Publication related to RSI or an RSI staff member
Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank.
BACKGROUND: Although a number of health outcomes such as CVDs, metabolic-related outcomes, neurological disorders, pregnancy outcomes, and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships. OBJECTIVES: To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records. METHODS: First, we performed a phenome-wide association study (PheWAS) to investigate the associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12, and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. RESULTS: In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P = 0.033), higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P = 0.018), and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P = 0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease. CONCLUSIONS: This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.
Authors
- Wang, Lijuan, Wang L, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
- Li, Xue, Li X, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Montazeri, Azita, Montazeri A, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
- MacFarlane, Amanda J, MacFarlane AJ, Nutrition Research Division, Health Canada, Ottawa, Ontario, Canada.
- Momoli, Franco, Momoli F, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
- Duthie, Susan, Duthie S, School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, United Kingdom.
- Senekal, Marjanne, Senekal M, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
- Eguiagaray, Ines Mesa, Eguiagaray IM, Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
- Munger, Ron, Munger R, Department of Nutrition and Food Sciences and the Center for Epidemiologic Studies, Utah State University, Logan, UT, USA.
- Bennett, Derrick, Bennett D, Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
- Campbell, Harry, Campbell H, Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
- Rubini, Michele, Rubini M, Department of Neuroscience and rehabilitation, University of Ferrara, Ferrara, Italy.
- McNulty, Helene, McNulty H, Nutrition Innovation Centre for Food and Health, Ulster University, Coleraine, Northern Ireland, United Kingdom.
- Little, Julian, Little J, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
- Theodoratou, Evropi, Theodoratou E, Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom; Cancer Research UK Edinburgh Centre, The University of Edinburgh MRC Institute of Genetics and Cancer, Edinburgh, United Kingdom. Electronic address: e.theodoratou@ed.ac.uk.
BACKGROUND: Although a number of health outcomes such as CVDs, metabolic-related outcomes, neurological disorders, pregnancy outcomes, and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships. OBJECTIVES: To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records. METHODS: First, we performed a phenome-wide association study (PheWAS) to investigate the associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12, and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. RESULTS: In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P = 0.033), higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P = 0.018), and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P = 0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease. CONCLUSIONS: This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.
