Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population

Abstract

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.

Fig 1. Allele frequency of variants within the 108 pharmacogenes in the dataset.

In the upper panel, the yellow line graph shows the gnomAD loss-of-function constraint metric (o/e score) of the respective genes. In the lower panel, the purple bars denote the variant counts in the 108 high-confidence pharmacogenes, while the red rectangles indicate respective gene transcript lengths. Consistent across genes, most variants belong to the very rare category (AF <0.1%). The relationship between variant count, gene transcript length, and constraint (o/e score reported in gnomAD) was analyzed using multiple linear regression analysis. There was significant association between gene transcript length and total variant count (P = 0.0073). In general, the number of variants increased by 0.17 for every kilobase increase in gene length, although outliers existed. In the highly polymorphic gene CYP2D6, 29.5 variants were observed for every kilobase of gene length.

Fig 2. Number of pharmacogenetic variants identified in exome sequencing per sample.

(A) Nearly all (99.6%) Hong Kong Chinese carried at least one known actionable pharmacogenetic variant, with a median of four variants. The highest number of actionable variants in a single sample was eight, occurring in 0.2% of samples. (B) Among 1,116 Hong Kong Chinese, 1,043 (93.5%) carried at least one rare deleterious variant in the 108 high-confidence pharmacogenes, with a median of two variants per individual. The highest number of variants observed was eight, occurring in 0.5% of the population.

Fig 3. Top 20 drugs with the highest estimated prescription impact on headcount.

This figure illustrates the top 20 drugs with the highest estimated prescription impact on headcount (left panel) and their respective predicted expenditure (right panel). Overall, most of the projected prescription impact was concentrated in a few drugs. The top three drugs projected to affect the greatest number of patients were the lipid-lowering drug simvastatin (146,167 patients, frequency: 25.81%), clopidogrel (26,304 patients, frequency: 57.21%), and anti-inflammatory drug ibuprofen (12,000 patients, frequency: 5.39%). It was estimated that 8,219,000 USD worth of drugs were prescribed to patients with an implicated actionable phenotype, where tacrolimus (4,301,000 USD), escitalopram (777,000 USD), and simvastatin (710,000 USD) accounted for 70.4% of the total expenditure. CPIC only recommends genotype-guided prescription of clopidogrel in patients with acute coronary syndrome receiving percutaneous coronary intervention. Indications for prescription is however not included in the CDARS system.

Fig 4. Frequency of the top ten actionable phenotypes in Hong Kong Chinese compared to that of Africans and Europeans.

This figure compares the top ten actionable phenotypes in Hong Kong Chinese with that of Africans and Europeans. The actionable phenotype frequency of Africans and Europeans was retrieved from data from Chanfreau-Coffinier et al., Walker et al. and supplementary information in the CPIC guideline [30,36]. Actionable phenotypes include CYP2C19 IM and PM; CYP3A5 EM and IM; CYP2B6 IM and PM; carrier of CYP4F2 decreased function allele; carrier of HLA-B*15:02; *57:01 and *58:01; SLCO1B1 intermediate and low-function diplotypes; NUDT15 IM and PM; IFNL3 unfavorable response genotype; CYP2D6 UM, IM, and PM; and CYP2C9 IM and PM. CYP2C19*17 is not readily detected in exome sequencing and therefore CYP2C19 RM and UM were not included. The frequency of actionable phenotypes in CYP2C19, HLA-B, and NUDT15 was found to be higher in Hong Kong Chinese than in Europeans and Africans. In contrast, actionable genotypes in CYP3A5, CYP2B6, and CYP2D6 were more prevalent in Africans, whereas actionable phenotypes in CYP4F2, SLCO1B1, IFNL3, and CYP2C9 were more prevalent in Europeans; however, all of these genes were within the top ten actionable phenotypes in Hong Kong. IM, intermediate metabolizer; PM, poor metabolizer; EM, extensive metabolizer; UM, ultrarapid metabolizer; RM, rapid metabolizer.