Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Nat Genet. 2012 Dec;44(12):1349-54. doi: 10.1038/ng.2466. Epub 2012 Nov 11.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
胰腺炎是一种复杂的、进行性破坏性的炎症性疾病。长期以来，人们一直认为酒精是主要的致病因素，但自从发现罕见的 PRSS1、CFTR 和 SPINK1 变体与胰腺炎风险相关以来，遗传因素就引起了人们的兴趣。我们现在通过两阶段全基因组研究（第一阶段：676 例病例和 4507 例对照；第二阶段：910 例病例和 4170 例对照）报告了两个全基因组显著关联，并在 PRSS1-PRSS2（P < 1×10(-12)) 和 X 连锁 CLDN2（P < 1×10(-21)) 处得到了复制。PRSS1 变体可能通过改变主要胰蛋白酶原基因的表达来影响疾病易感性。CLDN2 风险等位基因与胰腺腺泡细胞中 Claudin-2 的非典型定位有关。CLDN2 纯合子（或男性半合子）基因型赋予最大风险，其等位基因与饮酒相互作用以放大风险。这些结果部分解释了男性中酒精相关性胰腺炎的高频率（男性半合子频率为 0.26，而女性纯合子频率为 0.07）。
