目的 利用孟德尔随机化(MR)方法探究肠道菌群与矮小症之间的因果关系,为矮小症的临床诊疗提供参考。方法 从MiBioGen联盟获得18 340个样本的属水平肠道菌群全基因组关联研究数据作为暴露组,从FinnGen联盟R9获取矮小症的全基因组关联研究数据作为结局组。采用逆方差加权法作为主要分析方法进行MR分析,并采用留一法、异质性检验、多效性检验等进行敏感性分析,反向MR以排除反向因果关系。结果 肠道菌群中Prevotella9 (OR=1.76, 95%CI:1.10~2.82,P=0.018)、Alloprevotella (OR=1.82, 95%CI:1.22~2.72,P=0.003)、FamilyXIIIAD3011group (OR=1.86, 95%CI:1.04~3.31,P=0.036)与矮小症的发病呈正相关; Parasutterella (OR=0.58, 95%CI:0.37~0.92, P=0.020)、Clostridiumsensustricto1 (OR=0.50, 95%CI:0.25~0.99, P=0.045)、Roseburia(OR=0.48, 95%CI:0.26~0.89, P=0.020)与矮小症的发病呈负相关。结论 肠道菌群中Prevotella9、Alloprevotella、FamilyXIIIAD3011group会增加矮小症的发生风险,Parasutterella、Clostridiumsensustricto1、Roseburia对矮小症的发生有保护作用。
Abstract
Objective To investigate the causal relationship between gut microbiota and short stature by genomewide Mendelian randomization(MR), in order to proride reference of clinical treatment of short statue. Methods Genus level gut microbiota genome-wide association study data of 18 340 samples was obtained from the MiBioGen as the exposure group, and genome-wide association study data of short stature were obtained from FinnGen R9 as the outcome group. The inverse variance weighting method was used as the main analysis method forMR analysis, and sensitivity analysis such as leave-one-out, heterogeneity test, and pleiotropy analysis were performed, reverse MR to rule out reverse causality. Results Prevotella9 (OR=1.76, 95%CI:1.10 - 2.82, P=0.018), Alloprevotella (OR=1.82, 95%CI:1.22 - 2.72, P=0.003), and FamilyXIIIAD3011group (OR=1.86, 95%CI:1.04 - 3.31, P=0.036) were positively correlated with the onset of short stature. Parasutterella (OR=0.58, 95%CI: 0.37 - 0.92, P=0.020), Clostridiumsensustricto1 (OR=0.50, 95%CI: 0.25 - 0.99, P=0.045), and Roseburia (OR=0.48, 95%CI:0.26 - 0.89, P=0.020) were negatively correlated with the onset of short stature. Conclusion Prevotella9, Alloprevotella, and FamilyXIIIAD3011group increase the risk of short stature, while Parasutterella, Clostridiumsensustricto1 and Roseburia have protective effects on the occurrence of short stature.
关键词
矮小症 /
肠道菌群 /
孟德尔随机化 /
全基因组关联研究
Key words
short stature /
gut microbiota /
mendelian randomization /
genome-wide association study
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参考文献
[1] United Nations Children's Fund (UNICEF), World Health Organization, International Bank for Reconstruction and Development/The World Bank. Levels and trends in child malnutrition: Key findings of the 2019 Edition of the Joint Child Malnutrition Estimates[R/OL]. Geneva: World Health Organization; 2019 Licence: CC BY-NC-SA 3.0 IGO. https://www.unicef.org/reports/joint-child-malnutrition-estimates-levels-and-trends-child-malnutrition-2019
[2] Yengo L, Vedantam S, Marouli E, et al. A saturated map of common genetic variants associated with human height[J]. Nature, 2022,610(7933):704-712.
[3] Inzaghi E, Reiter E, Cianfarani S. The challenge of defining and investigating the causes of idiopathic short stature and finding an effective therapy[J]. Horm Res Paediatr, 2019,92(2):71-83.
[4] Andrade NLM, Funari MFA, Malaquias AC, et al. Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature[J]. Endocr Connect, 2022,11(12):e220214.
[5] Jones HJ, Bourke CD, Swann JR, et al. Malnourished Microbes: Host-microbiome interactions in child undernutrition[J]. Annu Rev Nutr, 2023, 43:327-353.
