12月6日发表在Genome Research杂志上的一篇药物基因组学研究的文章"Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition"中,研究人员以一个特定基因的罕见基因变异体为特点,该基因对用于治疗癌症和自身免疫疾病的药物有显著影响,这一发现将会有助于改善个性化护理的效果.
运用基因检测来预测患者对药物的反应在个性化医疗的发展显得越来越重要.但是,基因检测往往只是寻找最常见的基因变异.甲氨蝶呤是用于治疗癌症的药物,如急性淋巴细胞白血病和自身免疫疾病,包括风湿性关节炎.在SLCO1B1基因的常见基因变异体,编码一种肝脏转运子,是从机体清除药物的关键,在10%-15%的人口有出现,影响从机体清除甲氨蝶呤的效率.
甲氨蝶呤的低清除状况,导致血液中甲氨蝶呤的高含量并增强了副作用.罕见的变异体也能显著影响药物的清除,然而这种罕见的影响与普通SLCO1B1变异体在甲氨蝶呤清除的比较目前还没有探究.
甲氨蝶呤的显微镜下图
在这篇报道中,一个国际研究小组测定了一群接受甲氨蝶呤的小儿科患者的SLCO1B1外显子,基因编码蛋白的区域,发现稀有的基因变异体对从身体清除药物的效率产生作用.“我们展示了罕见的遗传基因组变异体,699人中只有1人出现这种情况,是血液甲氨蝶呤含量显著可变性比例的原因,”圣裘德儿童研究医院的Mary Relling博士说,“这意味着2%的人出现高的血含量是由于非常罕见的基因变异.”
研究小组接着利用计算机演算预测该研究鉴定的基因组变异体的潜在不利影响,基于SLCO1B1蛋白转运甲氨蝶呤的功能.然后他们在实验室的细胞株测试了这些预测,证实这些基因变异体让药物的运输能力下降.
“我们的发现很重要,但是SLCO1B1罕见的编码变体不仅仅是对甲氨蝶呤有影响,还有对其他药物的可能性,”圣裘德儿童研究医院Laura Ramsey博士说.Ramsey指出,SLCO1B1变体经试验告知他丁类药物适当剂量的选择,该药物常用语治疗或阻止高胆固醇.
Ramsey补充道,临床的遗传试验目前是有限的,一般只测试了最常见的SLCO1B1变体.“我们的研究结果,存在该基因额外的罕见功能性编码变异体,表明为了避免假阴性的试验结果,基因型检测需要扩大,包括稀有变异.”（生物谷Bioon.com）
doi:10.1101/gr.129668.111
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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.
