Genetic analysis of nonalcoholic fatty liver disease within a Caribbean–Hispanic population

Abstract

We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean–Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy‐proven NAFLD, 24 ethnically matched non‐NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome‐wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted.

CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses

“…CRACR2A gene is located on Chromosome 12 in humans, and GWAS has identified its link to diseases including Parkinson’s disease, NAFLD, atrial fibrillation, and chronic HIV infection, that are potentially related with immune functions (1-4). However, the role of CRACR2A proteins in these diseases is largely unknown due to minimal information about their physiological functions.…”

“…Human Ca 2+ release-activated Ca 2+ channel regulator 2A ( CRACR2A , or alternatively EFCAB4B ) gene is located on chromosome 12. Links between polymorphism in CRACR2A and human diseases have been identified from numerous genome-wide association studies (GWAS) of Parkinson’s disease, non-alcoholic fatty liver disease (NAFLD), atrial fibrillation (AF), and chronic infection of human immunodeficiency virus type 1 (HIV-1) (1-4). However, the mechanisms underlying this link are largely unknown due to lack of information on the physiological role of CRACR2A.…”

“…Statin treatment-induced de-prenylation causes dissociation of CRACR2A-a from vesicles, leading to its degradation, thereby impairing T cell activation. Although many GWAS have uncovered CRACR2A for susceptibility to various human diseases (1-4), the physiological role of CRACR2A proteins largely remains unknown due to a lack of appropriate animal models.…”

Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice

“…Finally, genome-wide association studies showed an association between the HSD17B13 locus and fatty liver disease (http:// www.ncbi.nlm.nih.gov/pmc/?term=hsd17b13%20NAFLD). (40,(50)(51)(52)(53)(54)(55)(56) However, all these studies are based on HSD17B13 mRNA expression, which could not always reflect the protein expression or activity of the enzyme. Further studies are required to clarify how expression and activity of HSD17B13 are modulated with FLD.…”

Disruption of the ERLIN–TM6SF2–APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease

“…ERLIN1 and ERLIN2 also suppress cholesterol production by blocking the export of sterol regulatory element-binding proteins from the ER to the Golgi under high cholesterol conditions [20]. Interestingly, a missense mutation in ERLIN1 is recently suggested to confer protection against fatty liver and hepatic inflammation [21,22]. How ERLINs are implicated in NAFLD is yet to be established.…”