Identification of the causal relationships between blood micronutrients and aneurysms: a Mendelian randomization study_West China Medical Journal

Authors：

 JIN Fengni ¹ , LI Mengkai ² , YAO Peng ³

1. Department of Clinical Nutrition, Yuncheng Central Hospital Affiliated to Shanxi Medical University, Yuncheng, Shanxi 044000, P. R. China;
2. Department of Neurosurgery, Yuncheng Central Hospital Affiliated to Shanxi Medical University, Yuncheng, Shanxi 044000, P. R. China;
3. Department of Cardiovascular Surgery, Yuncheng Central Hospital Affiliated to Shanxi Medical University, Yuncheng, Shanxi 044000, P. R. China;

Corresponding author：

JIN Fengni, Email: 176762999@qq.com

Keywords：

Micronutrients; aneurysm; causality; Mendelian randomization

DOI：

10.7507/1002-0179.202409226

Video：

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Objective To investigate the causal relationships between various circulating micronutrients and aneurysms at different sites using Mendelian randomization (MR) analysis. Methods Summary-level genetic data for 15 common blood micronutrients, including vitamin D, calcium, iron, copper, selenium, zinc, folate, carotene, vitamin C, vitamin B₁₂, vitamin E, magnesium, vitamin B₆, omega-3 fatty acids, and homocysteine, were obtained from the IEU Open GWAS database. Genetic associations with aneurysms, including intracranial aneurysm and thoracic aortic aneurysm, were retrieved from the GWAS Catalog and the FinnGen consortium. Bidirectional MR analyses were performed using seven MR approaches, with the inverse-variance weighted (IVW) method as the primary analysis. Multiple sensitivity analyses and visualization tools were used to assess pleiotropy and heterogeneity. Furthermore, multivariable MR was applied to explore the interactions and independent effects of multiple micronutrients on aneurysm risk, and meta-analysis was employed to integrate results from different data sources and minimize bias. Results Through multiple MR and sensitivity analyses, combined with multivariate MR and meta-analysis, the results confirmed that elevated blood levels of vitamin D could significantly increase the risk of intracranial aneurysm [odds ratio (OR)=1.65, 95% confidence interval (CI) (1.20, 2.29), P=0.002], while omega-3 fatty acids [OR=0.82, 95%CI (0.73, 0.92), P=0.001] could significantly reduce the risk. For thoracic aortic aneurysm, selenium [OR=1.08, 95%CI (1.00, 1.15), P=0.042] and folate [OR=1.45, 95%CI (1.13, 1.87), P=0.004] were identified as potential risk factors. No heterogeneity or horizontal pleiotropy was detected, and no reverse causality was found between micronutrients and aneurysm development. Conclusions Variations in circulating micronutrient levels can influence the risk of aneurysm development. These findings provide new insights into the potential roles of micronutrients in aneurysm prevention and treatment and offer a scientific basis for developing targeted clinical intervention strategies.