[6] Wang S, Cui J, Jiang S, et al. Early life gut microbiota: Consequences for health and opportunities for prevention[J]. Crit Rev Food Sci Nutr, 2022,12.20;1-25.
[7] Villa CR, Ward WE, Comelli EM. Gut microbiota-bone axis[J]. Crit Rev Food Sci Nutr, 2017,57(8):1664-1672.
[8] Schwarzer M, Makki K, Storelli G, et al. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition[J]. Science, 2016,351(6275):854-857.
[9] Yan J, Herzog JW, Tsang K, et al. Gut microbiota induce IGF-1 and promote bone formation and growth[J]. Proc Natl Acad Sci U S A,2016,113(47):e7554-e7563.
[10] Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review[J].Res Synth Methods, 2019,10(4):486-496.
[11] Li L, Chen L, Yang Y, et al. Characteristics of gut microbiome and its metabolites, short-chain fatty acids, in children with idiopathic short stature[J].Front Endocrinol (Lausanne), 2022. 13: p. 890200.
[12] Miao J, Lai P, Wang K, et al. Characteristics of intestinal microbiota in children with idiopathic short stature: A cross-sectional study[J]. Eur J Pediatr, 2023,182(10):4537-4546.
[13] Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition[J]. Nat Genet,2021,53(2):156-165.
[14] Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature,2023,613(7944):508-518.
[15] Wang Q, Dai H, Hou T, et al. Dissecting causal relationships between gut microbiota, blood metabolites, and stroke: A mendelian randomization study[J]. J Stroke,2023,25(3):350-360.
[16] Gill D, Efstathiadou A, Cawood K, et al. Education protects against coronary heart disease and stroke independently of cognitive function: Evidence from Mendelian randomization[J]. Int J Epidemiol, 2019,48(5):1468-1477.
[17] Chen S, Zhou Z, Zhou Z, et al. Non-targeted metabolomics revealed novel links between serum metabolites and primary ovarian insufficiency: A Mendelian randomization study[J].Front Endocrinol(Lausanne),2024,15:1307944.
[18] Murray PG, Clayton PE, Chernausek SD. A genetic approach to evaluation of short stature of undetermined cause[J]. Lancet Diabetes Endocrinol, 2018, 6(7):564-574.
[19] Lui JC. Gut microbiota in regulation of childhood bone growth[J]. Exp Physiol, 2024,109(5):662-671.
[20] Pietrucci D, Teofani A, Milanesi M, et al. Machine learning data analysis highlights the role of parasutterella andalloprevotella in autism spectrum disorders[J]. Biomedicines, 2022,10(8):2028.
[21] Zhang L, Jing J, Han L, et al. Characterization of gut microbiota, metabolism and cytokines in benzene-induced hematopoietic damage[J]. Ecotoxicol Environ Saf,2021.112956.doi:10.1016/j.ecoenv.2021.112956.
[22] Klis K, Wronka I. Associations between childhood and adolescence exposure to air pollution and adult height in polish women[J]. Environ Res,2020,189:109965.
[23] Ju T, Kong JY, Stothard P, et al.Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota[J]. ISME J, 2019,13(6):1520-1534.
[24] Chu W, Zhai J, Xu J, et al. Continuous light-induced PCOS-like changes in reproduction, metabolism, and gut microbiota in sprague-dawley rats[J]. Front Microbiol, 2020,10:3145.
[25] Lü N, Cai G, Pan X, et al. pH and hydraulic retention time regulation for anaerobic fermentation: Focus on volatile fatty acids production/distribution, microbial community succession and interactive correlation[J]. Bioresour Technol, 2022,347:126310.
[26] Tamanai-Shacoori Z, Smida I, Bousarghin L, et al. Roseburia spp.:A marker of health?[J]. Future Microbiol, 2017,12:157-170.
[27] Drabińska N, Jarocka-Cyrta E, Złotkowska D, et al. Dailyoligofructose-enriched inulin intake impacts bone turnover markers but not the cytokine profile in pediatric patients with celiac disease on a gluten-free diet: Results of a randomised, placebo-controlled pilot study[J]. Bone, 2019,122:184-192.
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