Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10⁻¹⁷, OR = 1.36, 95% CI = 1.31–1.40) and identified colocalization (PP = 0.87) with aberrant exon 5–7 CTRB2 splicing in pancreatic tissues (p_GTEx = 1.40 × 10⁻⁶⁹, β_GTEx = 1.99; p_LTG = 1.02 × 10⁻³⁰, β_LTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10⁻¹⁶, OR = 1.36, 95% CI = 1.31–1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.

全基因组关联研究 (GWAS) 在人类基因组中发现了 20 个风险位点，其中种系变异与欧洲血统人群中胰腺导管腺癌 (PDAC) 的风险相关。在这里，我们在 chr16q23.1 (rs72802365，p = 2.51 × 10 ⁻¹⁷ ，OR = 1.36，95% CI = 1.31–1.40) 上精细绘制了一个这样的位点，并确定了与异常外显子 5–7 的共定位 (PP = 0.87)胰腺组织中的CTRB2剪接（p _GTEx = 1.40 × 10 ^-69 ，β _GTEx = 1.99；p _LTG = 1.02 × 10 ^-30 ，β _LTG = 1.99）。将CTRB2外显子 6 重叠的 584 bp 结构变异推算到 GWAS 数据集中，结果与胰腺癌风险高度显着相关（p = 2.83 × 10 ⁻¹⁶ ，OR = 1.36，95% CI = 1.31–1.42），表明它可能是这个信号的基础。由于缺失（风险）等位基因而导致的外显子跳跃在CTRB2的外显子 7 中引入了提前终止密码子，产生了截短的胰凝乳蛋白酶原 B2 蛋白，该蛋白缺乏胰凝乳蛋白酶活性，分泌不良，并在内质网 (ER) 中积累于细胞内。我们提出，细胞内非功能性胰凝乳蛋白酶原 B2 蛋白的积累会导致 ER 应激和胰腺炎症，这可能解释了CTRB2外显子 6 缺失等位基因携带者胰腺癌风险增加的原因。