HLA-B, RYR1, CACNA1S, G6PD, mtRNR1

class I MHC molecules: HLA-A and HLA-B polymorphisms

• class I MHC (HLA) genes are amongst the most polymorphic human genes

• nomenclature of HLA gene polymorphism:

  • name (HLA-A or HLA-B) * and four numbers separated by colon

  • first 2 digits denote the antigen type and second two subtype

  • e.g. HLA-B * 15:01

drugs impacted by HLA-B polymorphism

• HLA-B*15:02

  • carbamazepine (also HLA-A*31:01)

  • oxcarbazepine

  • eslicarbazepine

  • phenyoin

  • fosphenytoin

• HLA-B*57:01

  • abacavir

• HLA-B*58:01

  • allopurinol

HLA-B genotype reporting

how does HLA-B polymorphism cause hypersensitivity reaction

physical interaction concept:

• drugs can interact with HLA allele or TCR leading to their docking and initiation of immune response

altered peptide repertoire:

• drugs can interact with HLA allele binding pocket so that a peptide becomes immune reactive and docks to TCR leading to initiation of immune reponse

HLA-B*15:02

• strong correlation between incidence of Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) in pts carrying HLA-B*15:02 and use of phenytoin, fosphenytoin, carbamazepine, oxycarbazepine

• a severe hypersensitivity reaction

• typically occurs within first 3 months of therapy

HLA-A*31:01

• correlation between incidence of Mild Maculopapular Eruptions (MPE) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in pts carrying HLA-A*31:01 and use of carbamazepine

Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)

• a medical emergency

• fever and flu-like symptoms

• unexplained widespread skin pain

• red or purple skin rashes that spreads tot he mucous membranes of mouth, nose, eyes, and genitals

• shedding of skin within days after blisters

• epidermal detachment affecting up to 10% of body surface area SJS, > 30% of the body surface area TEN

• mortality < 5% SJS, but TEN > 30%

HLA-B*15:02 CPIC recommendations for phenytoin, fosphenytoin, and oxcarbazepine

phenytoin treatment algorithm

carbamazepine: hypersensitivity reaction

• higher prevalence in HLA-A*31:01 with carbamazepine:

  • mild maculopapular eruptivo (MPE) in 10% patients which is a milder reaction without mucosal or organ invovlement

  • drug reaction with eosinophilia and systemic symptoms (DRESS) is severe hypersensitivity reaction characterized by generalized cutaneous eruption with systemic manifestations that can be life threatening

FDA label warning on carbamazepine

• FDA issued Health Alert in 2007 to include in carbamazepine label recommendations for genetic testing in patients with at-risk ancestry should be screened for the presence of HLA-B*15:02 allele prior to starting carbamazepine

• individuals at highest risk are those of Han Chinese descent, followed by those in Vietnam, Cambodia, the Reunion Islands, Thailand, India (specially Hindus), Malaysia, and Hong Kong

CPIC recommendations for carbamazepine

not all of ADEs associated with anticonvulsant hypersensitivty syndrome explained by PGx

• a triad of fever, skin eruptions (mild to severe), and lymphadenopathy within 1-8 weeks of exposure of aromatic anticonvulsant

  • phenytoin/fosphenytoin

  • carbamazepine/oxcarbazepine

  • cutaneous eruption in 3% of patins with or without organ involvement

HLA-B*58:01 CPIC recommendations for allopurinol

abacavir

• abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) for HIV treatment

• abacavir inhibits viral reverse transcriptase, suppressing HIV’s ability to convert its RNA genome into DNA before insertion into a host cell’s genome

• used in combination with other HIV medications, as part of highly active antiretroviral therapy

• commercially available as a single agent, Ziagen, or as a fixed dose combination with other nucleoside reverse transcriptase inhibitors, lamivudine (Epzicom/Kivexa) and lamivudine/zidovudine (Trizivir)

abacavir HSR

• generally well toelrated

• ~5-8% of pts may experience hypersensitivity reaction (HSR) during the first 6 weeks of treatment

• abacivr HSR symptoms (at least 2 of the following):

  • fever, rash, gastrointestinal symptoms (nausea, vomiting, abdominal pain), fatigue, cough, and dyspnea

