Abstract：
Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient\'s sensitivity to therapeutic alkylating agents.
摘要：
鉴定影响O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因调节的遗传因素，并通过单卵双胞胎对中的对内相关性估计MGMT基因的遗传贡献在各种类型的癌症中特别重要。例如胶质母细胞瘤。我们使用来自中年丹麦双胞胎（MADT）研究的448个单卵双胞胎的全血中的基因表达数据，通过对MGMT表达变异进行全基因组关联研究（GWAS）来研究MGMT基因的遗传调控。此外,我们估计了表达值的成对依赖性测量，以寻找重要鉴定基因的遗传影响。我们确定了243个单核苷酸多态性（SNP）显著（p<5e-8）与MGMT的表达，全部位于MGMT基因附近的10号染色体上。在243个SNP中，7是新颖的顺式-eQTL。通过进一步研究暗示性显著的SNP(将截止值增加到p=1e-6)，我们确定了位于17号染色体上的11个暗示性反式eQTLs。这些变异体位于或接近总共七个基因，可以调节MGMT的表达。MGMT表达的对内相关性,TRIM37和SEPT4提供了这些基因的上限遗传影响。总的来说,识别调节MGMT基因的顺式或反式遗传变异可以为更好地理解MGMT基因功能和最终理解患者对治疗性烷基化剂的敏感性铺平道路。
