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

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.

Genetic variants associated with steatohepatitis and liver fibrosis in HIV-infected patients with NAFLD

“…Studies analyzing the association between PNPLA3 and NAFLD in PLWHIV are more recent and report varying results ( Sherman et al, 2021 ) ( Price et al, 2014 ) ( Dold et al, 2017 ). It is important to note that the diagnostic methods used to identify NAFLD included CAP, liver ultrasound, and magnetic resonance, thus explaining in part this variability.…”

“…Such variable results could also be explained by racial and ethnic differences between the populations in the various studies. It is well known that problem alleles are not very frequent in Black individuals, whereas Latin Americans more frequently have the G allele ( Sherman et al, 2021 ). The percentages found for the different allelic variants of each gene in our study are within the expected frequencies in study populations according to race and ethnicity, thus explaining why we did not find an AA homozygote in TM6SF2 (the expected frequency is 0.08 in Europeans and 0.03 in Latin Americans) ( Trépo and Valenti, 2020 ).…”

“…The results have been contradictory, with few studies including liver biopsy samples. The populations of these studies differed considerably in terms of race, time with HIV infection, coinfection by hepatitis C virus (HCV) ( Scheiner et al, 2015 ; Núñez-Torres et al, 2016 ), and other comorbid conditions, thus potentially explaining the variability in the results reported ( Dold et al, 2017 ; Sherman et al, 2021 ). However, to date, no studies have analyzed the association between the genes PNPLA3 , TM6SF2 , and MBOAT7-TMC4 and biopsy-confirmed NAFLD in PLWHIV.…”

Diagnostic Ability of Simple Noninvasive Blood Tests to Predict Increased Liver Stiffness in People Living With HIV and Steatotic Liver Disease

“…Risk factors of developing NAFLD include features of the metabolic syndrome, including type 2 diabetes mellitus (T2DM) and insulin resistance, obesity, increased waist circumference, hypertension, and dyslipidemia (11). In PWH, additional risk factors include immune activation, adipose tissue dysfunction, ART associated with mitochondrial dysfunction, or genetic polymorphism (12,13). The spectrum of NAFLD can range from simple steatosis to steatohepatitis leading to fibrosis and cirrhosis.…”

Fatty liver disease in children living with HIV: a ghostly iceberg

“…As described in the previous series including adults living with HIV [5], we also found a significant group of lean patients presenting with NAFLD, suggesting again that body mass index and metabolic risk factors contribute to NAFLD pathogenesis but do not fully explain NAFLD among PWH. Genetic polymorphisms, among other factors, have been suggested to determine NAFLD among PWH [6,7]. As mentioned by Sabatini et al [1] intrauterine growth restriction has been identified as a key factor for future obesity in the general population, and it could definitely be playing a role here, as premature birth and low weight for height have been described among children born to HIV-infected mothers [8].…”