Background & Aims: Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the United States have a high prevalence of PNPLA3 I148M, which increases liver disease risk, and a low prevalence of HSD17B13 predicted loss-of-function (pLoF) variants, which reduce risk. Less is known about the prevalence of liver disease-associated variants among Hispanic/Latino subpopulations defined by country of origin and genetic ancestry. We evaluated the prevalence of HSD17B13 pLoF variants and PNPLA3 I148M, and their associations with quantitative liver phenotypes in Hispanic/Latino participants from an electronic health record-linked biobank in New York City.
Methods: This study included 8739 adult Hispanic/Latino participants of the BioMe biobank with genotyping and exome sequencing data. We estimated the prevalence of Hispanic/Latino individuals harboring HSD17B13 and PNPLA3 variants, stratified by genetic ancestry, and performed association analyses between variants and liver enzymes and Fibrosis-4 (FIB-4) scores.
Results: Individuals with ancestry from Ecuador and Mexico had the lowest frequency of HSD17B13 pLoF variants (10%/7%) and the highest frequency of PNPLA3 I148M (54%/65%). These ancestry groups had the highest outpatient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and the largest proportion of individuals with a FIB-4 score greater than 2.67. HSD17B13 pLoF variants were associated with reduced ALT level (P = .002), AST level (P < .001), and FIB-4 score (P = .045). PNPLA3 I148M was associated with increased ALT level, AST level, and FIB-4 score (P < .001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (P = .006).
Conclusions: Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.cgh.2022.12.025 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs.
Life Sci
December 2024
State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China. Electronic address:
Aims: This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease-susceptible transgenic pigs via multiomics analysis.
Materials And Methods: The triple-transgenic (PNPLA3-GIPR-hIAPP) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials.
Preclinical and Clinical Pharmacokinetics of JNJ-75220795, an siRNA Therapeutic Targeting PNPLA3, for Metabolic Dysfunction-Associated Steatohepatitis.
J Clin Pharmacol
December 2024
Janssen Research & Development, LLC, Raritan, NJ, USA.
JNJ-75220795 or ARO-PNPLA3 is an investigational small interfering ribonucleic acid agent conjugated with N-acetyl-d-galactosamine that targets the PNPLA3 gene, currently being developed for metabolic dysfunction-associated steatohepatitis (MASH). This study evaluated the pharmacokinetics (PK) profile of single subcutaneous doses of JNJ-75220795 in preclinical species as well as in human subjects with homozygous or heterozygous PNPLA3 I148M mutation in two phase 1 studies-a first-in-human study in the United States and a first-in-Japanese study in Japan. Preclinical PK in rats and non-human primates (NHP) showed a rapid systemic absorption and elimination following single subcutaneous doses.
View Article and Find Full Text PDFLipid droplet targeting of ABHD5 and PNPLA3 I148M is required to promote liver steatosis.
bioRxiv
November 2024
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, 48202.
The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD).
View Article and Find Full Text PDFStatin-associated regulation of hepatic PNPLA3 in patients without known liver disease.
J Intern Med
January 2025
Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
Background And Objectives: Statins are used for metabolic dysfunction-associated steatotic liver disease (MASLD) (NAFLD) treatment, but their role in this context is unclear. Genetic variants of patatin-like phospholipase domain containing 3 (PNPLA3) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study.
View Article and Find Full Text PDFPNPLA3 I148M Interacts With Environmental Triggers to Cause Human Disease.
Liver Int
November 2024
Department of Gastroenterology, Endocrinology and Intensive Care, RWTH Aachen University, Aachen, Germany.
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!