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.

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.

Significant resources have been invested in sequencing studies to investigate the role of rare variants in complex disease etiology. However, the diagnostic interpretation of individual rare variants remains a major challenge, and may require accurate variant functional classification and the collection of large numbers of variant carriers. Utilizing sequence data from 458 individuals with hypertriglyceridemia and 333 controls with normal plasma triglyceride levels, we investigated these issues using GCKR, encoding glucokinase regulatory protein. Eighteen rare non-synonymous GCKR variants identified in these 791 individuals were comprehensively characterized by a range of biochemical and cell biological assays, including a novel high-throughput-screening-based approach capable of measuring all variant proteins simultaneously. Functionally deleterious variants were collectively associated with hypertriglyceridemia, but a range of in silico prediction algorithms showed little consistency between algorithms and poor agreement with functional data. We extended our study by obtaining sequence data on family members; however, functional variants did not co-segregate with triglyceride levels. Therefore, despite evidence for their collective functional and clinical relevance, our results emphasize the low predictive value of rare GCKR variants in individuals and the complex heritability of lipid traits.

Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.