Causal Relationship Analysis Between 35 Blood/urine Metabolites and Gastroesophageal Reflux Disease: A Mendelian Randomization Combined Meta-analysis Study

Overview

Journal Medicine (Baltimore)

Specialty General Medicine

Date 2024 Aug 9

PMID 39121258

Authors

Daolei Chen

Wanxian Xu

Ying Wen

Xiaolan Tan

Jian Liu

Affiliations

Soon will be listed here.

Abstract

Gastroesophageal reflux disease (GERD) is a common condition worldwide. Despite numerous studies on GERD, the causal relationships between blood/urine metabolites and GERD remain unclear. This study aims to explore the causal relationships between GERD and 35 blood/urine metabolites. In this study, we conducted Mendelian randomization (MR) analyses for 35 blood/urine metabolites with GERD phenotypes from the FinnGen R10 and UKB databases separately. We then performed a meta-analysis of the inverse variance weighted results from the 2 MR analyses and applied multiple corrections to the significant P values from the meta-analysis. Finally, we conducted reverse causality validation for the corrected positive blood/urine metabolite phenotypes with GERD. After conducting MR analysis combined with meta-analysis and performing multiple corrections, we found significant positive causal associations between only 3 blood/urine metabolites and GERD, with no significant reverse associations. Among them, 2 are risk factors for the occurrence of GERD: alanine aminotransferase levels (odds ratio (OR) = 1.120, 95% confidence interval (CI) = 1.064-1.180, P = .0005) and urate levels (OR = 1.095, 95% CI = 1.044-1.147, P = .005). Additionally, sex hormone-binding globulin levels are protective against GERD (OR = 0.928, 95% CI = 0.896-0.961, P = .0009). Elevated levels of the metabolites alanine aminotransferase and urate are associated with an increased risk of GERD, identifying them as risk factors for the condition. In contrast, higher levels of SHBG are linked to a decreased risk of GERD, indicating that SHBG is a protective factor against the disease.

References

Hayden M . Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease. Medicina (Kaunas). 2023; 59(3). PMC: 10059871. DOI: 10.3390/medicina59030561. View

Sinnott-Armstrong N, Tanigawa Y, Amar D, Mars N, Benner C, Aguirre M . Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat Genet. 2021; 53(2):185-194. PMC: 7867639. DOI: 10.1038/s41588-020-00757-z. View

El-Serag H, Sweet S, Winchester C, Dent J . Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2013; 63(6):871-80. PMC: 4046948. DOI: 10.1136/gutjnl-2012-304269. View

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

Saleh S, Trujillo S, Ghoneim S, Thomas C, Fass R . Effect of Hormonal Replacement Therapy on Gastroesophageal Reflux Disease and its Complications in Postmenopausal Women. Clin Gastroenterol Hepatol. 2022; 21(2):549-551.e3. DOI: 10.1016/j.cgh.2022.01.058. View

Watanabe S, Hojo M, Nagahara A . Metabolic syndrome and gastrointestinal diseases. J Gastroenterol. 2007; 42(4):267-74. DOI: 10.1007/s00535-007-2033-0. View

Brand J, van der Tweel I, Grobbee D, Emmelot-Vonk M, van der Schouw Y . Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol. 2010; 40(1):189-207. DOI: 10.1093/ije/dyq158. View

Fass R, Sifrim D . Management of heartburn not responding to proton pump inhibitors. Gut. 2009; 58(2):295-309. DOI: 10.1136/gut.2007.145581. View

Orlando R . The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms. Best Pract Res Clin Gastroenterol. 2010; 24(6):873-82. PMC: 2995989. DOI: 10.1016/j.bpg.2010.08.008. View

10.

Leng X, Liao W, Zheng F . Gastroesophageal reflux disease and non-alcoholic fatty liver disease: a two-sample Mendelian randomization combined with meta-analysis. Sci Rep. 2024; 14(1):12633. PMC: 11144195. DOI: 10.1038/s41598-024-63646-z. View

11.

Sekula P, Del Greco M F, Pattaro C, Kottgen A . Mendelian Randomization as an Approach to Assess Causality Using Observational Data. J Am Soc Nephrol. 2016; 27(11):3253-3265. PMC: 5084898. DOI: 10.1681/ASN.2016010098. View

12.

Simo R, Saez-Lopez C, Barbosa-Desongles A, Hernandez C, Selva D . Novel insights in SHBG regulation and clinical implications. Trends Endocrinol Metab. 2015; 26(7):376-83. DOI: 10.1016/j.tem.2015.05.001. View

13.

Katz P, Gerson L, Vela M . Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013; 108(3):308-28. DOI: 10.1038/ajg.2012.444. View

14.

Zhang T, Zhang B, Tian W, Wei Y, Wang F, Yin X . Trends in gastroesophageal reflux disease research: A bibliometric and visualized study. Front Med (Lausanne). 2022; 9:994534. PMC: 9556905. DOI: 10.3389/fmed.2022.994534. View

15.

Lawlor D . Commentary: Two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol. 2016; 45(3):908-15. PMC: 5005949. DOI: 10.1093/ije/dyw127. View

16.

Zhang C, Wang N, Xu Y, Tan H, Li S, Feng Y . Molecular Mechanisms Involved in Oxidative Stress-Associated Liver Injury Induced by Chinese Herbal Medicine: An Experimental Evidence-Based Literature Review and Network Pharmacology Study. Int J Mol Sci. 2018; 19(9). PMC: 6165031. DOI: 10.3390/ijms19092745. View

17.

Langenau J, Boeing H, Bergmann M, Nothlings U, Oluwagbemigun K . The Association between Alcohol Consumption and Serum Metabolites and the Modifying Effect of Smoking. Nutrients. 2019; 11(10). PMC: 6836136. DOI: 10.3390/nu11102331. View

18.

Zheng Z, Shang Y, Wang N, Liu X, Xin C, Yan X . Current Advancement on the Dynamic Mechanism of Gastroesophageal Reflux Disease. Int J Biol Sci. 2021; 17(15):4154-4164. PMC: 8579455. DOI: 10.7150/ijbs.65066. View

19.

Li J, Zheng L, Katie Chan K, Zou X, Zhang J, Liu J . Sex Hormone-Binding Globulin and Risk of Coronary Heart Disease in Men and Women. Clin Chem. 2023; 69(4):374-385. PMC: 11599539. DOI: 10.1093/clinchem/hvac209. View

20.

Hughey C, Bracy D, Rome F, Goelzer M, Donahue E, Viollet B . Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice. Am J Physiol Endocrinol Metab. 2023; 326(1):E14-E28. PMC: 11193517. DOI: 10.1152/ajpendo.00289.2023. View