Part 6 - In Depth Notes on Polymorphism Types and Their Effects

Polymorphism Types

  • Single Nucleotide Polymorphism (SNP):

    • A single base substitution in a DNA sequence that can result in either a silent mutation or a functional change in protein.

    • Millions of SNPs have been identified throughout the human genome, with new ones continuously discovered due to advancements in sequencing technology.

    • SNPs can be classified based on their locations:

      • Intronic: Located within introns, not affecting protein coding.

      • Exonic: Found within coding regions and can alter amino acid sequences.

    • Categories of SNPs:

      • Synonymous Polymorphism: A nucleotide change that does not alter the amino acid sequence; for example, a change from GAA to GAG both coding for glutamic acid.

      • Non-synonymous Polymorphism: Changes that lead to alteration in the amino acid sequence, which may affect protein function, stability, or expression.

      • Premature Stop Codon: Leads to truncated proteins that often result in loss of function; for example, a change from CTA to TAA may lead to an early termination of translation.

  • Variable Number Tandem Repeat (VNTR):

    • Repeats of short sequences (typically 2-10 base pairs), varying in number among individuals, contributing to genetic diversity.

    • Often found in non-coding regions, VNTRs have applications in forensics, paternity testing, and population genetics studies.

  • Gene Deletion:

    • A form of genetic polymorphism where a portion of the DNA is missing, which can lead to phenotypic consequences.

    • Deletions can affect one or several genes and may result in loss of gene function or dosage effects, which can play significant roles in disease susceptibility.

  • Copy Number Variant (CNV):

    • A type of structural variation where genes or genomic regions are present in variable copy numbers among individuals.

    • CNVs can impact gene dosage and functionality, contributing to phenotypic diversity and implications in various diseases, including cancer and neurological disorders.

Effects of SNPs on Drug Metabolism

  • Polymorphisms in drug-metabolizing enzymes significantly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, influencing plasma drug concentrations, efficacy, and toxicity.

  • Wild Type vs Variant: Genetic variants may lead to altered enzyme function:

    • Rapid Metabolizers: Individuals with variants that enhance enzyme activity may metabolize drugs too quickly, reducing efficacy.

    • Slow Metabolizers: Variants that reduce enzyme function can cause drug accumulation and increased risk of adverse drug reactions, leading to therapeutic failure or toxicity.

Examples of SNPs

  • Synonymous SNP Example:

    • Gene ABCB1 encodes P-glycoprotein, involved in drug transport across cell membranes.

    • Polymorphism: ABCB1 3435C>T (rs1045642)

      • Change: C > T, resulting in no alteration in the amino acid sequence (Isoleucine remains unchanged).

      • Reference nucleotide sequence: GMGT

      • Affected drugs: efavirenz, cyclosporine; variations can lead to altered absorption and bioavailability of these medications.

  • Non-Synonymous SNP Example:

    • Gene TPMT encodes thiopurine methyltransferase, crucial for the metabolism of thiopurine drugs used in cancers and autoimmune diseases.

    • Changes in the nucleotide sequence lead to:

      • TPMT 615 G>A: Alters alanine to threonine, reducing enzyme activity.

      • TPMT 874 A>G: Alters tyrosine to cysteine, completely abolishing enzymatic function.

    • Functional Impact: Reduced TPMT activity can lead to severe toxicities with medications like azathioprine and 6-mercaptopurine.

    • Reference sequence: GCA | TTA | AAG | TTA | TAT | CTA

      • Corresponding amino acids: Ala | Leu | Lys | Leu | Tyr | Leu.

Clinical Case Studies

  • Case #1:

    • Patient: 7-year-old Caucasian male diagnosed with acute lymphoblastic leukemia.

    • Decision: To evaluate the necessity of genetic screening for TPMT polymorphisms before initiating treatment with 6-mercaptopurine.

    • ☑ Results: Genetic screening revealed the patient carried the TPMT3A/3A genotype, indicating a high risk of severe myelosuppression when treated, prompting a dose adjustment or alternative therapy.

  • Case #2:

    • Patient: 35-year-old Asian female experiencing H. pylori peptic ulcer disease.

    • Medication: Combination treatment with omeprazole, amoxicillin, and clarithromycin.

    • Polymorphism: Identified CYP2C19*3 variant leading to no CYP2C19 enzyme activity, resulting in elevated plasma levels of omeprazole and enhanced therapeutic outcomes.

Summary of Polymorphism Impact

  • Understanding genetic polymorphisms is crucial for predicting variability in enzyme activity, significantly influencing the pharmacokinetics and pharmacodynamics of drugs.

  • CYP2C19 example:

    • Genotype: CYP2C193/3 confers no functional enzyme, impacting metabolite levels and clinical outcomes, especially for drugs like omeprazole, which are extensively metabolized by this enzyme.

Takeaway Points

  • Genetic variations in drug metabolism underscore the importance of personalized medicine, tailoring drug therapies to individual genetic profiles for optimal efficacy and minimal adverse effects.

  • Routine genetic screening for relevant polymorphisms, particularly in diverse populations with known frequency variations, could significantly enhance patient care and pharmacotherapy outcomes.