Platelet response to aspirin in UK and Irish pregnancy cohorts: a genome-wide approach

A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pregnant women taking low dose aspirin. Objectives were to (i) develop pregnancy-specific 95% reference intervals for a range of laboratory based platelet function tests (PFTs); (ii) select an optimal and acceptable PFT that reflected aspirin’s COX-1 inhibition in women with confirmed aspirin adherence in pregnancy; and (iii) identify genomic variants that may influence pregnant women’s platelet response to aspirin. The study included two independent cohorts of pregnant women. A range of PFTs and matched phenotyping with urinary 11-dehydrothromboxane B₂ (11DTXB2) and nuclear magnetic resonance (NMR) spectroscopy detection of urinary salicyluric acid as a measure of aspirin adherence were performed. Genome-wide data was acquired from the UK Biobank Axiom® (Thermo Fisher Scientific). 11DTXB2 in combination with adherence testing with NMR salicyluric acid was an accurate and acceptable testing strategy for detecting biochemical aspirin responsiveness in pregnant women, with the provision of relevant reference ranges. GWAS meta-analysis found no significant single nucleotide polymorphisms in association with response to aspirin in pregnancy. Further evaluation in relation to effective dosing of aspirin in pregnancy and optimizing the benefits to specific subgroups should now be a priority for future research.

一项多中心前瞻性横断面全基因组关联研究（Genome-Wide Association Study, GWAS）纳入了服用低剂量阿司匹林的孕妇群体。本研究的核心目标包括：① 针对一系列实验室检测的血小板功能试验（Platelet Function Tests, PFTs）建立妊娠特异性95%参考区间；② 筛选出可反映确诊妊娠期间阿司匹林依从性女性体内阿司匹林对环氧合酶-1（cyclooxygenase-1, COX-1）抑制效果的最优且可接受的血小板功能检测方法；③ 筛选可能影响孕妇血小板对阿司匹林应答反应的基因组变异位点。本研究纳入两批独立的孕妇队列，对受试者开展了一系列血小板功能检测，并辅以匹配的表型分析：包括尿液11-脱氢血栓烷B₂（11-dehydrothromboxane B₂, 11DTXB2）检测，以及以尿液水杨尿酸检测作为阿司匹林依从性评估指标的核磁共振（Nuclear Magnetic Resonance, NMR）波谱分析。全基因组数据取自英国生物库Axiom®基因分型芯片（赛默飞世尔科技，Thermo Fisher Scientific）。结合尿液11DTXB2检测与NMR水杨尿酸依从性检测的方案，可为妊娠女性体内阿司匹林生化应答反应的检测提供准确且可接受的检测策略，并可配套提供相关参考区间。全基因组关联研究荟萃分析未发现与妊娠期间阿司匹林应答反应显著相关的单核苷酸多态性位点。未来研究应优先开展针对妊娠期间阿司匹林有效给药剂量的进一步评估，并探索如何优化特定亚组人群的获益效果。