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2.	Boese AC, Kim SC, Yin KJ, et al. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol, 2017, 313(3): H524-H545.
3.	Makrygiannis G, Courtois A, Drion P, et al. Sex differences in abdominal aortic aneurysm: the role of sex hormones. Ann Vasc Surg, 2014, 28(8): 1946-1958.
4.	Xu Z, Rui YN, Hagan JP, et al. Intracranial aneurysms: pathology, genetics, and molecular mechanisms. Neuromolecular Med, 2019, 21(4): 325-343.
5.	Pontes FGB, da Silva EM, Baptista-Silva JC, et al. Treatments for unruptured intracranial aneurysms. Cochrane Database Syst Rev, 2021, 5(5): CD013312.
6.	Pinard A, Jones GT, Milewicz DM. Genetics of thoracic and abdominal aortic diseases. Circ Res, 2019, 124(4): 588-606.
7.	Salameh MJ, Black JH, Ratchford EV. Thoracic aortic aneurysm. Vasc Med, 2018, 23(6): 573-578.
8.	Zoroddu MA, Aaseth J, Crisponi G, et al. The essential metals for humans: a brief overview. J Inorg Biochem, 2019, 195: 120-129.
9.	Ralston J, Reddy KS, Fuster V, et al. Cardiovascular diseases on the global agenda: the United Nations high level meeting, sustainable development goals, and the way forward. Glob Heart, 2016, 11(4): 375-379.
10.	Sullivan JL. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp Biol Med (Maywood), 2007, 232(8): 1014-1020.
11.	Mohammadifard N, Humphries KH, Gotay C, et al. Trace minerals intake: risks and benefits for cardiovascular health. Crit Rev Food Sci Nutr, 2019, 59(8): 1334-1346.
12.	Chrysant SG, Chrysant GS. Controversy regarding the association of high calcium intake and increased risk for cardiovascular disease. J Clin Hypertens (Greenwich), 2014, 16(8): 545-550.
13.	Sarmento RA, Silva FM, Sbruzzi G, et al. Antioxidant micronutrients and cardiovascular risk in patients with diabetes: a systematic review. Arq Bras Cardiol, 2013, 101(3): 240-248.
14.	Nyström-Rosander C, Frisk P, Edvinsson M, et al. Thoracic aortic aneurysm patients with Chlamydophila pneumoniae infection showed a shift in trace element levels in serum and diseased aortic tissue. J Trace Elem Med Biol, 2009, 23(2): 100-106.
15.	Rolles B, Wessels I, Doukas P, et al. Retrospective observational study evaluating zinc plasma level in patients undergoing thoracoabdominal aortic aneurysm repair and its correlation with outcome. Sci Rep, 2021, 11(1): 24348.
16.	Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
17.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
18.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR Statement. JAMA, 2021, 326(16): 1614-1621.
19.	Jiang X, O’Reilly PF, Aschard H, et al. Genome-wide association study in 79, 366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun, 2018, 9(1): 260.
20.	Barton AR, Sherman MA, Mukamel RE, et al. Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses. Nat Genet, 2021, 53(8): 1260-1269.
21.	Benyamin B, Esko T, Ried JS, et al. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. Nat Commun, 2014, 5: 4926.
22.	Evans DM, Zhu G, Dy V, et al. Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Hum Mol Genet, 2013, 22(19): 3998-4006.
23.	Kettunen J, Demirkan A, Würtz P, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun, 2016, 7: 11122.
24.	Wood AR, Perry JR, Tanaka T, et al. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation. PLoS One, 2013, 8(5): e64343.
25.	Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet, 2021, 53(10): 1415-1424.
26.	Larsson SC. Mendelian randomization as a tool for causal inference in human nutrition and metabolism. Curr Opin Lipidol, 2021, 32(1): 1-8.
27.	Yuan S, Mason AM, Carter P, et al. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med, 2021, 19(1): 97.
28.	Burgess S, Thompson SG, CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
29.	Shen Y, Liu H, Meng X, et al. The causal effects between gut microbiota and hemorrhagic stroke: a bidirectional two-sample Mendelian randomization study. Front Microbiol, 2023, 14: 1290909.
