Background: Genome-wide association studies (GWAS) have identified susceptibility loci for colorectal cancer (CRC), but the underlying mechanisms remain unclear. This study investigates functional genetic variants in promoter regions of Leucine Rich Repeat Containing 6 (LRRC6) at 8q24 and Myotubularin Related Protein 10 (MTMR10) at 15q13.3 and their association with CRC susceptibility.
Methods: Bioinformatics and ChIP-seq data for H3K4me3 were used to identify SNPs in CRC risk regions 8q24 and 15q13.3 that might affect transcription factor binding, gene expression, or prognosis. These variants were validated in a case-control study of 840 CRC patients and 840 healthy controls from China. SNP functionality was evaluated using luciferase assays.
Results: Two significant SNPs, LRRC6 rs79600483 (8q24) and MTMR10 rs3743231 (15q13.3), were identified. Expression analysis revealed higher LRRC6 mRNA levels in CRC tissues, correlating with improved survival, while lower MTMR10 expression was linked to better outcomes. Case-control analysis showed that the LRRC6 rs79600483 GG genotype (OR = 2.43, 95 % CI = 1.04-5.67, P = 0.040) and AG genotype (OR = 1.26, 95 % CI = 1.01-1.57, P = 0.045), and the MTMR10 rs3743231 CC genotype (OR = 2.83, 95 % CI = 1.55-5.19, P = 0.001), significantly increased CRC risk. Luciferase assays demonstrated that the G allele of LRRC6 rs79600483 and C allele of MTMR10 rs3743231 increased promoter activity.
Conclusions: Polymorphisms in LRRC6 and MTMR10 genes contribute to CRC susceptibility by modulating gene expression and transcription. These findings enhance understanding of CRC genetic susceptibility and may guide future therapeutic strategies.
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