Central Illustration: Schematic of GWAS to Functional Validation of TTC39B HDL Locus Using Relevant Mouse Models

(Top) Regional association plot for lead single nucleotide polymorphism (orange circle) and variants in linkage disequilibrium associated with high-density lipoprotein (HDL) levels at TTC39B locus on chromosome 9. Negative log p values are shown on the left axis, and recombination rate (blue line) is shown on the right axis. (Middle) Genetic variation at TTC39B or potential drug targeting TTC39B leads to TTC39B (T39) deficiency and post-transcriptional increase/stabilization of liver X receptor (LXR) protein levels. This results in increased LXR target gene expression and increased HDL cholesterol, but reduced low-density lipoprotein (LDL) cholesterol and triglyceride (TG) levels. (Bottom) Pathways targeted as a result of T39 deficiency in mouse liver hepatocytes, intestine enterocytes, and atherosclerotic artery macrophage/foam cells. LXR protein binds deoxyribonucleic acid along with its obligate partner, retinoid X receptor (RXR) activating transcription of target genes, such as ABCA1 (major cholesterol efflux transporter) involved in formation of HDL, or ABCG5/8 (major biliary cholesterol transporters). Sterol regulatory element-binding protein (SREBP-1c) processing to the active deoxyribonucleic acid binding complex is reduced by altered phosphatidylcholine metabolism, thus preventing activation of lipogenic gene expression. Ultimately, both hepatosteatosis and atherosclerosis are reduced by T39 deficiency.