30.	Lin Y, Wang G, Li Y, et al. Circulating inflammatory cytokines and female reproductive diseases: a Mendelian randomization analysis. J Clin Endocrinol Metab, 2023, 108(12): 3154-3164.
31.	Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study. BMC Med, 2023, 21(1): 66.
32.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
33.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
34.	Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
35.	Sanderson E. Multivariable Mendelian randomization and mediation. Cold Spring Harb Perspect Med, 2021, 11(2): a038984.
36.	Vermeulen JJM, Meijer M, de Vries FBG, et al. A systematic review summarizing local vascular characteristics of aneurysm wall to predict for progression and rupture risk of abdominal aortic aneurysms. J Vasc Surg, 2023, 77(1): 288-298.
37.	Chen S, Swier VJ, Boosani CS, et al. Vitamin D deficiency accelerates coronary artery disease progression in swine. Arterioscler Thromb Vasc Biol, 2016, 36(8): 1651-1659.
38.	Aleksova A, Belfiore R, Carriere C, et al. Vitamin D deficiency in patients with acute myocardial infarction: an Italian single-center study. Int J Vitam Nutr Res, 2015, 85(1/2): 23-30.
39.	Yilmaz O, Olgun H, Ciftel M, et al. Dilated cardiomyopathy secondary to rickets-related hypocalcaemia: eight case reports and a review of the literature. Cardiol Young, 2015, 25(2): 261-266.
40.	Charytan DM, Padera RF, Helfand AM, et al. Association of activated vitamin D use with myocardial fibrosis and capillary supply: results of an autopsy study. Ren Fail, 2015, 37(6): 1067-1069.
41.	Kimura T, Rahmani R, Miyamoto T, et al. Vitamin D deficiency promotes intracranial aneurysm rupture. J Cereb Blood Flow Metab, 2024, 44(7): 1174-1183.
42.	Krishna SM. Vitamin D as a protector of arterial health: potential role in peripheral arterial disease formation. Int J Mol Sci, 2019, 20(19): 4907.
43.	Briones AM, Hernanz R, García-Redondo AB, et al. Role of inflammatory and proresolving mediators in endothelial dysfunction. Basic Clin Pharmacol Toxicol, 2025, 136(5): e70026.
44.	Akagi D, Chen M, Toy R, et al. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. Faseb j, 2015, 29(6): 2504-2513.
45.	Abeywardena MY, Head RJ. Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovasc Res, 2001, 52(3): 361-371.
46.	Artiach G, Carracedo M, Clària J, et al. Opposing effects on vascular smooth muscle cell proliferation and macrophage-induced inflammation reveal a protective role for the proresolving lipid mediator receptor ChemR23 in intimal hyperplasia. Front Pharmacol, 2018, 9: 1327.
47.	Bhattarai U, Xu R, He X, et al. High selenium diet attenuates pressure overload-induced cardiopulmonary oxidative stress, inflammation, and heart failure. Redox Biol, 2024, 76: 103325.
48.	Zachariah M, Maamoun H, Milano L, et al. Endoplasmic reticulum stress and oxidative stress drive endothelial dysfunction induced by high selenium. J Cell Physiol, 2021, 236(6): 4348-4359.
49.	Shah AK, Dhalla NS. Effectiveness of some vitamins in the prevention of cardiovascular disease: a narrative review. Front Physiol, 2021, 12: 729255.
50.	Koseki K, Maekawa Y, Bito T, et al. High-dose folic acid supplementation results in significant accumulation of unmetabolized homocysteine, leading to severe oxidative stress in Caenorhabditis elegans. Redox Biol, 2020, 37: 101724.
51.	Leng YP, Ma YS, Li XG, et al. l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia. Br J Pharmacol, 2018, 175(8): 1157-1172.
52.	Vacek JC, Behera J, George AK, et al. Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. J Cell Physiol, 2018, 233(4): 3080-3092.
53.	Singh Y, Samuel VP, Dahiya S, et al. Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension. Biotechnol Appl Biochem, 2019, 66(5): 715-719.