• suspicion of a HSR warrants immediate discontinuation of abacavir. If the symptoms of clinically diagnosed HSR resolve after discontinuation of abacavir, drug-rechallenge is contraindicated because of immediate and life-threatening reactions, including anaphylaxis and even fatalities

• recommended that an allergy to abacavir should be noted in the patient’s medical record

abacavir FDA recommendations

• PREDICT trial prompted FDA to implement a black box warning in 2008

• recommended that all patients be screened before being treated with abacavir (including those who had previously tolerated the drug and were beings restarted on the therapy) and that abacavir SHOULD NOT be imitate din carriers of HLA-B*57:01

• abacavir is one of a limited number of drugs for which the FDA has recommended genetic testing prior to use, and it remains one of the best examples to date of pharmacogenetics being integrated into routine medical practice

CPIC guideliens and abacavir treatment algorithm

RYR1 and CACNA1S in malignant hyperthermia susceptibility (MHS)

• potent volatile anesthetic used in general anesthesia

  • sevoflurane, halothane, enflurane, isoflurane, methoxyglurane, desflurane

• depolarizing muscle relaxant, succinylcholine

MHS diagnosis

• inherited autosomal domino pattern fro both RYR1 and CACNA1S

  • “MHS causative” variants

• upon exposure to a triggering agent, MHS patient can have:

  • sustained increase of cytoplasmic calcium within skeletal muscle leading to uncontrolled muscle contraction

  • other indications of MH:

    • tachycardia and an increase in end-tidal CO2 followed by skeletal muscle rigidity, metabolic and respiratory acidosis, and hyperkalemia, hyperthermia, and arrhythmia

    • if left untreated, an MH reaction can result in cardiac arrest and death

• one of 2 criteria:

  • positive response to a muscle biospy (fresh) by caffeine-halothane contracture test (CHCT) —> gold standard

  • presence of pathogenic variants in RYR1 or CACNA1S

    • absence of causative mutation does NOT rule out MH susceptibility

safe anesthetics for MHS patients

• all local anesthetics (lidocaine)

• IV anesthetics:

  • propofol

  • benzos

  • ketamine

  • etomidate

• inhaled non-volatile general anesthetic such as nitrous oxide

• non-depolarizing muscle relaxants

  • rocuronium

  • atracurium

  • cis-atracurium

• barbiturates and opioids

glucose-6-phosphate dehydrogenase (G6PD) enzyme polymorphism

• gene encoding for G6PD enzyme is present on X chromosome

• males can be either function or loss of function

• females can be homozygous normal function, heterozygous normal function (carrier), or homozygous loss of function

• more than 2 dozen SNPs reported

• all alleles are loss of function

• prevalence is high in Africa, Asia, the Mediterranean, and the Middle East

G6PD Function

• to generate NADPH for antioxidant defense

• RBCs are esp susceptible to oxidant stress acne they have no nucleus and cannot synthesis damaged proteins

G6PD polymorphism

• foods (fava beans)

• some drugs can cause oxidative stress

• results in RBCs rupture leading to hemolytic anemia in individuals homozygous for loss of function G6PD

• signs and symptoms: weakness, fatigue, breathlessness, brown urine, jaundice

medications that should be avoided in G6PD deficiency

aminoglycosides

• aminoglycosides are a large class of antibiotics

  • amikacin, gentamicin, kanamycin, paromomycin, plazomicin, streptomycin, tobramycin

• typically administered IV/IM for serious Gram(-) bacterial infections or as synergistic treatment for Gram (+) bacterial infecitons

• MOA: inhibit protein synthesis by binding to 16s rRNA of bacterial 30S ribosome

• side effects: nephrotoxicity (overall reversible), hearing loss (permanent)

  • aminoglydoside-induced hearing loss (AIHL) even with single dose

MT-RNR1 in AIHL

• variants in MT-RNR1 that predispose to AIHL cause the 12s rRNA subunit to more closely resemble the bacterial 16s rRNA subunit

  • amino glycoside bind more readily —> increased risk of AIHL

• mitochondrial DNA is encoded for the genetic information required by mitochondria whereas nuclear DNA is encoded for the genetic information required by the entire cell

assignment of MT-RNR1 Phenotype based on genotype

CPIC recommendation for aminoglycosides in children and adults