Pharmacogenomic science (PGx) works by utilizing DNA sequencing information and applying it to your daily clinical decisions.
PGx focuses on the proteins involved in drug metabolism. The genes coding for these proteins tend to have more variety (polymorphism) than other genes5 . This is the genetic mechanism behind the wide variability in patient drug response.
One key example is the cytochrome P450 superfamily. These proteins are involved in the metabolism of 80% of the drugs on the market6. Based on the sequence, the proteins can have varying degrees of function. Some patients are normal metabolizers, meaning the drugs prescribed work as intended. However, many patients are either intermediate or poor metabolizers, which can contribute to either lack of therapeutic response or increase in adverse drug response, depending on the type of drug.
Prodrugs, such as Plavix, need to be metabolized to be effective. Poor and intermediate metabolizers of Plavix will take the drug dutifully without receiving any therapeutic effects7. Other drugs, like warfarin, need to be metabolized to be cleared from the body. Poor and intermediate metabolizers taking these medications will clear the drug more slowly from their system. They may reach toxic levels or experience adverse drug reactions while on a normal dose8.
And that’s only one protein family. Our team tests for single nucleotide polymorphisms in a wide variety of genes involved in cardiovascular disease risk and metabolism for over 180 drugs.
GnomeDX Gene Information Table. This table includes the clinical category of the genes tested in our panel tests, the clinical implications and epidemiological projections associated with each gene. One projection to note is the gene VKORC1, which is involved with warfarin metabolism has a epidemiological protection of 58% increased sensitivity in the population. Epidemiological projections were calculated from Global Allelic Frequency in the NCBI database, dbSNP, build 145, accessed 09/2015. The clinical implication of homo- and heterozygosity were take into account. Odds were calculated based only on most common haplotype for each gene.
There are two genes primarily involved in warfarin PGx. The first is VKORC1, the protein that warfarin acts upon to achieve therapeutic effect. The second is CYP2C9, the liver enzyme that metabolizes warfarin so it can be cleared from the body11. A 2010 study of 10,000 patients found that 69% had at least one actionable variant related to warfarin dosing11. CPIC and the FDA issue the same recommendations for genotype-guided warfarin therapy, covering every combination of CYP2C9 and VKORC1 status11. Good metabolizers with normal sensitivity receive the standard dose: 5-7 mg. For poor metabolizers with increased sensitivity, that dosage would be a 10-fold overdose, putting them at risk for a bleed - the most clinically significant complication with warfarin therapy.
Clopidrogrel is a prodrug which must be activated in the liver to achieve therapeutic effect. However, 25% of Caucasians, 30% of Blacks, and 50% of Asians12 have a variant which decreases the function of CYP2C19, the liver enzyme responsible for that activation. These patients have significantly higher rates of cardiovascular death, myocardial infarction, or stoke and very significantly higher rates of stent thrombosis because less of the drug gets activated in their systems7. Studies show by adjusting treatment, clinicians can spare their patients from these increased risks13. CPIC has published guidelines recommending alternative therapy for poor and intermediate CYP2C19 metabolizers. The same recommendation has been issued by the FDA as a black box warning on the clopidogrel label.
Simvastatin must move from the bloodstream into the liver both to achieve therapeutic effect and to be cleared from the body. However, a quarter (25.7%) of the US population has a variant decreasing the expression of the SLCO1B1 protein11. This protein is responsible for transporting simvastatin into the liver. Without access to the liver, the drug stays in the blood longer, affecting the skeletal muscle and causing the most common adverse effect, myopathy14. Myopathy is also the leading cause of poor patient adherence to their drug regimen.
The magnitude of the effect is comparable to drinking grapefruit juice. Both drinking grapefruit juice15 and having the SLCO1B1 variant gene16 cause a 3x increase in drug exposure. Just as there are guidelines to adjust dosage/drug because of grapefruit juice, there are also published CPIC guidelines that recommend decreased dosage or choosing a different statin (less reliant on the SLCO1B1 transporter) for patients with the SLCO1B1 variant17.