Objective: To analyze the distribution of clopidogrel metabolism-related gene variability in Kawasaki disease (KD) children with coronary artery lesions (CAL) across different age groups and the impact of genetic variability on the efficacy of clopidogrel antiplatelet therapy. Methods: A retrospective cohort study was conducted. Clinical data were collected from 46 KD children with CAL who were hospitalized in the Cardiovascular Center of Children's Hospital of Fudan University between January 2021 and August 2022 and were treated with clopidogrel, including gender, age, body mass index, course of KD, CAL severity grade, and baseline platelet count. According to their age, the children were divided into ≥2-year-old group and <2-year-old group. Their platelet responsiveness was assessed by adenosine diphosphate-induced platelet inhibition rate (ADPi) calculated via thromboelastography, and children were categorized into high on-treatment platelet reactivity (HTPR) and normal on-treatment platelet reactivity (NTPR) groups. Genotypes of CYP2C19, PON1 and ABCB1 were detected. The t test, one-way analysis of variance and Chi-square test were used for intergroup comparison. Results: Among the 46 KD children with CAL, 34 were male and 12 were female; 37 were ≥2-year-old and 9 were <2-year-old; 25 cases were in the HTPR group and 21 cases were in the NTPR group, with 19 HTPR and 18 NTPR in the ≥2-year-old group, and 6 HTPR and 3 NTPR in the <2-year-old group. Genetic analysis showed that 92 alleles among the 46 children, with frequencies of CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*17, PON1 192Q, PON1 192R, ABCB1 3435C, ABCB1 3435T at 59% (54/92), 32% (29/92), 9% (8/92), 1% (1/92), 36% (36/92), 64% (59/92), 63% (58/92) and 37% (34/92), respectively. Analysis of the impact of genotype on ADPi revealed that in children aged ≥2 years, those with CYP2C19*1/*3 genotype had significantly lower ADPi than those with CYP2C19*1/*1 genotype ((34±15)% vs. (61±29)%, t=2.18, P=0.036). There were also no significant difference in ADPi among children with PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes ((40±22)% vs. (52±33)% vs. (65±27)%, F=2.17, P=0.130), or among those with ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((55±34)% vs. (60±27)% vs. (49±24)%, F=0.33, P=0.719). In <2-year-old group, there were no significant differences in ADPi across CYP2C19*1/*1, CYP2C19*1/*2 and CYP2C19*2*2 genotypes ((40±20)% vs. (53±37)% vs. (34±16)%, F=0.37, P>0.05). There were no significant differences in ADPi across CYP2C19*1/*1 and CYP2C19*1/*3 genotypes ((44±27)% vs. (42±20)%, t=0.08, P>0.05). There were no significant differences in ADPi across PON1 192Q homozygous, PON1 192R heterozygote and PON1 192R homozygous genotypes (45% vs. (55±27)% vs. (24±5)%, F=1.83, P>0.05). There were no significant differences in ADPi across ABCB1 3435C homozygous, ABCB1 3435T heterozygote and ABCB1 3435T homozygous genotypes ((36±16)% vs. (50±35)% vs. 45%, F=0.29, P>0.05). The risk analysis of HTPR in different genotypes revealed that in children aged ≥2 years, carrying at least 1 or 2 loss-of-function alleles of CYP2C19 was a risk factor for HTPR (OR=4.69, 10.00, 95%CI 1.11-19.83, 0.84-119.32, P=0.033, 0.046, respectively), and PON1 192R homozygosity and carrying at least one PON1 192R allele were protective factors against HTPR (OR=0.08, 0.13, 95%CI 0.01-0.86, 0.01-1.19, P=0.019, 0.043, respectively). Conclusion: KD children aged ≥2 years carrying CYP2C19 loss-of-function alleles and PON1 192Q are more likely to develop HTPR.
目的： 分析不同年龄段川崎病合并冠状动脉病变（CAL）患儿氯吡格雷代谢相关基因变异性的分布及其对氯吡格雷抗血小板治疗的疗效影响。 方法： 回顾性队列研究。分析2021年1月至2022年8月在复旦大学附属儿科医院心内科住院的46例川崎病合并CAL并接受氯吡格雷治疗患儿的临床资料，包括性别、年龄、体质指数、川崎病病程、CAL严重程度分级和基线血小板计数等。根据发病年龄分为≥2岁和<2岁组；通过血栓弹力图检测患儿血小板抑制率（ADPi）确定血小板的反应性，将患儿分为高治疗血小板反应（HTPR）组和正常治疗血小板反应（NTPR）组，检测患儿CYP2C19、PON1及ABCB1基因变异性分布。采用t检验、单因素方差分析、χ2检验进行组间比较。 结果： 46例川崎病伴CAL患儿中，男34例、女12例，≥2岁37例、<2岁9例，HTPR组25例、NTPR组21例。≥2岁患儿中HTPR 19例、NTPR 18例；<2岁中HTPR 6例、NTPR 3例。基因检测显示46例患儿共92个等位基因，其中CYP2C19*1、CYP2C19*2、CYP2C19*3、CYP2C19*17，PON1 192Q、PON1 192R，ABCB1 3435C和ABCB1 3435T等位基因检出频率分别为59%（54/92）、32%（29/92）、9%（8/92）、1%（1/92）、36%（36/92）、64%（59/92）、63%（58/92）、37%（34/92）。基因型对血小板抑制率的影响结果分析显示，≥2岁中CYP2C19*1/*3患儿的ADPi明显低于CYP2C19*1/*1［（34±15）%比（61±29）%，t=2.18，P=0.036］。PON1 192Q纯合、PON1 192R杂合和PON1 192R纯合患儿的ADPi差异无统计学意义［（40±22）%比（52±33）%比（65±27）%，F=2.17，P=0.130］；ABCB1 3435C纯合、ABCB1 3435T杂合和ABCB1 3435T纯合患儿的ADPi差异无统计学意义［（55±34）%比（60±27）%比（49±24）%，F=0.33，P=0.719］。<2岁组中CYP2C19*1/*1、CYP2C19*1/*2与CYP2C19*2/*2患儿的ADPi差异无统计学意义［（40±20）%比（53±37）%比（34±16）%，F=0.37，P>0.05］。CYP2C19*1/*1与CYP2C19*1/*3患儿的ADPi差异无统计学意义［（44±27）%比（42±20）%，t=0.08，P>0.05］。PON1 192Q纯合、PON1 192R杂合与PON1 192R纯合患儿的ADPi差异无统计学意义［45%比（55±27）%比（24±5）%，F=1.83，P>0.05］。ABCB1 3435C纯合、ABCB1 3435T杂合与ABCB1 3435T纯合患儿的ADPi差异无统计学意义［（36±16）%比（50±35）%比45%，F=0.29，P>0.05］。不同基因型发生HTPR的风险分析显示，在≥2岁患儿携带至少1和2个功能缺失等位基因均是HTPR发生的危险因素（OR=4.69、10.00，95%CI 1.11~19.83、0.84~119.32，P=0.033、0.046）；PON1 192R纯合基因型和携带至少1个PON1 192R等位基因均是HTPR发生的保护因素（OR=0.08、0.13，95%CI 0.01~0.86、0.01~1.19，P=0.019、0.043）。 结论： 携带CYP2C19功能缺失基因和PON1 192Q的≥2岁患儿更容易发生HTPR。.