Naushad Shaik Mohammad, Hussain Tajamul, Alrokayan Salman A, Kutala Vijay Kumar
Department of Pharmacogenomics, Sandor Speciality Diagnostics Pvt Ltd, Hyderabad, India.
Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia.
J Gene Med. 2021 Jan;23(1):e3289. doi: 10.1002/jgm.3289. Epub 2020 Nov 20.
The present study aimed to delineate the pharmacologically relevant dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population.
We screened 2000 Indian subjects for DPYD variants using the Infinium Global Screening Array (GSA) (Illumina Inc., San Diego, CA, USA).
The GSA analysis identified seven coding, two intronic and three synonymous DPYD variants. Level 1A alleles (rs75017182, rs3918290, P633Qfs5 and D949V) were found to be rare (minor allele frequency: 1.889%), whereas Level 3 alleles were observed to be predominant (C29R: 24.91%, I543V: 9.047%, M166V: 8.993% and V732I: 8.44%). In silico predictions revealed that all Level 1A alleles were deleterious, whereas three (M166V, S534N and V732I) of seven Level 3 alleles were damaging. CUPSAT analysis revealed that two Level 1A (P633Qfs, D949V) and three Level 3 (I543V, V732I and S534N) variants were thermolabile. The pooled Indian data showed that V732I, S534N and rs3918290 variants were associated with 5-FU/capecitabine toxicity, whereas C29R, I543V and M166V variants exhibited the null association. A comparison of our data with other population data from the 'Allele Frequency Aggregator' (https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/) database showed similarities with the South Asian data.
We have identified four Level 1A (non-functional/dysfunctional) and seven Level 3 variants in the DPYD gene. The pooled Indian data revealed the association of V732I, S534N and rs3918290 variants with 5-FU/capecitabine toxicity. Clustering analysis revealed the similarities in the DPYD profiles of the Indian and South Asian populations.
本研究旨在确定印度人群中与药理学相关的二氢嘧啶脱氢酶（DPYD）变体。
我们使用Infinium全球筛选阵列（GSA）（美国加利福尼亚州圣地亚哥市Illumina公司）对2000名印度受试者进行DPYD变体筛查。
GSA分析确定了7个编码变体、2个内含子变体和3个同义DPYD变体。发现1A类等位基因（rs75017182、rs3918290、P633Qfs5和D949V）较为罕见（次要等位基因频率：1.889%），而3类等位基因占主导地位（C29R：24.91%、I543V：9.047%、M166V：8.993%和V732I：8.44%）。计算机模拟预测显示，所有1A类等位基因均有害，而7个3类等位基因中的3个（M166V、S534N和V732I）具有破坏性。CUPSAT分析显示，2个1A类（P633Qfs、D949V）和3个3类（I543V、V732I和S534N）变体具有热不稳定性。汇总的印度数据显示，V732I、S534N和rs3918290变体与5-氟尿嘧啶/卡培他滨毒性相关，而C29R、I543V和M166V变体则无关联。将我们的数据与“等位基因频率汇总器”（https://www.ncbi.nlm.nih.gov/snp/docs/gsr/alfa/）数据库中的其他人群数据进行比较，发现与南亚数据相似。
我们在DPYD基因中确定了4个1A类（无功能/功能失调）和7个3类变体。汇总的印度数据显示，V732I、S534N和rs3918290变体与5-氟尿嘧啶/卡培他滨毒性相关。聚类分析显示，印度和南亚人群的DPYD谱具有相似性。
