目的 使用两样本孟德尔随机化方法探索肠道菌群及其代谢通路与矮身材的因果关系。方法 使用荷兰微生物组计划(DMP)和FINRISK 2002(FR02)的肠道菌群全基因关联分析(GWAS)汇总数据和来自于GIANT Consortium的身高遗传信息数据。采用逆方差加权法(IVW)、MR Egger回归、加权中位数(WME)、Simple mode、Weighted mode研究肠道菌群及代谢通路与矮身材之间的因果关系,其中以IVW法为主。结合敏感性分析、异质性检验、基因多效性检验和异常值检验等方法来验证结果的稳定性和可靠性。结果 IVW结果显示有5种肠道微生物、3条代谢通路与矮身材存在因果关系,其中,Bacillales (OR=1.24,95%CI: 1.11~1.38,PFDR =0.007) 、GCA-900066755(OR=1.06,95%CI: 1.03~1.09,PFDR <0.001) 、“丙酮酸发酵为乙酸盐和乳酸II” (OR=1.04,95%CI: 1.02~1.06,PFDR <0.001)、“尿酸盐生物合成/肌苷5'-磷酸降解” (OR=1.05,95%CI: 1.02~1.08,PFDR =0.042)与身高呈正相关。Clostridium E sporosphaeroides (OR=0.93,95%CI: 0.89~0.97,PFDR =0.023) 、Escherichia flexneri (OR=0.96,95%CI: 0.94~0.98,PFDR <0.001)、GCA-900199385 sp900320755(OR=0.88,95%CI: 0.84~0.93,PFDR <0.001)、“来自谷氨酸的血红素B生物合成”(OR=0.97,95%CI: 0.96~0.98,PFDR<0.001)与身高呈负相关,未发现 IVs 存在基因多效性或显著异质性。结论 肠道菌群及相关代谢通路与矮身材之间存在明确的因果关系,其具体生物学机制有待进一步研究,相关靶点可为后续研究提供参考。
Abstract
Objective To explore the causal correlation of gut microbiota and their metabolic pathways with short stature using a two-sample Mendelian randomization (MR) approach. Methods Genome-wide association study (GWAS) summary data on gut microbiota from the Dutch Microbiome Project (DMP) and FINRISK 2002 (FR02), as well as genetic data on height from the GIANT Consortium, were utilized. The inverse variance weighted (IVW) method, MR Egger regression, weighted median (WME), simple mode, and weighted mode were employed to investigate the causal relationship between gut microbiota, metabolic pathways, and short stature, with the IVW method serving as the primary approach. Sensitivity analysis, heterogeneity testing, pleiotropy testing, and outlier detection were conducted to validate the stability and reliability of the results. Results The IVW results indicated a causal relationship between five gut microbial taxa, three metabolic pathways, and short stature. Specifically, Bacillales (OR=1.24, 95%CI: 1.11 - 1.38, PFDR=0.007), GCA-900066755 (OR=1.06, 95%CI: 1.03 - 1.09, PFDR<0.001), "pyruvate fermentation to acetate and lactate II" (OR=1.04, 95%CI: 1.02 - 1.06, PFDR<0.001), and "urate biosynthesis/inosine 5'-phosphate degradation" (OR=1.05, 95%CI: 1.02 - 1.08, PFDR=0.042) were positively associated with height. Conversely, Clostridium E sporosphaeroides (OR=0.93, 95%CI: 0.89 - 0.97, PFDR=0.023), Escherichia flexneri (OR=0.88, 95%CI: 0.84 - 0.93, PFDR<0.001), GCA-900199385 sp900320755 (OR=0.96, 95%CI: 0.94 - 0.98, PFDR<0.001), and "heme B biosynthesis from glutamate" (OR=0.97, 95%CI: 0.96 - 0.98, PFDR<0.001) were negatively associated with height. No significant pleiotropy or heterogeneity was detected among the instrumental variables (IVs). Conclusions There is a clear causal relationship between gut microbiota, related metabolic pathways, and short stature. The specific biological mechanisms require further investigation, and the identified targets may provide valuable insights for future research.
关键词
肠道菌群 /
矮身材 /
孟德尔随机化
Key words
gut microbiota /
short stature /
mendelian randomization
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基金
山东省中医药科技发展计划项目(2019-0227)
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