Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

Abstract

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of "healthy" subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia.

Keywords: PCSK9 inhibitors; ezetimibe; familial hypercholesterolemia; novel lipid-lowering therapy; pharmacogenomics; statins.

Figure 1

Scheme representing the cholesterol metabolism pathway and pharmacological targets for classical and novel lipid-lowering therapies (generated with BioRender.com). Unique hepatic and intestinal transporters (ABCG5 and ABCG8) release bile acids, phospholipids, and cholesterol into the biliary system. Inversely, the NPC1L1 protein modulates cholesterol returning to hepatocytes. Ezetimibe inhibits cholesterol entry into the intestine and liver by the NPC1L1 transporter. Next, chylomicrons are generated through the assembly of TG, cholesterol, and ApoB-48, and released into the blood circulation (see intestinal lipoproteins pathway). The speed-limiting enzyme of endogenous cholesterol synthesis, HMGCR (see hepatic lipoproteins pathway), is inhibited via statins. The activated bempedoic acid decreases the hepatic synthesis of acetyl CoA and cholesterol catabolism by blocking the ACL protein. ApoB-100, phospholipid, ApoC-III, and cholesterol assembly into VLDL depends on the activity of MTP, which is blocked by lomitapide. The degradation of hepatic messenger ribonucleic acid (mRNA) transcript of ApoB-100 and ApoC-III is mediated by mipomersen and gemcabene, respectively. The heteroexchange of TGs and cholesteryl esters between ApoB-lipoproteins particles relies on CETP activity, which is blocked by CETP inhibitors such as anacetrapib. LDLR interacts and removes LDL-cholesterol from the blood circulation with the assistance of LDLRAP1. Lysosomal catabolism of LDLR is mediated by PCSK9. Anti-PCSK9 antibodies, including evolocumab, alirocumab, and inclisiran inhibit the endogenous production and release of PCSK9. Evinacumab blocks the inhibition of hepatic lipoprotein lipase activity by ANGPTL3. Abbreviations: ApoB-48/100, Apolipoprotein B protein member 48 & 100; ApoC-III, Apolipoprotein C protein, member III; ApoE, Apolipoprotein E protein; HDL, High-density lipoprotein cholesterol; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; TG, triglyceride; LDLR, LDL-receptor; LDLRAP1, LDLR-adaptor protein, member 1; ABCG2, atp-binding cassette, subfamily g, member 2; HMGCR, β-hydroxy-β-methylglutaryl Coenzyme A Reductase; NPC1L1, Niemann-Pick C1-like 1 transporter protein; ACL, adenosine triphosphate citrate lyase; MTP, microsomal triglyceride transfer protein; LPL, lipoprotein lipase; CETP, cholesteryl ester transfer protein; ANGPTL3, angiopoietin-like protein 3; PCSK9, proprotein convertase subtilin/kexin 9 protein.

Figure 2

A schematic representation of the pharmacokinetic modulator genes involved in absorption, distribution, metabolism, and clearance of lipid-lowering therapy (created with BioRender.com). Oral lipid-antagonists enter the circulatory system via the enteric SLC and ABC gene-transporters. While intravenous anti-lipids enter directly into the circulation and reach the liver, the agents administrated subcutaneously are slowly absorbed through the blood capillaries. The liver and kidneys are the major metabolic sites for lipid-lowering medicines. The main catalytic proteins involved in their metabolic pathway are CYP and UGT, which inactivate or activate drugs. Members of the ABC family then mediate their elimination through kidneys, biliary, or intestinal pathways. Some drugs accumulate for a long-time in the muscle or adipose tissue. Abbreviations: ABCG2/5/8, atp-binding cassette, subfamily g, member 2, 5, or 8; SLCO1B1, solute carrier organic anion transporter 1B1; CYP3A4, Cytochrome P450, family 3, subfamily A, member 4; UGT2B7, uridine 5′-diphosphate (UDP)-glucuronosyltransferase 2B7; UGT1A1/3, uridine 5′-diphosphate (UDP)-glucuronosyltransferase 1A1 or 3.

Figure 3

Flowchart illustration of the recommended genomic screening process for different groups of FH patients and their families (generated with BioRender.com). * Diagnostic Criteria of FH based on Dutch-MEDPED guideline: total cholesterol > 250 mg/dL, LDL-C > 190 mg/dL (adults) or >160 mg/dL (children), in addition to family history of similar findings or with premature cardiovascular diseases, tendon xanthomas, arcus cornealis, or DNA-based evidence of LDLR, APOB, or PCSK9 functionality mutations [6]. ** Morbidities associated with FH: cardiovascular diseases such as coronary heart disease, stroke, & peripheral vascular disease, diabetes, hypertension, and erectile dysfunction. Θ Regularly monitor and compare the response and safety of medications according to each individual genotypes. Abbreviations: LDL-C, low-density lipoprotein-cholesterol; LDLR, LDL-receptor; APOB, Apolipoprotein B; PCSK9, proprotein convertase subtilin/kexin 9 protein, LDLRAP1, LDLR-adaptor protein, member 1, APOE, Apolipoprotein E.