Polymorphic markers for pharmacogenetic HLA risk alleles
We have identified panels of proxy single nucleotide polymorphisms (SNPs) that are highly predictive of particular HLA risk alleles, and concordant across multi-ethnic populations. Accordingly, methods are provided involving clinical DNA testing for HLA panel markers to assess risk for life-threatening adverse drug reactions associated with the human leucocyte antigen (HLA) alleles HLA-B*57:01, HLA-B*15:02, HLA-A*31:01 and HLA-B*58:01. Methods of treating a subject with a drug associated with an adverse drug reaction (ADR) are provided. Based on the assessed risk to a subject for developing an adverse drug reaction in response to a drug, appropriate administrations of the drug can be made. In some embodiments of the method, the drug is administered when there is a low assessed risk of ADR in the subject. Alternatively, when there is a high assessed risk of ADR in the subject, a reduced dosage of the drug, or no drug, can be administered.
1 . A method comprising:
(a) assaying for one or more genetic markers each independently selected from rs114776910_G, rs138415245_G, rs12665140_A, rs148590958_C, and rs114716190_G, in a sample from a subject,
wherein the one or more genetic markers are in linkage disequilibrium with an HLA allele associated with the ADR and selected from HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01;
(b) assessing a risk of adverse drug reaction (ADR) in the subject in response to a drug associated with the ADR,
wherein an elevated risk is assessed when the one or more genetic markers are present in the sample and an average risk is assessed when the one or more genetic markers are absent from the sample,
wherein the assessing comprises detecting a presence or absence of the HLA allele in the subject based on the one or more genetic markers,
wherein the detecting has a positive predictive value of at least 0.92 and a negative predictive value of at least 0.99 across a set of multi-ethnic populations,
wherein the set of multi-ethnic populations comprises an African American population, a European population, a Hispanic population, an East Asian population, and a South Asian population; and
(c) administering the drug to the subject when an average risk of the ADR is assessed in the subject, or declining to administer the drug to the subject when an elevated risk of the ADR is assessed in the subject;
wherein the drug is capable of treating a disease or condition of the subject; and
wherein the disease or condition of the subject comprises human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), epilepsy, gout, neuropathic pain, a mood disorder, anxiety, kidney stones, or chemotherapy side effects.
2 . The method of claim 1 , wherein the drug is selected from abacavir, carbamazepine, phenytoin, and allopurinol.
3 . The method of claim 1 , wherein the ADR is selected from acute hepatitis, hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and mild cutaneous ADR.
4 . The method of claim 1 , wherein the sample from the subject is selected from saliva, urine, whole blood, plasma, serum, peripheral blood, and hair.
5 . The method of claim 1 , wherein the assaying comprises isolating or amplifying genomic deoxyribonucleic acid (DNA) from the subject.
6 . The method of claim 1 , wherein the assaying comprises sequencing, selective hybridization, or selective amplification.
7 . The method of claim 1 , wherein:
an average risk of the ADR in the subject is assessed when all of the one or more genetic markers for the HLA allele that are assayed are absent; and
an elevated risk of the ADR in the subject is assessed when all of the one or more genetic markers for the HLA allele that are assayed are present.
8 . The method of claim 1 , wherein the detecting has an average of 99% sensitivity and 99% specificity across the set of multi-ethnic populations.