12月6日發(fā)表在Genome Research雜志上的一篇藥物基因組學研究的文章"Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition"中,研究人員以一個特定基因的罕見基因變異體為特點,該基因?qū)τ糜谥委煱┌Y和自身免疫疾病的藥物有顯著影響,這一發(fā)現(xiàn)將會有助于改善個性化護理的效果.
運用基因檢測來預(yù)測患者對藥物的反應(yīng)在個性化醫(yī)療的發(fā)展顯得越來越重要.但是,基因檢測往往只是尋找最常見的基因變異.甲氨蝶呤是用于治療癌癥的藥物,如急性淋巴細胞白血病和自身免疫疾病,包括風濕性關(guān)節(jié)炎.在SLCO1B1基因的常見基因變異體,編碼一種肝臟轉(zhuǎn)運子,是從機體清除藥物的關(guān)鍵,在10%-15%的人口有出現(xiàn),影響從機體清除甲氨蝶呤的效率.
甲氨蝶呤的低清除狀況,導(dǎo)致血液中甲氨蝶呤的高含量并增強了副作用.罕見的變異體也能顯著影響藥物的清除,然而這種罕見的影響與普通SLCO1B1變異體在甲氨蝶呤清除的比較目前還沒有探究.
甲氨蝶呤的顯微鏡下圖
在這篇報道中,一個國際研究小組測定了一群接受甲氨蝶呤的小兒科患者的SLCO1B1外顯子,基因編碼蛋白的區(qū)域,發(fā)現(xiàn)稀有的基因變異體對從身體清除藥物的效率產(chǎn)生作用.“我們展示了罕見的遺傳基因組變異體,699人中只有1人出現(xiàn)這種情況,是血液甲氨蝶呤含量顯著可變性比例的原因,”圣裘德兒童研究醫(yī)院的Mary Relling博士說,“這意味著2%的人出現(xiàn)高的血含量是由于非常罕見的基因變異.”
研究小組接著利用計算機演算預(yù)測該研究鑒定的基因組變異體的潛在不利影響,基于SLCO1B1蛋白轉(zhuǎn)運甲氨蝶呤的功能.然后他們在實驗室的細胞株測試了這些預(yù)測,證實這些基因變異體讓藥物的運輸能力下降.
“我們的發(fā)現(xiàn)很重要,但是SLCO1B1罕見的編碼變體不僅僅是對甲氨蝶呤有影響,還有對其他藥物的可能性,”圣裘德兒童研究醫(yī)院Laura Ramsey博士說.Ramsey指出,SLCO1B1變體經(jīng)試驗告知他丁類藥物適當劑量的選擇,該藥物常用語治療或阻止高膽固醇.
Ramsey補充道,臨床的遺傳試驗?zāi)壳笆怯邢薜?一般只測試了最常見的SLCO1B1變體.“我們的研究結(jié)果,存在該基因額外的罕見功能性編碼變異體,表明為了避免假陰性的試驗結(jié)果,基因型檢測需要擴大,包括稀有變異.”（生物谷Bioon.com）
doi:10.1101/gr.129668.111
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PMID:
Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition
Laura B. Ramsey1, Gitte H. Bruun2, Wenjian Yang1, Lisa R. Trevi?o1, Selina Vattathil3,Paul Scheet3, Cheng Cheng4,5, Gary L. Rosner6, Kathleen M. Giacomini7, et. al.
Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic leukemia (ALL). Inter-individual variation in clearance of methotrexate results in heterogeneous systemic exposure, clinical efficacy, and toxicity. In a genome-wide association study of children with ALL, we identified SLCO1B1 as harboring multiple common polymorphisms associated with methotrexate clearance. The extent of influence of rare versus common variants on pharmacogenomic phenotypes remains largely unexplored. We tested the hypothesis that rare variants in SLCO1B1 could affect methotrexate clearance and compared the influence of common versus rare variants in addition to clinical covariates on clearance. From deep resequencing of SLCO1B1 exons in 699 children, we identified 93 SNPs, 15 of which were non-synonymous (NS). Three of these NS SNPs were common, with a minor allele frequency (MAF) >5%, one had low frequency (MAF 1%–5%), and 11 were rare (MAF <1%). NS SNPs (common or rare) predicted to be functionally damaging were more likely to be found among patients with the lowest methotrexate clearance than patients with high clearance. We verified lower function in vitro of four SLCO1B1 haplotypes that were associated with reduced methotrexate clearance. In a multivariate stepwise regression analysis adjusting for other genetic and non-genetic covariates, SLCO1B1 variants accounted for 10.7% of the population variability in clearance. Of that variability, common NS variants accounted for the majority, but rare damaging NS variants constituted 17.8% of SLCO1B1's effects (1.9% of total variation) and had larger effect sizes than common NS variants. Our results show that rare variants are likely to have an important effect on pharmacogenetic phenotypes.
