Opportunistic analysis of clinically actionable DPYD gene variants in a germline testing cohort in India

Dihydropyrimidine dehydrogenase (DPYD) plays a critical role in the metabolism of fluoropyrimidine-based chemotherapies such as 5-fluorouracil (5-FU), capecitabine, and tegafur. Genetic variants in DPYD can lead to partial or complete enzyme deficiency, resulting in toxic accumulation of these drugs and severe, sometimes fatal, adverse reactions. Whole‑exome sequencing data from 1,612 individuals were analyzed for DPYD variants. Variants were classified as decreased, no function, or potentially deleterious. Comparative allele frequency analysis was performed using global population datasets to identify inter-population differences. A total of 95 individuals (5.3%) carried at least one decreased or no function DPYD variant, indicating a significant prevalence of clinically actionable genotypes in this Indian cohort. The most frequent variant, c.1236 G > A (HapB3), was found in 53 individuals (3.28%), supporting its relevance in the Indian population. Comparative analysis revealed distinct population patterns and novel variants not captured in current guidelines. These results support the urgency in implementing preemptive DPYD genotyping to avoid adverse drug reactions and further studies to gather evidence on rare and novel variants in the Indian population. To the best of our knowledge, this is the largest population analysis of DPYD variants from India.

二氢嘧啶脱氢酶（DPYD）在氟嘧啶类化疗药物（如5-氟尿嘧啶（5-FU）、卡培他滨及替加氟）的代谢过程中发挥关键作用。DPYD基因的遗传变异可导致该酶部分或完全功能缺失，进而造成上述药物在体内的毒性蓄积，引发严重甚至致命的不良反应。本研究对1612名个体的全外显子组测序数据进行分析，以筛查DPYD基因变异。研究将检出的变异分为功能降低、功能缺失及潜在致病变异三类。本研究借助全球人群数据集开展等位基因频率对比分析，以识别不同人群间的变异差异。共计95名个体（占比5.3%）携带至少1个功能降低或功能缺失型DPYD变异，提示该印度队列中具有临床干预价值的基因型检出率较高。最常见的变异为c.1236 G>A（HapB3），共在53名个体中检出（占比3.28%），证实该变异在印度人群中具有临床相关性。对比分析结果显示，印度人群存在独特的变异分布特征，且检出了当前临床指南未覆盖的新发变异。上述研究结果提示，亟需开展DPYD基因的前置基因分型检测以规避药物不良反应，同时还需开展进一步研究以积累印度人群中罕见及新发DPYD变异的相关证据。据我们所知，本研究是目前针对印度人群DPYD变异开展的规模最大的人群分析。