Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank
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. To explore th...
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| Veröffentlicht in: | The American journal of clinical nutrition 2023-03, Vol.117 (3), p.564-575 |
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| creator | Wang, Lijuan Li, Xue Montazeri, Azita MacFarlane, Amanda J. Momoli, Franco Duthie, Susan Senekal, Marjanne Eguiagaray, Ines Mesa Munger, Ron Bennett, Derrick Campbell, Harry Rubini, Michele McNulty, Helene Little, Julian Theodoratou, Evropi |
| description | 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.
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.
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 |
| doi_str_mv | 10.1016/j.ajcnut.2023.01.005 |
| format | Article |
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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.
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.
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.
This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.</description><identifier>ISSN: 0002-9165</identifier><identifier>EISSN: 1938-3207</identifier><identifier>DOI: 10.1016/j.ajcnut.2023.01.005</identifier><identifier>PMID: 36811473</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Anemia ; B vitamins ; Biobanks ; Bioinformatics ; Biological properties ; Biological samples ; Biological Specimen Banks ; Biomarkers ; Calculi ; Cerebrovascular diseases ; Cyanocobalamin ; Dose-response effects ; Electronic health records ; Electronic medical records ; Female ; Folic Acid ; Homocysteine ; Humans ; Hypercholesterolemia ; Kidney diseases ; Kidneys ; Mendelian randomization ; Mendelian Randomization Analysis ; Metabolism ; Metabolites ; Neurological diseases ; Nonlinear response ; phenome-wide association study ; Phenotypes ; Pregnancy ; Pyridoxine ; United Kingdom ; Vitamin A ; Vitamin B 12 ; Vitamin B 6 ; Vitamin B Complex ; Vitamin B12 ; Vitamin B6 ; Vitamin K ; Vitamins</subject><ispartof>The American journal of clinical nutrition, 2023-03, Vol.117 (3), p.564-575</ispartof><rights>2023 American Society for Nutrition</rights><rights>Copyright © 2023 American Society for Nutrition. All rights reserved.</rights><rights>Copyright American Society for Clinical Nutrition, Inc. Mar 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-31ea5897967e705253c066ced73c420102fb78a4f7c7bcd6fba43eab4444757d3</citedby><cites>FETCH-LOGICAL-c491t-31ea5897967e705253c066ced73c420102fb78a4f7c7bcd6fba43eab4444757d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36811473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lijuan</creatorcontrib><creatorcontrib>Li, Xue</creatorcontrib><creatorcontrib>Montazeri, Azita</creatorcontrib><creatorcontrib>MacFarlane, Amanda J.</creatorcontrib><creatorcontrib>Momoli, Franco</creatorcontrib><creatorcontrib>Duthie, Susan</creatorcontrib><creatorcontrib>Senekal, Marjanne</creatorcontrib><creatorcontrib>Eguiagaray, Ines Mesa</creatorcontrib><creatorcontrib>Munger, Ron</creatorcontrib><creatorcontrib>Bennett, Derrick</creatorcontrib><creatorcontrib>Campbell, Harry</creatorcontrib><creatorcontrib>Rubini, Michele</creatorcontrib><creatorcontrib>McNulty, Helene</creatorcontrib><creatorcontrib>Little, Julian</creatorcontrib><creatorcontrib>Theodoratou, Evropi</creatorcontrib><title>Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank</title><title>The American journal of clinical nutrition</title><addtitle>Am J Clin Nutr</addtitle><description>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.
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.
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.
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.
This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.</description><subject>Anemia</subject><subject>B vitamins</subject><subject>Biobanks</subject><subject>Bioinformatics</subject><subject>Biological properties</subject><subject>Biological samples</subject><subject>Biological Specimen Banks</subject><subject>Biomarkers</subject><subject>Calculi</subject><subject>Cerebrovascular diseases</subject><subject>Cyanocobalamin</subject><subject>Dose-response effects</subject><subject>Electronic health records</subject><subject>Electronic medical records</subject><subject>Female</subject><subject>Folic Acid</subject><subject>Homocysteine</subject><subject>Humans</subject><subject>Hypercholesterolemia</subject><subject>Kidney diseases</subject><subject>Kidneys</subject><subject>Mendelian randomization</subject><subject>Mendelian Randomization Analysis</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Neurological diseases</subject><subject>Nonlinear response</subject><subject>phenome-wide association study</subject><subject>Phenotypes</subject><subject>Pregnancy</subject><subject>Pyridoxine</subject><subject>United Kingdom</subject><subject>Vitamin A</subject><subject>Vitamin B 12</subject><subject>Vitamin B 6</subject><subject>Vitamin B Complex</subject><subject>Vitamin B12</subject><subject>Vitamin B6</subject><subject>Vitamin K</subject><subject>Vitamins</subject><issn>0002-9165</issn><issn>1938-3207</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Ustu1DAUjRCIDoU_QMgSGzYZ_EjihAVSW_ESlWBB15Zj3zR3mthD7EyV_-FDcTSlPBZ4Y_n63HN8j0-WPWd0yyirXu-2emfcHLeccrGlbEtp-SDbsEbUueBUPsw2lFKeN6wqT7InIewoZbyoq8fZiahqxgopNtmPrz04P0J-ixaIDsEb1BG9IyHOdiG-I9fgIKLRw7CQ_QQWTQRLzskBox7RBaKdJb0fvVlCBHRAWvSjnm5gCuQWY0_GeYi4H4D0oId0XhssBtABiJ-jSfrhTarqYQkYVs3YA7n6TM7Rt9rdPM0edXoI8OxuP82u3r_7dvExv_zy4dPF2WVuiobFXDDQZd3IppIgaclLYWhVGbBSmIJTRnnXyloXnTSyNbbqWl0I0G2RliylFafZ2yPvfm5HsAZcnPSg9hOmcRblNaq_bxz26toflKxYwWuaCF7dEUz--wwhqhGDgWHQDvwcFJeyESXnYoW-_Ae68_OULFhRtawko2WZUMURZSYfwgTd_WMYVWsM1E4dY6DWGCjKVIpBanvx5yD3Tb_-_fekkOw8IEwqGASXvMIJTFTW4_8VfgJaisnd</recordid><startdate>202303</startdate><enddate>202303</enddate><creator>Wang, Lijuan</creator><creator>Li, Xue</creator><creator>Montazeri, Azita</creator><creator>MacFarlane, Amanda J.