講演情報
[OE7-1]東アジアおよび民族横断的なゲノムワイド関連メタ解析による消化性潰瘍疾患の遺伝的メカニズム解明
○賀 云野1, 小井土 大1, 須藤 洋一2, 史 明陽1, 山崎 弥生2, 森崎 隆幸3, 永井 亜貴子3, 村上 善則3, 谷川 千津1, 八谷 剛史2, 松田 浩一1,3, 清水 厚志2, 鎌谷 洋一郎1 (1.東京大学 大学院新領域創成科学研究科, 2.岩手医科大学 いわて東北メディカル・メガバンク機構, 3.東京大学 医科学研究所)
Peptic ulcer disease (PUD) is the acid-induced injury of the digestive tract, mainly occurring in the stomach (Gastric ulcer; GU) or duodenum (Duodenal ulcer; DU). Despite several risk loci for PUD identified in previous genome-wide association studies (GWAS), the underlying genetics largely remain unclear. We conducted a large-scale cross-ancestry meta-analysis for PUD GWAS with four Japanese and two European studies (52,032 cases and 905,344 controls), discovering 29 novel independent loci that were highly concordant across ancestries. GU shared the same risk loci with DU but showed smaller genetic effect sizes than DU, indicating higher heterogeneity of GU. Downstream analyses highlighted plausible biologies, such as blood coagulation by integrating expression and protein quantitative trait locus analyses. Moreover, the gene-level analysis showed that genetic factors are enriched in highly expressed genes in stomach tissue, especially in somatostatin-producing D cells from stomach and duodenum single-cell RNA sequencing datasets. We found that EFNA1, PTGER4, and PSCA showed strong but opposite effects on DU and gastric cancers (GC), suggesting the potential mechanisms contributing to the decreased risk of GC in DU patients. H.pylori (HP)-stratified analysis found HP-related host genetic locus at CCKBR, marking its role in HP-mediated PUD etiology. In summary, we revealed potential genes and biological mechanisms involved in genetic susceptibility to PUD and its subtypes, and their genetic similarities as well as differences from GC.