Abstract 4362033: <i>APOH</i> plays a distinct role in lipid trait dysregulation and increased CVD risk

Background: Variants at the APOH genomic locus have been associated with lipid traits, Lp(a), coagulation traits, coronary artery disease, and fatty liver disease. The mechanisms by which the ApoH protein influences these cardiometabolic phenotypes are not understood. An APOH missense variant C325G (rs1801689) has a minor allele frequency of 2.8% and is predicted to impact protein structure, making it a potential genetic tool for understanding ApoH biology. Hypothesis: We hypothesize that the association of APOH C325G with clinical phenotypes and circulating proteins and metabolites will provide new insights into the relationship between APOH and cardiometabolic traits. Methods: We accessed internal data from the Penn Medicine BioBank (PMBB) and publicly available data from the UK Biobank, the Million Veteran Program, and the All of Us cohort for these analyses. In addition, siRNA was used to knock down APOH in HuH-7 hepatocytes. Results: PheWAS of APOH C325G in the PMBB identified association with a number of cardiometabolic conditions, several of which were replicated in the other cohorts. Analyses of lab data indicated that APOH C325G was associated with lower triglyceride (TG) levels and higher LDL-C, apoB, and Lp(a) levels (p &lt; 0.01). Analysis of NMR-derived plasma metabolites in UKB showed that APOH C325G is associated with highly significant reductions in the larger VLDL particle subclasses, increases in the small VLDL particle subclasses, and increases in all LDL subclasses. Analysis of UKB proteomic data revealed that APOH C325G is associated with significantly reduced plasma levels of the ApoH protein and changes in other circulating proteins that are related to lipid metabolism and cardiometabolic traits (p &lt; 5 x 10 -8 ). Mendelian randomization analysis suggested that genetically determined lower ApoH plasma levels causally decrease plasma TG levels (p &lt; 5 x 10 -8 ). Finally, siRNA silencing of APOH in human Huh7 cells led to reduced TG secretion (two-sample t-test, p &lt; 0.05). Conclusions: The APOH missense variant C325G is associated with reduced TGs, large VLDLs, and increased LDL, apoB, Lp(a), and cardiometabolic conditions. It may serve as a useful genetic tool to understand the biology of APOH . Silencing of APOH in hepatocytes reduces TG production. Recall-by-genotype deep phenotyping of APOH C325G carriers in the PMBB is underway.