HKU identifies rare, actionable pharmacogenetic variants specific to Hong Kong/Southern Chinese

After analyzing 108 pharmacogenes from the largest set of exome sequencing data from Chinese subjects to date, researchers from the University of Hong Kong (HKU) have identified 96 rare, previously unreported deleterious variants with actionable potential in clinical practice.

“Pharmacogenetic testing has the potential to guide personalized drug prescription and improve drug dosing thereby enhancing efficacy and preventing adverse reactions. However, its implementation is limited among Chinese patients due to the lack of Chinese-specific pharmacogenetics data,” wrote the researchers. “In this study, we used exome sequencing data from 1,116 Hong Kong Chinese subjects, who are representative of the Southern Chinese subpopulation, to analyze rare, potentially actionable variants among 108 high-confidence pharmacogenes from Pharmacogenomics Knowledgebase.” [PLoS Genet 2021;17:e1009323]

Consistent with other populations, nearly all of Hong Kong Chinese subjects carried at least one known actionable pharmacogenetic variant (99.6 percent) and at least one rare, deleterious variant (93.5 percent) in the 108 high-confidence pharmacogenes. [Clin Pharmacol Ther 2016;100:160-169; Pharmacogenomics J 2018;18:187-195] The median number of actionable variants was four, while a small minority of subjects (0.2 percent) had as many as eight actionable variants.  

Genes encoding drug-metabolizing enzymes, CYP2C19 (57.2 percent), CYP3A5 (43.4 percent), and CYP2B6 [40.5 percent] had the highest frequency of actionable genotypes, meaning that the individual drugs whose prescribing would be most frequently impacted by pharmacogenetics testing among the Hong Kong Chinese, are the antiplatelet drug clopidogrel, immunosuppressant tacrolimus, and anticoagulant warfarin. At the same time, the three most widely prescribed drugs that would be impacted by pharmacogenetics testing are the lipid-lowering drug simvastatin (146,167 patients), clopidogrel (26,304 patients), and anti-inflammatory drug ibuprofen (12,000 patients).

Notably, the spectrum of actionable genotypes among the Hong Kong Chinese was different compared to that of African and European populations. The most frequent actionable genotypes, IFNL3 (predictive of response to antiviral agents, simeprivir and ribavirin) and CYP3A5 (affecting tacrolimus and midazolam clearance, among others), which occur in >80 percent of Europeans and Africans, respectively, were found in less than half of Hong Kong Chinese subjects. [Medical Genetics Summaries. Simeprevir Therapy and IFNL3 Genotype. 2016; Pharmacogenet Genomics 2012;22:555-558]

In contrast, NUDT15 ranked seventh-highest among the actionable genotypes in Hong Kong Chinese (frequency, 18.6 percent), yet it only occurs in 1 percent of Europeans and Africans. “It is therefore important to consider defective NUDT15 alleles when prescribing azathioprine to Chinese patients,” noted the researchers.

In addition to identifying actionable pharmacogenetic variants, the researchers projected their potential impact on prescribing within Hong Kong's public healthcare system. “Based on the prescription data in 2019, 13.4 percent of the Hong Kong population received at least one of the 36 drugs with clinical pharmacogenetics guideline recommendations,” reported the researchers. This proportion increased to 31.9 percent among patients aged >60 years.

“The 36 drugs had a total expenditure of 33,520,000 USD, which accounted for 3.6 percent of the annual drug expenditure of Hong Kong’s Health Authority in the 2018–2019 fiscal year. It was estimated that 8,219,000 USD worth of drugs were prescribed to patients with an implicated actionable genotype, where tacrolimus [4,301,000 USD], escitalopram [777,000 USD], and simvastatin [710,000 USD] accounted for 70.4 percent of the total expenditure,” they added.

“Our findings demonstrate the potential of pharmacogenetic testing in improving patient care and resource allocation in Chinese patients,” concluded the researchers.