1. Boczar KE, Coutinho T. Sex considerations in aneurysm formation, progression, and outcomes. Can J Cardiol, 2018, 34(4): 362-370.
2. Boese AC, Kim SC, Yin KJ, et al. Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. Am J Physiol Heart Circ Physiol, 2017, 313(3): H524-H545.
3. Makrygiannis G, Courtois A, Drion P, et al. Sex differences in abdominal aortic aneurysm: the role of sex hormones. Ann Vasc Surg, 2014, 28(8): 1946-1958.
4. Xu Z, Rui YN, Hagan JP, et al. Intracranial aneurysms: pathology, genetics, and molecular mechanisms. Neuromolecular Med, 2019, 21(4): 325-343.
5. Pontes FGB, da Silva EM, Baptista-Silva JC, et al. Treatments for unruptured intracranial aneurysms. Cochrane Database Syst Rev, 2021, 5(5): CD013312.
6. Pinard A, Jones GT, Milewicz DM. Genetics of thoracic and abdominal aortic diseases. Circ Res, 2019, 124(4): 588-606.
7. Salameh MJ, Black JH, Ratchford EV. Thoracic aortic aneurysm. Vasc Med, 2018, 23(6): 573-578.
8. Zoroddu MA, Aaseth J, Crisponi G, et al. The essential metals for humans: a brief overview. J Inorg Biochem, 2019, 195: 120-129.
9. Ralston J, Reddy KS, Fuster V, et al. Cardiovascular diseases on the global agenda: the United Nations high level meeting, sustainable development goals, and the way forward. Glob Heart, 2016, 11(4): 375-379.
10. Sullivan JL. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp Biol Med (Maywood), 2007, 232(8): 1014-1020.
11. Mohammadifard N, Humphries KH, Gotay C, et al. Trace minerals intake: risks and benefits for cardiovascular health. Crit Rev Food Sci Nutr, 2019, 59(8): 1334-1346.
12. Chrysant SG, Chrysant GS. Controversy regarding the association of high calcium intake and increased risk for cardiovascular disease. J Clin Hypertens (Greenwich), 2014, 16(8): 545-550.
13. Sarmento RA, Silva FM, Sbruzzi G, et al. Antioxidant micronutrients and cardiovascular risk in patients with diabetes: a systematic review. Arq Bras Cardiol, 2013, 101(3): 240-248.
14. Nyström-Rosander C, Frisk P, Edvinsson M, et al. Thoracic aortic aneurysm patients with Chlamydophila pneumoniae infection showed a shift in trace element levels in serum and diseased aortic tissue. J Trace Elem Med Biol, 2009, 23(2): 100-106.
15. Rolles B, Wessels I, Doukas P, et al. Retrospective observational study evaluating zinc plasma level in patients undergoing thoracoabdominal aortic aneurysm repair and its correlation with outcome. Sci Rep, 2021, 11(1): 24348.
16. Sekula P, Del Greco MF, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
17. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
18. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR Statement. JAMA, 2021, 326(16): 1614-1621.
19. Jiang X, O’Reilly PF, Aschard H, et al. Genome-wide association study in 79, 366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun, 2018, 9(1): 260.
20. Barton AR, Sherman MA, Mukamel RE, et al. Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses. Nat Genet, 2021, 53(8): 1260-1269.
21. Benyamin B, Esko T, Ried JS, et al. Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. Nat Commun, 2014, 5: 4926.
22. Evans DM, Zhu G, Dy V, et al. Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Hum Mol Genet, 2013, 22(19): 3998-4006.
23. Kettunen J, Demirkan A, Würtz P, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun, 2016, 7: 11122.
24. Wood AR, Perry JR, Tanaka T, et al. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation. PLoS One, 2013, 8(5): e64343.
25. Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet, 2021, 53(10): 1415-1424.
26. Larsson SC. Mendelian randomization as a tool for causal inference in human nutrition and metabolism. Curr Opin Lipidol, 2021, 32(1): 1-8.
27. Yuan S, Mason AM, Carter P, et al. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med, 2021, 19(1): 97.
28. Burgess S, Thompson SG, CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
29. Shen Y, Liu H, Meng X, et al. The causal effects between gut microbiota and hemorrhagic stroke: a bidirectional two-sample Mendelian randomization study. Front Microbiol, 2023, 14: 1290909.
