Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer
نویسندگان
چکیده
Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19×10(-8). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51×10(-6); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.
منابع مشابه
بررسی نقش پلی مورفیسمهای ژن O6 – متیل گوانین متیل ترانسفراز در سرطان کولورکتال
Abstract Background: Sporadic colorectal cancer is the fourth most common cancer in Iran. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is involved in the cellular defense against alkylating agents. Genetic alterations in the MGMT gene may impair the protein’s ability to remove alkyl groups from the O6-position of guanine, thereby raising the mutation rate and increasi...
متن کاملAssociation of leptin gene (rs 7799039) polymorphism and colorectal cancer
Introduction: Studies show polymorphism in leptin gene cause increase in level of leptin hormone and increased level of leptin hormon is associated with abosity, insulin resistance and increased risk of colorectal cancer. The aim of this study was to assess the incidence of leptin gene polymorphism rs 7799039 in Tehran and to investigate the influence of this polymorphism in increased risk of c...
متن کاملPromoter hypermethylation of KLOTHO; an anti-senescence related gene in colorectal cancer patients of Kashmir valley
Hypermethylation of CpG islands located in the promoter regions of genes is a major event in the development of the majority of cancer types, due to the subsequent aberrant silencing of important tumor suppressor genes. KLOTHO; a novel gene associated primarily with suppressing senescence has been shown to contribute to tumorigenesis as a result of its impaired function. Recently the relevance ...
متن کاملStudy of the role of HOTAIR gene on colorectal cancer using Real-time PCR
BBackground: Despite advances in cancer studies, colorectal cancer, as the third most common cancer, has the highest mortality rate worldwide. Due to its high prevalence in the younger ages and advanced stages, screening of this cancer with molecular methods is necessary. Studies have shown that HOTAIR gene plays an important role in cancers. Our aim in the present study was to determine the...
متن کاملMutation Analysis of TP53 Tumor Suppressor Gene in Colorectal Cancer in Patients from Iran (Kerman Province)
Objective(s) P53 is an important tumor suppressor, which is mutated in later stages of many cancers and leads to resistance to chemotherapy. The aim of this study was to reveal mutations of TP53 in colorectal cancer in Kerman province. Materials and Methods A total of Forty-three colon cancer specimens as paraffin block or fresh tissues, which passed stage IIIA, were selected. Three exons 5,...
متن کاملBroadening Gene Pool of Rice for Resistance to Biotic Stresses Through Wide Hybridization
Variability in the cultivated germplasm for economic traits such as resistance to rice tungro virus, sheathblight, yellow stem borer, drought and salt tolerance is limited. This necessitated search for the genes in secondary and tertiary gene pool of genus Oryza. Fortunately, wild species are an important reservoir ofuseful genes for resistance to major disease, pest and tolerance t...
متن کامل