Patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis are at the highest risk for progressing to end-stage liver disease. We constructed and validated a scoring system consisting of routinely measured and readily available clinical and laboratory data to separate NAFLD patients with and without advanced fibrosis. A total of 733 patients with NAFLD confirmed by liver biopsy were divided into 2 groups to construct (n = 480) and validate (n = 253) a scoring system. Routine demographic, clinical, and laboratory variables were analyzed by multivariate modeling to predict presence or absence of advanced fibrosis. Age, hyperglycemia, body mass index, platelet count, albumin, and AST/ALT ratio were independent indicators of advanced liver fibrosis. A scoring system with these 6 variables had an area under the receiver operating characteristic curve of 0.88 and 0.82 in the estimation and validation groups, respectively. By applying the low cutoff score (-1.455), advanced fibrosis could be excluded with high accuracy (negative predictive value of 93% and 88% in the estimation and validation groups, respectively). By applying the high cutoff score (0.676), the presence of advanced fibrosis could be diagnosed with high accuracy (positive predictive value of 90% and 82% in the estimation and validation groups, respectively). By applying this model, a liver biopsy would have been avoided in 549 (75%) of the 733 patients, with correct prediction in 496 (90%). a simple scoring system accurately separates patients with NAFLD with and without advanced fibrosis, rendering liver biopsy for identification of advanced fibrosis unnecessary in a substantial proportion of patients.
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            Diagnostic Accuracy of the Triglyceride and Glucose Index for Insulin Resistance: A Systematic Review

            Introduction. The triglyceride and glucose (TyG) index has been described as a biochemical marker of insulin resistance (IR); however, its diagnostic accuracy remains uncertain. Objective To summarize the evidence assessing the diagnostic accuracy of the TyG index regarding IR. Methods A comprehensive search in MEDLINE, EMBASE, Web of Science, and Scopus was performed without any language restriction. Studies assessing the diagnostic accuracy of the TyG index against the hyperinsulinemic-euglycemic clamp (HIEC) or any other IR biochemical were assessed independently and in duplicate. Diagnostic accuracy measures (sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios) were extracted independently and in duplicate. The QUADAS-2 tool was used to assess the risk of bias of independent studies. Results We identified 15 eligible studies with 69,922 participants and an overall quality of low to moderate. The TyG index was evaluated by HIEC and HOMA as reference tests. The highest achieved sensitivity was 96% using HIEC, and the highest specificity was of 99% using HOMA-IR, with a cutoff value of 4.68. AUC values varied from 0.59 to 0.88. Cutoff values for IR were variable between studies, limiting its comparability. Conclusion In this systematic review, we found moderate-to-low quality evidence about the usefulness of the TyG index as a surrogate biochemical marker of IR. Due to the lack of a standardized IR definition and heterogeneity between studies, further validation and standardized cutoff values are needed to be used in clinical practice.
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              Variant in PNPLA3 is associated with alcoholic liver disease.

              Two genome-wide association studies (GWAS) have described associations of variants in PNPLA3 with nonalcoholic fatty liver and plasma liver enzyme levels. We investigated the contributions of these variants to liver disease in Mestizo subjects with a history of alcohol dependence. We found that rs738409 in PNPLA3 is strongly associated with alcoholic liver disease and clinically evident alcoholic cirrhosis (unadjusted OR= 2.25, P=1.7 x 10(-10); ancestry-adjusted OR=1.79, P=1.9 x 10(-5)).
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biology (Basel)
                Biology (Basel)
                biology
                Biology
                MDPI
                2079-7737
                21 March 2021
                March 2021
                : 10
                : 3
                : 242
                Affiliations
                [1 ]University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; susan.rouster@ 123456uc.edu (S.D.R.); Heidi.Meeds@ 123456uc.edu (H.M.)
                [2 ]Robert Stempel School of Public Health, Florida International University, Miami, FL 33199, USA; jtama025@ 123456fiu.edu (J.T.); baumm@ 123456fiu.edu (M.B.)
                [3 ]Mayo Clinic, Department of Radiology, Rochester, MN 57058, USA; Chen.Jun@ 123456mayo.edu (J.C.); ehman.richard@ 123456mayo.edu (R.E.)
                Author notes
                Author information
                https://orcid.org/0000-0002-0560-0019
                https://orcid.org/0000-0001-9385-9049
                https://orcid.org/0000-0002-6577-685X
                Article
                biology-10-00242
                10.3390/biology10030242
                8004031
                35833348-bec7-4db5-8372-d7c899abc985
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 February 2021
                : 18 March 2021
                Categories
                Article

                fatty liver,steatosis,hiv,coinfection,fibrosis,gene polymorphism

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