12月6日發(fā)表在Genome Research雜志上的一篇藥物基因組學(xué)研究的文章"Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition"中,研究人員以一個(gè)特定基因的罕見(jiàn)基因變異體為特點(diǎn),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(huì)有助于改善個(gè)性化護(hù)理的效果.
運(yùn)用基因檢測(cè)來(lái)預(yù)測(cè)患者對(duì)藥物的反應(yīng)在個(gè)性化醫(yī)療的發(fā)展顯得越來(lái)越重要.但是,基因檢測(cè)往往只是尋找最常見(jiàn)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(xì)胞白血病和自身免疫疾病,包括風(fēng)濕性關(guān)節(jié)炎.在SLCO1B1基因的常見(jiàn)基因變異體,編碼一種肝臟轉(zhuǎn)運(yùn)子,是從機(jī)體清除藥物的關(guān)鍵,在10%-15%的人口有出現(xiàn),影響從機(jī)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(qiáng)了副作用.罕見(jiàn)的變異體也能顯著影響藥物的清除,然而這種罕見(jiàn)的影響與普通SLCO1B1變異體在甲氨蝶呤清除的比較目前還沒(méi)有探究.
甲氨蝶呤的顯微鏡下圖
在這篇報(bào)道中,一個(gè)國(guó)際研究小組測(cè)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(duì)從身體清除藥物的效率產(chǎn)生作用.“我們展示了罕見(jiàn)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(shuō),“這意味著2%的人出現(xiàn)高的血含量是由于非常罕見(jiàn)的基因變異.”
研究小組接著利用計(jì)算機(jī)演算預(yù)測(cè)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(yùn)甲氨蝶呤的功能.然后他們?cè)趯?shí)驗(yàn)室的細(xì)胞株測(cè)試了這些預(yù)測(cè),證實(shí)這些基因變異體讓藥物的運(yùn)輸能力下降.
“我們的發(fā)現(xiàn)很重要,但是SLCO1B1罕見(jiàn)的編碼變體不僅僅是對(duì)甲氨蝶呤有影響,還有對(duì)其他藥物的可能性,”圣裘德兒童研究醫(yī)院Laura Ramsey博士說(shuō).Ramsey指出,SLCO1B1變體經(jīng)試驗(yàn)告知他丁類藥物適當(dāng)劑量的選擇,該藥物常用語(yǔ)治療或阻止高膽固醇.
Ramsey補(bǔ)充道,臨床的遺傳試驗(yàn)?zāi)壳笆怯邢薜?一般只測(cè)試了最常見(jiàn)的SLCO1B1變體.“我們的研究結(jié)果,存在該基因額外的罕見(jiàn)功能性編碼變異體,表明為了避免假陰性的試驗(yàn)結(jié)果,基因型檢測(cè)需要擴(kuò)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.
