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

Abstract

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 × 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.

Association between a polymorphic variant in the CDKN2B‐AS1/ANRIL gene and pancreatic cancer risk

“…24 They also have analysed rs1412832 and reported an association that is very similar to what we observed: OR = 1.12, 95% CI = 1.00-1.27, P = .046. 24 We performed a meta-analysis with their results and obtained an even more statistically significant association (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 Â 10 À9 , I 2 = 21.3%). The result of the meta-analysis is reported in Figure 2.…”

“…A combined analysis of this SNP, consisting of all the datasets together (PanC4, PanScan I‐III, JaPAN, FinnGen and PANDoRA), showed an association between the T allele and increased risk of developing PDAC below the genome‐wide significance threshold (OR = 1.11, 95% CI = 1.07‐1.15, P = 3.92 × 10 −8 ). Additionally, in a study focusing on Chinese individuals Zhu and colleagues investigated the 9p21.3 region, in a sample of 1567 PDAC and 4956 controls, and found numerous associations with risk of developing the disease 24 . They also have analysed rs1412832 and reported an association that is very similar to what we observed: OR = 1.12, 95% CI = 1.00‐1.27, P = .046 24 .…”

“…Additionally, in a study focusing on Chinese individuals Zhu and colleagues investigated the 9p21.3 region, in a sample of 1567 PDAC and 4956 controls, and found numerous associations with risk of developing the disease 24 . They also have analysed rs1412832 and reported an association that is very similar to what we observed: OR = 1.12, 95% CI = 1.00‐1.27, P = .046 24 . We performed a meta‐analysis with their results and obtained an even more statistically significant association (OR = 1.11, 95% CI = 1.07‐1.15, P = 5.25 × 10 −9 , I 2 = 21.3%).…”

Conserved regulatory logic at accessible and inaccessible chromatin during the acute inflammatory response in mammals

“…For example, a unique enrichment for stroke phenotypes 91 was observed for the three-species category (13-fold, p < 1.0 × 10 −6 ). This enrichment was due to SNPs at three loci: rs10776752, an EC-specific peak in the WNT2A intron 1; rs10786772, a HAEC-specific peak found at the NEURL/SH3PXD2A locus, as well as rs1537373, a HAEC/adipocyte peak also near CDKN2B, which has been functionally assayed and implicated as a pancreatic cancer susceptibility SNP 92 (Supplementary Dataset 8).…”

Interactive effects of CDKN2B‐AS1 gene polymorphism and habitual risk factors on oral cancer

“…Five SNPs from CDKN2B-AS1 gene were selected in this study according to their potential interactions with the predisposition to various disorders. [39][40][41][42][43] DNA from the whole blood was isolated by using QIAamp DNA Blood Mini kit (Qiagen). 44,45 Evaluation of allelic discrimination for these five loci was carried out by using the TaqMan assay with an ABI StepOne™ Real-Time PCR System (Applied Biosystems) and subsequently analysed by SDS version 3.0 software (Applied Biosystems).…”