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Candidate-gene analysis of white matter hyperintensities on neuroimaging
BACKGROUND: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789815/ https://www.ncbi.nlm.nih.gov/pubmed/25835038 http://dx.doi.org/10.1136/jnnp-2014-309685 |
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author | Tran, Theresa Cotlarciuc, Ioana Yadav, Sunaina Hasan, Nazeeha Bentley, Paul Levi, Christopher Worrall, Bradford B Meschia, James F Rost, Natalia Sharma, Pankaj |
author_facet | Tran, Theresa Cotlarciuc, Ioana Yadav, Sunaina Hasan, Nazeeha Bentley, Paul Levi, Christopher Worrall, Bradford B Meschia, James F Rost, Natalia Sharma, Pankaj |
author_sort | Tran, Theresa |
collection | PubMed |
description | BACKGROUND: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). METHODS: Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. RESULTS: We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(−344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90−3.41; observed OR=1.68; 95% CI, 0.97−2.94). Neither CYP11B2 T(−344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. CONCLUSIONS: There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest. |
format | Online Article Text |
id | pubmed-4789815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47898152016-03-23 Candidate-gene analysis of white matter hyperintensities on neuroimaging Tran, Theresa Cotlarciuc, Ioana Yadav, Sunaina Hasan, Nazeeha Bentley, Paul Levi, Christopher Worrall, Bradford B Meschia, James F Rost, Natalia Sharma, Pankaj J Neurol Neurosurg Psychiatry Cerebrovascular Disease BACKGROUND: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). METHODS: Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. RESULTS: We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(−344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90−3.41; observed OR=1.68; 95% CI, 0.97−2.94). Neither CYP11B2 T(−344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. CONCLUSIONS: There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest. BMJ Publishing Group 2016-03 2015-04-02 /pmc/articles/PMC4789815/ /pubmed/25835038 http://dx.doi.org/10.1136/jnnp-2014-309685 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Cerebrovascular Disease Tran, Theresa Cotlarciuc, Ioana Yadav, Sunaina Hasan, Nazeeha Bentley, Paul Levi, Christopher Worrall, Bradford B Meschia, James F Rost, Natalia Sharma, Pankaj Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title | Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title_full | Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title_fullStr | Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title_full_unstemmed | Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title_short | Candidate-gene analysis of white matter hyperintensities on neuroimaging |
title_sort | candidate-gene analysis of white matter hyperintensities on neuroimaging |
topic | Cerebrovascular Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789815/ https://www.ncbi.nlm.nih.gov/pubmed/25835038 http://dx.doi.org/10.1136/jnnp-2014-309685 |
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