A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

被引:16
作者
Zhu, Beibei [1 ,2 ,3 ]
Zhu, Ying [2 ,3 ]
Tian, Jianbo [2 ,3 ]
Shen, Na [2 ,3 ]
Li, Jiaoyuan [2 ,3 ]
Lou, Jiao [2 ,3 ]
Ke, Juntao [2 ,3 ]
Yang, Yang [2 ,3 ]
Gong, Yajie [2 ,3 ]
Gong, Jing [2 ,3 ]
Chang, Jiang [2 ,3 ]
Miao, Xiaoping [2 ,3 ]
Zhong, Rong [2 ,3 ]
机构
[1] Anhui Med Univ, Dept Maternal Child & Adolescent, Hefei, Anhui, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, Wuhan 430030, Hubei, Peoples R China
[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ,Key Lab Environm & Hlth, Wuhan 430030, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
9p21; 3; ANRIL; functional variant; pancreatic cancer; two-stage case-control study; GENOME-WIDE ASSOCIATION; TUMOR-SUPPRESSOR GENES; CHROMOSOME; 9P21; POLYCOMB CBX7; IDENTIFIES; LOCI; SUSCEPTIBILITY; P16; INACTIVATION; DNA;
D O I
10.1002/mc.22968
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 x 10(-4)). In conclusion, our study provided evidence that rs1537373 in ANRIL may influence transcription factor binding and regulate CDKN2B expression, thus confer the susceptibility to PC.
引用
收藏
页码:760 / 766
页数:7
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