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. Nygard, Matthew P. Johnson, Shaun Brennecke, Eric K. Moses, Line Bjorge, Ann-Charlotte Iversen

Research output: Contribution to journalArticleResearchpeer-review

5 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 genomewide 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.

Original languageEnglish
Pages (from-to)132-139
Number of pages8
JournalJournal of Hypertension
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 2017
Externally publishedYes

Keywords

  • Blood pressure regulation
  • Hypertension
  • Methylenetetrahydrofolate reductase
  • Pleiotropy
  • Preeclampsia
  • Single nucleotide polymorphism

Cite this

Thomsen, L. C. V., McCarthy, N. S., Melton, P. E., Cadby, G., Austgulen, R., Nygard, O. K., ... Iversen, A-C. (2017). The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia. Journal of Hypertension, 35(1), 132-139. https://doi.org/10.1097/HJH.0000000000001131
Thomsen, Liv Cecilie V. ; McCarthy, Nina S. ; Melton, Phillip E ; Cadby, Gemma ; Austgulen, Rigmor ; Nygard, Ottar K. ; Johnson, Matthew P. ; Brennecke, Shaun ; Moses, Eric K. ; Bjorge, Line ; Iversen, Ann-Charlotte. / The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia. In: Journal of Hypertension. 2017 ; Vol. 35, No. 1. pp. 132-139.
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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 genomewide 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.",
keywords = "Blood pressure regulation, Hypertension, Methylenetetrahydrofolate reductase, Pleiotropy, Preeclampsia, Single nucleotide polymorphism",
author = "Thomsen, {Liv Cecilie V.} and McCarthy, {Nina S.} and Melton, {Phillip E} and Gemma Cadby and Rigmor Austgulen and Nygard, {Ottar K.} and Johnson, {Matthew P.} and Shaun Brennecke and Moses, {Eric K.} and Line Bjorge and Ann-Charlotte Iversen",
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Thomsen, LCV, McCarthy, NS, Melton, PE, Cadby, G, Austgulen, R, Nygard, OK, Johnson, MP, Brennecke, S, Moses, EK, Bjorge, L & Iversen, A-C 2017, 'The antihypertensive MTHFR gene polymorphism rs17367504-G is a possible novel protective locus for preeclampsia', Journal of Hypertension, vol. 35, no. 1, pp. 132-139. 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; Nygard, Ottar K.; Johnson, Matthew P.; Brennecke, Shaun; Moses, Eric K.; Bjorge, Line; Iversen, Ann-Charlotte.

In: Journal of Hypertension, Vol. 35, No. 1, 01.2017, p. 132-139.

Research output: Contribution to journalArticleResearchpeer-review

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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 - Nygard, Ottar K.

AU - Johnson, Matthew P.

AU - Brennecke, Shaun

AU - Moses, Eric K.

AU - Bjorge, Line

AU - Iversen, Ann-Charlotte

PY - 2017/1

Y1 - 2017/1

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 genomewide 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.

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 genomewide 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.

KW - Blood pressure regulation

KW - Hypertension

KW - Methylenetetrahydrofolate reductase

KW - Pleiotropy

KW - Preeclampsia

KW - Single nucleotide polymorphism

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