</creator><creator>Momoli, Franco</creator><creator>Duthie, Susan</creator><creator>Senekal, Marjanne</creator><creator>Eguiagaray, Ines Mesa</creator><creator>Munger, Ron</creator><creator>Bennett, Derrick</creator><creator>Campbell, Harry</creator><creator>Rubini, Michele</creator><creator>McNulty, Helene</creator><creator>Little, Julian</creator><creator>Theodoratou, Evropi</creator><general>Elsevier Inc</general><general>American Society for Clinical Nutrition, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T7</scope><scope>7TS</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202303</creationdate><title>Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank</title><author>Wang, Lijuan ; Li, Xue ; Montazeri, Azita ; MacFarlane, Amanda J. ; Momoli, Franco ; Duthie, Susan ; Senekal, Marjanne ; Eguiagaray, Ines Mesa ; Munger, Ron ; Bennett, Derrick ; Campbell, Harry ; Rubini, Michele ; McNulty, Helene ; Little, Julian ; Theodoratou, Evropi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-31ea5897967e705253c066ced73c420102fb78a4f7c7bcd6fba43eab4444757d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Anemia</topic><topic>B vitamins</topic><topic>Biobanks</topic><topic>Bioinformatics</topic><topic>Biological properties</topic><topic>Biological samples</topic><topic>Biological Specimen Banks</topic><topic>Biomarkers</topic><topic>Calculi</topic><topic>Cerebrovascular diseases</topic><topic>Cyanocobalamin</topic><topic>Dose-response effects</topic><topic>Electronic health records</topic><topic>Electronic medical records</topic><topic>Female</topic><topic>Folic Acid</topic><topic>Homocysteine</topic><topic>Humans</topic><topic>Hypercholesterolemia</topic><topic>Kidney diseases</topic><topic>Kidneys</topic><topic>Mendelian randomization</topic><topic>Mendelian Randomization Analysis</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Neurological diseases</topic><topic>Nonlinear response</topic><topic>phenome-wide association study</topic><topic>Phenotypes</topic><topic>Pregnancy</topic><topic>Pyridoxine</topic><topic>United Kingdom</topic><topic>Vitamin A</topic><topic>Vitamin B 12</topic><topic>Vitamin B 6</topic><topic>Vitamin B Complex</topic><topic>Vitamin B12</topic><topic>Vitamin B6</topic><topic>Vitamin K</topic><topic>Vitamins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lijuan</creatorcontrib><creatorcontrib>Li, Xue</creatorcontrib><creatorcontrib>Montazeri, Azita</creatorcontrib><creatorcontrib>MacFarlane, Amanda J.</creatorcontrib><creatorcontrib>Momoli, Franco</creatorcontrib><creatorcontrib>Duthie, Susan</creatorcontrib><creatorcontrib>Senekal, Marjanne</creatorcontrib><creatorcontrib>Eguiagaray, Ines Mesa</creatorcontrib><creatorcontrib>Munger, Ron</creatorcontrib><creatorcontrib>Bennett, Derrick</creatorcontrib><creatorcontrib>Campbell, Harry</creatorcontrib><creatorcontrib>Rubini, Michele</creatorcontrib><creatorcontrib>McNulty, Helene</creatorcontrib><creatorcontrib>Little, Julian</creatorcontrib><creatorcontrib>Theodoratou, Evropi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Physical Education Index</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The American journal of clinical nutrition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Lijuan</au><au>Li, Xue</au><au>Montazeri, Azita</au><au>MacFarlane, Amanda J.</au><au>Momoli, Franco</au><au>Duthie, Susan</au><au>Senekal, Marjanne</au><au>Eguiagaray, Ines Mesa</au><au>Munger, Ron</au><au>Bennett, Derrick</au><au>Campbell, Harry</au><au>Rubini, Michele</au><au>McNulty, Helene</au><au>Little, Julian</au><au>Theodoratou, Evropi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank</atitle><jtitle>The American journal of clinical nutrition</jtitle><addtitle>Am J Clin Nutr</addtitle><date>2023-03</date><risdate>2023</risdate><volume>117</volume><issue>3</issue><spage>564</spage><epage>575</epage><pages>564-575</pages><issn>0002-9165</issn><eissn>1938-3207</eissn><abstract>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.
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.
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.
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.
This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36811473</pmid><doi>10.1016/j.ajcnut.2023.01.005</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anemia B vitamins Biobanks Bioinformatics Biological properties Biological samples Biological Specimen Banks Biomarkers Calculi Cerebrovascular diseases Cyanocobalamin Dose-response effects Electronic health records Electronic medical records Female Folic Acid Homocysteine Humans Hypercholesterolemia Kidney diseases Kidneys Mendelian randomization Mendelian Randomization Analysis Metabolism Metabolites Neurological diseases Nonlinear response phenome-wide association study Phenotypes Pregnancy Pyridoxine United Kingdom Vitamin A Vitamin B 12 Vitamin B 6 Vitamin B Complex Vitamin B12 Vitamin B6 Vitamin K Vitamins |
| title | Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank |
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