MTHFR和TYMS的多态性预测转移性乳腺癌患者因卡培他滨诱发的手足综合征

背景与目的乳腺癌是一个全球性问题,每年都会诊断出大量的新发病例。卡培他滨对转移性乳腺癌(metastatic breast cancer,MBC)患者有效。手足综合征(hand-foot syndrome,HFS)是卡培他滨的常见不良反应。在本文中,我们研究了卡培他滨代谢通路相关基因中的单核苷酸多态性(single nucleotide polymorphisms,SNPs)与卡培他滨诱导的中国MBC患者HFS之间的相关性,以确定一些具有预测性的生物标志物基因。方法我们选择了3个参与卡培他滨代谢的基因,并筛选了这些靶基因的遗传变体。我们对342例接受卡培他滨化疗的MBC患者的胸苷酸合酶基因(thymidylate synthase gene,TYMS)、亚甲基四氢叶酸还原酶基因(methylene tetrahydrofolate reductase gene,MTHFR)和核糖核苷酸还原酶M1基因(ribonucleotide reductaseM1gene,RRM1)中的22个SNPs进行了基因分型。使用Pearson’sχ2检验评估患有和不患有HFS的患者中每个SNP的基因型分布,并使用logistic回归分析确定HFS与SNP的基因型之间的相关性。使用血液表达数量定量性状基因座(expression quantitative trait loci,e QTL)Browser在线工具分析了SNP及其对应基因表达之间的相关性。结果我们在TYMS和MTHFR基因中发现了4个HFS阳性位点:TYMS rs2606241(P=0.022)、TYMS rs2853741(P=0.019)、MTHFR rs3737964(P=0.029)和MTHFR rs4846048(P=0.030)。Logistic回归分析显示,MTHFR rs3737964[比值比(odds ratio,OR)=0.54,95%置信区间(confidence interval,CI):0.3–0.97,P=0.038]和MTHFRrs4846048(OR=0.54,95%CI:0.30–0.98,P=0.042)的基因型AG是HFS的保护因素,而TYMS rs2853741的基因型CT(OR=2.25,95%CI:1.31–3.87,P=0.012)增加了HFS的风险。TYMSrs2606241的基因型GT(OR=1.27,95%CI:0.73–2.23,P=0.012)与HFS之间的相关性尚不确定。进一步的e QTL分析证实,rs3737964和rs4846048的等位基因影响顺式MTHFR的基因表达水平。结论我们已经确定了4个潜在有效的药物遗传学标记,TYMS rs2606241、TYMS rs2853741、MTHFR rs3737964和MTHFR rs4846048可以预测卡培他滨诱导的MBC患者的HFS。

Decoding the biochemical dialogue:metabolomic insights into soybean defense strategies against diverse pathogens

Soybean,a crucial global leguminous crop,confronts persistent threats from diverse pathogens,exerting a profound impact on global yields.While genetic dimensions of soybean-pathogen interactions have garnered attention,the intricate biochemical responses remain poorly elucidated.In this study,we applied targeted and untargeted liquid chromatography coupled to mass spectrometry(LC-MS)metabolite profiling to dissect the complex interplay between soybeans and five distinct pathogens.Our analysis uncovered 627 idMS/MS spectra,leading to the identification of four main modules,encompassing flavonoids,isoflavonoids,triterpenoids,and amino acids and peptides,alongside other compounds such as phenolics.Profound shifts were observed in both primary and secondary metabolism in response to pathogenic infections.Particularly notable were the bidirectional changes in total flavonoids across diverse pathogenic inoculations,while triterpenoids exhibited a general declining trend.Noteworthy among the highly inducible total flavonoids were known representative antipathogen compounds(glyceollin I),backbone forms of isoflavonoids(daidzein,genistein,glycitein,formononetin),and newly purified compounds in this study(prunin).Subsequently,we delved into the biological roles of these five compounds,validating their diverse functions against pathogens:prunin significantly inhibited the vegetative growth and virulence of Phytophthora sojae;genistein exhibited a pronounced inhibitory effect on the vegetative growth and virulence of Phomopsis longicolla;daidzein and formononetin displayed significant repressive effects on the virulence of P.longicolla.This study underscores the potent utility of metabolomic tools,providing in-depth insights into plant-pathogen interactions from a biochemical perspective.The findings not only contribute to plant pathology but also offer strategic pathways for bolstering plant resistance against diseases on a broader scale.

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer

Background:Breast cancer is a global problem,and a large number of new cases are diagnosed every year.Capecit-abine is effective in patients with metastatic breast cancer(MBC).Hand-foot syndrome(HFS)is a common adverse effect of capecitabine.In this study,we investigated the association between single nucleotide polymorphisms(SNPs)in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.Methods:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes.We genotyped a total of 22 SNPs in the thymidylate synthase gene(TYMS),the methylene tetrahydrofolate reductase gene(MTHFR),and the ribonucleotide reductase M1 gene(RRM1)in 342 MBC patients treated with capecit-abine-based chemotherapy.The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson’sχ^(2)test,and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis.The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci(eQTL)browser online tools.Results:We found 4 positive sites for HFS in the TYMS and MTHFR genes:TYMS rs2606241(P=0.022),TYMS rs2853741(P=0.019),MTHFR rs3737964(P=0.029),and MTHFR rs4846048(P=0.030).Logistic regression analyses showed that the genotype AG of MTHFR rs3737964[odds ratio(OR)=0.54,95%confidence interval(CI)0.31-0.97,P=0.038]and MTHFR rs4846048(OR=0.54,95%CI 0.30-0.98,P=0.042)were protective factors of HFS,whereas the genotype CT of TYMS rs2853741(OR=2.25,95%CI 1.31-3.87,P=0.012)increased the risk of HFS.The association between the genotype GT of TYMS rs2606241(OR=1.27,95%CI 0.73-2.23,P=0.012)and HFS was uncertain.Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.Conclusions:We have identified four potentially useful pharmacogenetic markers,TYMS rs2606241,TYMS rs2853741,MTHFR rs3737964,and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.