Biodiversity
A secondary analysis of patients enrolled in TRIUMPH, a multicentre prospective trial that included 72 062 Caucasians and 670 African-Americans hospitalised with acute MI26 sought to evaluate genetic mediators of racial disparities in outcomes among these patients treated with clopidogrel to assess whether cytochrome P450 polymorphisms were associated with morbidity and mortality. The results showed that African Americans with the CYP2C19*17 (ultra-rapid metaboliser) variant were more likely to experience bleeding.27 The CYP2C19*2 variant was not associated with increased mortality, neither unadjusted (HR 0.66; 95% CI 0.29 to 1.47; p=0.30) or adjusted (HR 0.63; 95% CI 0.28 to 1.41; p=0.26). The CYP2C19*17 variant was associated with significantly increased mortality (33.3% 1-year mortality for CYP2C19*17/*17 homozygotes vs 9.8% for CYP2C19*17/*1 heterozygote vs 4.9% for *1/*1 homozygote; log-rank p=1e-05).27 These data showed a statistically significant interaction between ethnicity and mortality for CYP2C19*2 (p=0.042) and CYP2C19*17 (p=0.011).27 When compared with Caucasians, there was a trend of increased recurrent MI in carriers of the CYP2C19*2 variants in unadjusted (HR 2.08; 95% CI 0.95 to 4.59; p=0.0687) and adjusted (HR 2.10; 95% CI 0.95 to 4.63; p=0.0661) models, but these patients were not shown to have increased bleeding events.27 The CYP2C19*2 variant was associated with significantly increased all-cause mortality (5.4% 1-year mortality for CYP2C19*2 allele carriers vs 3% for *1/*1 homozygote).27 The interaction between CYP2C19*2 SNP and clopidogrel treatment for mortality in Caucasian TRIUMPH patients discharged on clopidogrel was not significant (p=0.860).27
In an analysis of more than 82 000 patients in Europe, the frequency of CYP2C19*2 was highest in Northern and Western European countries, including Cyprus (21%) and Malta (20%), whereas the lowest was in the Czech Republic. CYP2C19*17 was more common in Central Europe while lower in Southern European countries.28 Thus, these findings by Petrović et al28 suggest the need to refine pharmacogenomic mapping to guide precision public health, especially in populations with a high incidence of these polymorphisms and an increased likelihood of experiencing MACE or other consequences of clopidogrel resistance.
In another study, Khalil et al assessed the prevalence of CYP2C19 variants in patients living in the Mediterranean region and its impact on MACE outcomes in those treated with clopidogrel. Carriers of CYP2C19 loss of function alleles were more likely to experience MACE (OR 2.52, 95% CI 1.23 to 5.15, p=0.011).29 These authors also reported a statistically significant association between body mass index and MACE incidence, suggesting a possible role for lifestyle management to mitigate the impact of these variants.29 Overall, replication of the association of genetic polymorphisms in CYP alleles and MACE reported in previous studies suggests the need for individualised genetic testing and optimisation of antiplatelet treatment to improve outcomes and potentially reduce the morbidity and mortality of MACE.
Further studies determined that when allelic frequency estimations were compared for CYP2C19*2 and CYP2C19*3 in other ethnic populations, the allelic frequency of CYP2C19*2 in Asian populations was up to 30.0%, and 15.0%–17.0% in European and black patients.30 31 The allelic frequencies of the CYP2C19*2 in the west South American, Asian, Scandinavian, European and African-American populations were relatively low.32 Compared with other ethnicities, the prevalence of CYP2C19 loss-of-function alleles was higher in Asiatic populations. Overall, the allelic frequency of CYP2C19*2 in the Hakka subjects (31.06%) was closer to that of Chinese-Dai (30%), but they were in between that of populations from Chinese Li (25%) and Chinese-Han ethnic groups (37%).33–35
The CYP2C19*3 allele was found with a frequency of 0.0461% in the Hakka population, which was consistent with findings within East Asian populations.36 In contrast, other studies reported that CYP2C19*3 was present in lower frequency or nearly absent in Turkish, Swedish, Russian, Italian, Bolivian, Faroese, Tanzanian, Ethiopian and Zimbabwean populations.32 37 38
Zhong et al noted that the prevalence of CYP2C19*3 was consistent with previous reports on the Chinese population, but it was lower than in Japanese, Korean, Vietnamese and Thai populations.36 These authors also implored that more attention should be paid to the populations that had a higher frequency of the loss-of-function of CYP2C19, especially in China, since people with the CYP2C19*2 or CYP2C19*3 variants were more likely to be predisposed to abnormal metabolism of clopidogrel.36 A comprehensive tabular array of the multiethnic CYP2C19 allele frequencies and phenotypes are found in online supplemental tables 1 and 2, respectively.39 40