Introduction

Overview

The human leukocyte antigen (HLA) genes are located on chromosome 6p21.3 of the human genome and are highly polymorphic. They play a crucial role in normal human immunological functions and are linked to many human diseases of the immune system. Recently, various HLA genotypes have also been found to be highly associated with adverse drug reactions (ADRs), leading to the increasing number of FDA approved drug labels recommending HLA genetic tests, such as for carbamazepine-induced Stevens-Johnson syndrome in patients carrying HLA-B*15:02 and abacavir-induced hypersensitivity syndrome in patients carrying HLA-B*57:01. However, to date there is not a central information portal dedicated to the reported drug-HLA pairs associated with ADRs.

  1. HLADR currently consists of more than 1,700 records of drug-HLA association pairs involving more than 50 FDA-approved drugs, over 450 HLA alleles, and 30 different types of ADRs from more than 190 original research articles.
  2. The most important information for each database entry (i.e., a drug-HLA pair associated with an ADR) is a 2 by 2 confusion matrix on which performance metrics for each drug-HLA pair were calculated in a consistent manner and thus could be compared across different studies.
  3. For each drug-HLA record, we re-calculated and normalized the p value, odds ratio, sensitivity, specificity, positive predictive value, and negative predictive value to show the different performance aspects for a given drug-HLA pair to serve as a safety biomarker against an ADR.
  4. The ethnical and geographical origins of the study subjects as well as the molecular structural information and FDA drug label changes resulting from the drug-HLA association were also provided when available.
  5. In addition to listing matched records one-by-one, summary results is also displayed so that users can get needed information fast, accurately, and well organized. For example, when searching by drug name, the HLA allele or ADR symptom associated with the query drug are sorted and displayed by the number of records matching the drug.
  6. Additionally, we added links to databases about HLAs (allele frequency, peptide binding affinity, and crystal structures), drugs (DrugBank and PubChem), and ADRs (PharmaGKB).

The HLADR database serves as a central portal for the readers to acquire integrated information about drug-HLA associations with ADRs, an exciting area of research and clinic significances as healthcare is getting personal. Mining the rich information in HLADR may also lead to new research directions. This database will also raise awareness to physicians and pharmacists on the importance of HLA-mediated ADRs. It is the hoped that HLADR will provide a foundation to promote the safer use of drugs and personalized medicine by eventually help develop predictive models that link ADRs to interactions between drugs and patient-specific polymorphic HLAs.

Statistical analysis

By January 2015, this database currently includes more than 1,700 associations of drug-induced ADRs with HLA. We obtained over 450 HLA alleles, more than 50 FDA-approved drugs, and 30 different types of ADRs. Statistics as followings:

The table of unique HLA alleles:

Gene locus A B C DR Other locus
Number 79 162 65 183 16


Figure 1. The increasing tendency of studies on associations of drug-induced ADRs with HLA


Figure 2. The distribution of ethnicity in the database


Figure 3. Drugs statistics: the distribution of the whole drugs in the current database


Figure 4a. ADR statistics, the distribution of the whole ADRs in the current database


Figure 4b. Severe cutaneous adverse reactions, the distribution of severe cutaneous adverse reactions

Reference:

Chung WH, Hung SI, Hong HS, et al. A marker for Stevens-Johnson syndrome. Nature 2004; 428: 486.