Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors
Genome-Wide Associations and Functional Genomic Studies of Musculoskeletal Adverse Events in Women Receiving Aromatase Inhibitors
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DOI：
10.1200/jco.2010.28.5064
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发表时间：
2010-11-01
影响因子：
45.3
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
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作者：
Ingle, James N.;Schaid, Daniel J.;Weinshilboum, Richard M.
目的：我们进行了一项病例对照全基因组关联研究（GWAS），以确定在接受芳香酶抑制剂（AIs）治疗的早期乳腺癌女性中与肌肉骨骼不良事件（ms - ae）相关的单核苷酸多态性（snp）。患者和方法采用嵌套病例对照设计选择纳入MA的患者。27期III期试验比较阿那曲唑和依西美坦。病例与两个对照组相匹配，定义为3级或4级MS-AE患者（根据美国国家癌症研究所不良事件通用术语标准v3.0）或在前2年内因任何级别MS-AE停止治疗的患者。使用Illumina Human610-Quad BeadChip进行基因分型。结果GWAS纳入293例，对照组585例。共分析了551,358个snp，随后对第14号染色体上感兴趣的区域进行了植入和精细定位。14号染色体上4个snp的P值最低（2.23E-06 ~ 6.67E-07）。t细胞白血病1A （TCL1A）是与这四个snp最接近的基因（926-7000 bp）。功能基因组研究显示，其中一个SNP （rs11849538）产生了一个雌激素应答元件，TCL1A的表达依赖于雌激素，与雌激素受体α转染的雌二醇处理的淋巴母细胞样细胞的变异SNP基因型相关，并与白细胞介素17受体A （IL17RA）的表达直接相关。结论：该GWAS在接受AIs治疗的女性中发现了与ms - ae相关的snp，并与基因（TCL1A）相关，而该基因又与细胞因子（IL17）相关。这些发现为进一步研究确定ms - ae风险患者和探索这些不良事件的机制提供了重点。
PurposeWe performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer.Patients and MethodsA nested case-control design was used to select patients enrolled onto the MA. 27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip.ResultsThe GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression.ConclusionThis GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.