Using Pharmacogenetics to Find Treatment for Familial Hypercholesterolemia Patients with Both apoB and PCSK9 Mutations

• Main Author: Cho, Elizabeth
• Format: Others
• Published: Scholarship @ Claremont 2019
• Subjects: Familial Hypercholesterolemia; Pharmacogenetics; Single Nucleotide Plymorphism; Genetics; Medicinal Chemistry and Pharmaceutics
• Online Access: https://scholarship.claremont.edu/scripps_theses/1229; https://scholarship.claremont.edu/cgi/viewcontent.cgi?article=2377&context=scripps_theses

Familial hypercholesterolemias (FH) are inherited mutations that cause elevated total cholesterol and low-density lipoprotein cholesterol levels (LDL-C) which lead to premature coronary heart diseases. Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect the patient’s response to the drug. Single Nucleotide Morphism (SNP) mutations in the LDLR, apoB, LDRAP1, and PCSK9 genes are linked to familial hypercholesterolemia. The mutations in the LDLR gene are the most common while mutations in the apoB and PCSK9 genes are the least common in hypercholesterolemia patients. My research will study how pharmacogenetics can be used to diagnose and prescribe patients with FH who have apoB and PCSK9 double gene mutations. I will genotype and sequence the PCR amplified gene segments of the patients with FH to identify any of the 6 apoB SNPs and any of the 3 PCSK9 SNPs that are known. Then, I will provide 4 different treatments: placebo, antisense therapy (mipomersen), PCSK9 inhibitor (alirocumab), and a combination of mipomersen + alirocumab, and I will measure the LDL-C levels before and after a 12-week trial. I hypothesize that individuals with both apoB and PCSK9 gene mutations with the known SNPs that cause loss of function will be more responsive when given both treatments by observing a significant decrease in LDL-C levels.