Qi Cancan, Li An, Su Fengyuan, Wang Yu, Zhou Longyuan, Tang Ce, Feng Rui, Mao Ren, Chen Minhu, Chen Lianmin, Koppelman Gerard H, Bourgonje Arno R, Zhou Hongwei, Hu Shixian
Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, China.
Commun Biol. 2024 Dec 24;7(1):1696. doi: 10.1038/s42003-024-07416-7.
Comorbidity among atopic diseases (ADs) and gastrointestinal diseases (GIDs) has been repeatedly demonstrated by epidemiological studies, whereas the shared genetic liability remains largely unknown. Here we establish an atlas of the shared genetic architecture between 10 ADs or related traits and 11 GIDs, comprehensively investigating the comorbidity-associated genomic regions, cell types, genes and genetically predicted causality. Although distinct genetic correlations between AD-GID are observed, including 14 genome-wide and 28 regional correlations, genetic factors of Crohn's disease (CD), ulcerative colitis (UC), celiac disease and asthma subtypes are converged on CD4 T cells consistently across relevant tissues. Fourteen genes are associated with comorbidities, with three genes are known treatment targets, showing probabilities for drug repurposing. Lower expressions of WDR18 and GPX4 in PBMC CD4 T cells predict decreased risk of CD and asthma, which could be novel drug targets. MR unveils certain ADs led to higher risk of GIDs or vice versa. Taken together, here we show distinct genetic correlations between AD-GID pairs, but the correlated genomic loci converge on the dysregulation of CD4 T cells. Inhibiting WDR18 and GPX4 expressions might be candidate therapeutic strategies for CD and asthma. Estimated causality indicates potential guidance for preventing comorbidity.
特应性疾病（ADs）和胃肠道疾病（GIDs）之间的共病现象已被流行病学研究反复证实，而共同的遗传易感性在很大程度上仍不清楚。在此，我们建立了10种ADs或相关性状与11种GIDs之间共享遗传结构的图谱，全面研究了与共病相关的基因组区域、细胞类型、基因和遗传预测的因果关系。尽管观察到AD-GID之间存在不同的遗传相关性，包括14种全基因组相关性和28种区域相关性，但克罗恩病（CD）、溃疡性结肠炎（UC）、乳糜泻和哮喘亚型的遗传因素在相关组织中始终在CD4 T细胞上汇聚。14个基因与共病相关，其中3个基因是已知的治疗靶点，显示出药物再利用的可能性。PBMC CD4 T细胞中WDR18和GPX4的低表达预示着CD和哮喘风险降低，这可能是新的药物靶点。孟德尔随机化（MR）揭示某些ADs会导致GIDs风险升高，反之亦然。综上所述，我们在此展示了AD-GID对之间不同的遗传相关性，但相关的基因组位点在CD4 T细胞的失调上汇聚。抑制WDR18和GPX4的表达可能是治疗CD和哮喘的候选策略。估计的因果关系为预防共病提供了潜在指导。
