The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia

Liv Cecilie V Thomsen, Nina S. Mccarthy, Phillip E. Melton, Gemma Cadby, Rigmor Austgulen, Ottar K. Nygård, Matthew P. Johnson, Shaun Brennecke, Eric K. Moses, Line Bjørge, Ann Charlotte Iversen

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    OBJECTIVE:: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS:: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n?=?1006) and nonpreeclamptic controls (n?=?816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS:: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P?=?0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency?=?0.15). CONCLUSION:: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

    Original languageEnglish (US)
    JournalJournal of Hypertension
    DOIs
    StateAccepted/In press - Oct 17 2016

    Fingerprint

    Methylenetetrahydrofolate Reductase (NADPH2)
    Pre-Eclampsia
    Antihypertensive Agents
    Genes
    Single Nucleotide Polymorphism
    Hypertension
    Alleles
    Licensure
    Inflammation
    Cardiovascular Diseases
    Logistic Models
    Odds Ratio
    Confidence Intervals
    Genome-Wide Association Study
    Proteinuria
    Folic Acid
    Gene Frequency

    ASJC Scopus subject areas

    • Internal Medicine
    • Physiology
    • Cardiology and Cardiovascular Medicine

    Cite this

    Thomsen, L. C. V., Mccarthy, N. S., Melton, P. E., Cadby, G., Austgulen, R., Nygård, O. K., ... Iversen, A. C. (Accepted/In press). The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia. Journal of Hypertension. https://doi.org/10.1097/HJH.0000000000001131

    The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia. / Thomsen, Liv Cecilie V; Mccarthy, Nina S.; Melton, Phillip E.; Cadby, Gemma; Austgulen, Rigmor; Nygård, Ottar K.; Johnson, Matthew P.; Brennecke, Shaun; Moses, Eric K.; Bjørge, Line; Iversen, Ann Charlotte.

    In: Journal of Hypertension, 17.10.2016.

    Research output: Contribution to journalArticle

    Thomsen, LCV, Mccarthy, NS, Melton, PE, Cadby, G, Austgulen, R, Nygård, OK, Johnson, MP, Brennecke, S, Moses, EK, Bjørge, L & Iversen, AC 2016, 'The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia', Journal of Hypertension. https://doi.org/10.1097/HJH.0000000000001131
    Thomsen, Liv Cecilie V ; Mccarthy, Nina S. ; Melton, Phillip E. ; Cadby, Gemma ; Austgulen, Rigmor ; Nygård, Ottar K. ; Johnson, Matthew P. ; Brennecke, Shaun ; Moses, Eric K. ; Bjørge, Line ; Iversen, Ann Charlotte. / The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia. In: Journal of Hypertension. 2016.
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    title = "The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia",
    abstract = "OBJECTIVE:: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS:: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n?=?1006) and nonpreeclamptic controls (n?=?816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS:: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95{\%} confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P?=?0.68, odds ratio 1.05, 95{\%} confidence interval 0.83–1.32, minor allele frequency?=?0.15). CONCLUSION:: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0",
    author = "Thomsen, {Liv Cecilie V} and Mccarthy, {Nina S.} and Melton, {Phillip E.} and Gemma Cadby and Rigmor Austgulen and Nyg{\aa}rd, {Ottar K.} and Johnson, {Matthew P.} and Shaun Brennecke and Moses, {Eric K.} and Line Bj{\o}rge and Iversen, {Ann Charlotte}",
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    T1 - The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia

    AU - Thomsen, Liv Cecilie V

    AU - Mccarthy, Nina S.

    AU - Melton, Phillip E.

    AU - Cadby, Gemma

    AU - Austgulen, Rigmor

    AU - Nygård, Ottar K.

    AU - Johnson, Matthew P.

    AU - Brennecke, Shaun

    AU - Moses, Eric K.

    AU - Bjørge, Line

    AU - Iversen, Ann Charlotte

    PY - 2016/10/17

    Y1 - 2016/10/17

    N2 - OBJECTIVE:: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS:: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n?=?1006) and nonpreeclamptic controls (n?=?816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS:: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P?=?0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency?=?0.15). CONCLUSION:: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

    AB - OBJECTIVE:: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia. METHODS:: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n?=?1006) and nonpreeclamptic controls (n?=?816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model. RESULTS:: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53–0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case–control cohort (P?=?0.68, odds ratio 1.05, 95% confidence interval 0.83–1.32, minor allele frequency?=?0.15). CONCLUSION:: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

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