30. Lin Y, Wang G, Li Y, et al. Circulating inflammatory cytokines and female reproductive diseases: a Mendelian randomization analysis. J Clin Endocrinol Metab, 2023, 108(12): 3154-3164.
31. Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study. BMC Med, 2023, 21(1): 66.
32. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
33. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
34. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med, 2022, 20(1): 443.
35. Sanderson E. Multivariable Mendelian randomization and mediation. Cold Spring Harb Perspect Med, 2021, 11(2): a038984.
36. Vermeulen JJM, Meijer M, de Vries FBG, et al. A systematic review summarizing local vascular characteristics of aneurysm wall to predict for progression and rupture risk of abdominal aortic aneurysms. J Vasc Surg, 2023, 77(1): 288-298.
37. Chen S, Swier VJ, Boosani CS, et al. Vitamin D deficiency accelerates coronary artery disease progression in swine. Arterioscler Thromb Vasc Biol, 2016, 36(8): 1651-1659.
38. Aleksova A, Belfiore R, Carriere C, et al. Vitamin D deficiency in patients with acute myocardial infarction: an Italian single-center study. Int J Vitam Nutr Res, 2015, 85(1/2): 23-30.
39. Yilmaz O, Olgun H, Ciftel M, et al. Dilated cardiomyopathy secondary to rickets-related hypocalcaemia: eight case reports and a review of the literature. Cardiol Young, 2015, 25(2): 261-266.
40. Charytan DM, Padera RF, Helfand AM, et al. Association of activated vitamin D use with myocardial fibrosis and capillary supply: results of an autopsy study. Ren Fail, 2015, 37(6): 1067-1069.
41. Kimura T, Rahmani R, Miyamoto T, et al. Vitamin D deficiency promotes intracranial aneurysm rupture. J Cereb Blood Flow Metab, 2024, 44(7): 1174-1183.
42. Krishna SM. Vitamin D as a protector of arterial health: potential role in peripheral arterial disease formation. Int J Mol Sci, 2019, 20(19): 4907.
43. Briones AM, Hernanz R, García-Redondo AB, et al. Role of inflammatory and proresolving mediators in endothelial dysfunction. Basic Clin Pharmacol Toxicol, 2025, 136(5): e70026.
44. Akagi D, Chen M, Toy R, et al. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. Faseb j, 2015, 29(6): 2504-2513.
45. Abeywardena MY, Head RJ. Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovasc Res, 2001, 52(3): 361-371.
46. Artiach G, Carracedo M, Clària J, et al. Opposing effects on vascular smooth muscle cell proliferation and macrophage-induced inflammation reveal a protective role for the proresolving lipid mediator receptor ChemR23 in intimal hyperplasia. Front Pharmacol, 2018, 9: 1327.
47. Bhattarai U, Xu R, He X, et al. High selenium diet attenuates pressure overload-induced cardiopulmonary oxidative stress, inflammation, and heart failure. Redox Biol, 2024, 76: 103325.
48. Zachariah M, Maamoun H, Milano L, et al. Endoplasmic reticulum stress and oxidative stress drive endothelial dysfunction induced by high selenium. J Cell Physiol, 2021, 236(6): 4348-4359.
49. Shah AK, Dhalla NS. Effectiveness of some vitamins in the prevention of cardiovascular disease: a narrative review. Front Physiol, 2021, 12: 729255.
50. Koseki K, Maekawa Y, Bito T, et al. High-dose folic acid supplementation results in significant accumulation of unmetabolized homocysteine, leading to severe oxidative stress in Caenorhabditis elegans. Redox Biol, 2020, 37: 101724.
51. Leng YP, Ma YS, Li XG, et al. l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia. Br J Pharmacol, 2018, 175(8): 1157-1172.
52. Vacek JC, Behera J, George AK, et al. Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. J Cell Physiol, 2018, 233(4): 3080-3092.
53. Singh Y, Samuel VP, Dahiya S, et al. Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension. Biotechnol Appl Biochem, 2019, 66(5): 715-719.

West China Medical Journal

Latest ArticlesIdentification of the causal relationships between blood micronutrients and aneurysms: a Mendelian randomization study

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