Advancing personalized medicine: Tailoring drugs to fit a patient's genetic predisposition

Drugs are not equally effective on all patients. A treatment that is dramatically effective on some patients can be ineffective on others. Drugs can also have serious side effects; in the worst case, a drug used to treat a disease can produce a fatal outcome. By examining genetic differences among individuals and administering drugs on the basis of such findings, the impact of side effects can be reduced. Taisei Mushiroda, the Laboratory Head of the Research Group for Pharmacogenomics at the RIKEN Center for Genomic Medicine, is making advances in personalized medicine with research into how drugs can be tailored to a patient's genetic information through the analysis of single nucleotide polymorphisms (SNPs).

Identifying the single nucleotide polymorphism (SNP) that plays a key role in drug rash

Japan's Ministry of Health, Labor and Welfare announced that the gout treatment allopurinol, the antiepileptic drug carbamazepine and the analgesic, anti-inflammatory, antipyretic drug loxoprofen hold the highest incidence of serious drug rash.

"The data we collected showed that the great majority of drug rash cases were caused by carbamazepine. We therefore proceeded to clarify the relationship between carbamazepine and drug rash, using Genome- Wide Association Study (GWAS). We divided our study population into two groups: those who experienced side effects and those who did not. We performed a comprehensive analysis of single nucleotide polymorphisms (SNPs) on the genome to statistically extract SNPs that are significantly associated with drug rash. The gene involved in drug rash was then identified from among those positioned near the SNPs"

Strands of DNA carry genetic information in the sequenced arrangement of the four bases A (adenine), T (thymine), G (guanine) and C (cytosine). Consisting of some three billion base pairs, the human genome carries the complete genetic information of a human being. Although there is more than 99% base sequence homology in all people, the remaining 1% of base sequences differ individually. "These differences are SNPs. It is estimated that more than 10 million SNPs are present in the human genome. They are associated with the appearance and constitution of the individual, and even with how drugs work and what side effects develop."

Relationship between drug rash caused by the antiepileptic drug carbamazepine and the HLA-A*3101 gene

Mushiroda and his colleagues conducted a study on Japanese epileptic patients undergoing treatment with carbamazepine. Of the sixty-one patients who experienced drug rash, 37 (about 61%) were found to have the HLA- A*3101 gene. In contrast, of the 376 patients who did not experience drug rash, 329 (about 88%) were found to lack HLA-A*3101.

"Reportedly, about 3% of Japanese patients experience drug rash when taking carbamazepine. About 60% of those have HLA-A*3101. It is therefore recommended that 60% of 3% (about 2%) of Japanese epileptic patients take antiepileptic drugs other than carbamazepine. In this way, the incidence of drug rash can be reduced by 2%," says Mushiroda. However, as this association was only discovered in 2010, further evidence must be presented before it can be useful in a clinical setting.

Personalized medicine expected to find clinical applications in 1 or 2 years

The next step after identifying the associated SNP is to determine its applicability in the clinical setting. It is also necessary to verify that SNP diagnosis is effective in both therapeutic and cost-benefit aspects. In ongoing prospective clinical research of nevirapine, it has been estimated that SNP diagnosis would cut annual medical expenditures by about US$60,000 (about ¥5 million) per hospital. This next phase will be necessary for successful application of the new system to the antiepileptic drug carbamazepine.

Before SNP genotyping can be firmly established in medical practice, however, a quick and accurate method to examine SNPs at the lowest cost is needed. In collaboration with Toppan Printing Co. Ltd. and RIKEN Genesis Co. Ltd., Mushiroda's team have developed the TPSA-003 genotype analysis system which can help to deliver more economical SNP genotyping (Fig. 3). The system provides results automatically in just one hour, simply by placing a single drop of untreated blood in the dedicated container and inserting the sample in the machine. "This is a groundbreaking machine. The conventional method involves the complex process of separating leukocytes from the blood sample, extracting the DNA from the leukocytes and applying the DNA to the machine to analyze SNPs. Conventionally, DNA extraction alone requires at least half a day even when undertaken by a highly skilled person. With the new system, the same task, including SNP genotyping, is completed in 60 minutes. This means that an accurate diagnosis can be obtained while the patient stays in the waiting room. Quick diagnosis is a big advantage for the patient as well."