Common Polymorphisms in the CYP11B1 and CYP11B2 Genes:

Evidence for a Digenic Influence on Hypertension

Samantha Alvarez-Madrazo, Scott M. MacKenzie, Eleanor Davies, Robert Fraser, Wai-Kwong Lee, Morris Brown, Mark J. Caulfield, Anna F. Dominiczak, Martin Farrall, Mark Lathrop, Thomas Hedner, Olle Melander, Patricia B. Munroe, Nilesh Samani, Paul M. Stewart, Bjorn Wahlstrand, John Webster, Colin N. A. Palmer, Sandosh Padmanabhan, John M. Connell (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    17 Citations (Scopus)

    Abstract

    The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement

    Original languageEnglish
    Pages (from-to)232-239
    Number of pages8
    JournalHypertension
    Volume61
    Issue number1
    Early online date12 Nov 2012
    DOIs
    Publication statusPublished - 2013

    Keywords

    • EXCRETION
    • GENOME-WIDE ASSOCIATION
    • CONSEQUENCES
    • cortisol
    • 11-BETA HYDROXYLASE
    • CYP11B1
    • CYP11B2
    • aldosterone
    • haplotypes
    • ALDOSTERONE SYNTHASE
    • METAANALYSIS
    • DAHL RAT
    • BLOOD-PRESSURE VARIATION
    • LINKAGE
    • hypertension
    • MUTATIONS
    • population

    Cite this

    Alvarez-Madrazo, S., MacKenzie, S. M., Davies, E., Fraser, R., Lee, W-K., Brown, M., ... Connell, J. M. (2013). Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension. Hypertension, 61(1), 232-239. https://doi.org/10.1161/HYPERTENSIONAHA.112.200741
    Alvarez-Madrazo, Samantha ; MacKenzie, Scott M. ; Davies, Eleanor ; Fraser, Robert ; Lee, Wai-Kwong ; Brown, Morris ; Caulfield, Mark J. ; Dominiczak, Anna F. ; Farrall, Martin ; Lathrop, Mark ; Hedner, Thomas ; Melander, Olle ; Munroe, Patricia B. ; Samani, Nilesh ; Stewart, Paul M. ; Wahlstrand, Bjorn ; Webster, John ; Palmer, Colin N. A. ; Padmanabhan, Sandosh ; Connell, John M. / Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension. In: Hypertension. 2013 ; Vol. 61, No. 1. pp. 232-239.
    @article{3c805215f5da4ac2b6062bc8249f7594,
    title = "Common Polymorphisms in the CYP11B1 and CYP11B2 Genes:: Evidence for a Digenic Influence on Hypertension",
    abstract = "The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement",
    keywords = "EXCRETION, GENOME-WIDE ASSOCIATION, CONSEQUENCES, cortisol, 11-BETA HYDROXYLASE, CYP11B1, CYP11B2, aldosterone, haplotypes, ALDOSTERONE SYNTHASE, METAANALYSIS, DAHL RAT, BLOOD-PRESSURE VARIATION, LINKAGE, hypertension, MUTATIONS, population",
    author = "Samantha Alvarez-Madrazo and MacKenzie, {Scott M.} and Eleanor Davies and Robert Fraser and Wai-Kwong Lee and Morris Brown and Caulfield, {Mark J.} and Dominiczak, {Anna F.} and Martin Farrall and Mark Lathrop and Thomas Hedner and Olle Melander and Munroe, {Patricia B.} and Nilesh Samani and Stewart, {Paul M.} and Bjorn Wahlstrand and John Webster and Palmer, {Colin N. A.} and Sandosh Padmanabhan and Connell, {John M.}",
    year = "2013",
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    language = "English",
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    pages = "232--239",
    journal = "Hypertension",
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    }

    Alvarez-Madrazo, S, MacKenzie, SM, Davies, E, Fraser, R, Lee, W-K, Brown, M, Caulfield, MJ, Dominiczak, AF, Farrall, M, Lathrop, M, Hedner, T, Melander, O, Munroe, PB, Samani, N, Stewart, PM, Wahlstrand, B, Webster, J, Palmer, CNA, Padmanabhan, S & Connell, JM 2013, 'Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension', Hypertension, vol. 61, no. 1, pp. 232-239. https://doi.org/10.1161/HYPERTENSIONAHA.112.200741

    Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension. / Alvarez-Madrazo, Samantha; MacKenzie, Scott M.; Davies, Eleanor; Fraser, Robert; Lee, Wai-Kwong; Brown, Morris; Caulfield, Mark J.; Dominiczak, Anna F.; Farrall, Martin; Lathrop, Mark; Hedner, Thomas; Melander, Olle; Munroe, Patricia B.; Samani, Nilesh; Stewart, Paul M.; Wahlstrand, Bjorn; Webster, John; Palmer, Colin N. A.; Padmanabhan, Sandosh; Connell, John M. (Lead / Corresponding author).

    In: Hypertension, Vol. 61, No. 1, 2013, p. 232-239.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Common Polymorphisms in the CYP11B1 and CYP11B2 Genes:

    T2 - Evidence for a Digenic Influence on Hypertension

    AU - Alvarez-Madrazo, Samantha

    AU - MacKenzie, Scott M.

    AU - Davies, Eleanor

    AU - Fraser, Robert

    AU - Lee, Wai-Kwong

    AU - Brown, Morris

    AU - Caulfield, Mark J.

    AU - Dominiczak, Anna F.

    AU - Farrall, Martin

    AU - Lathrop, Mark

    AU - Hedner, Thomas

    AU - Melander, Olle

    AU - Munroe, Patricia B.

    AU - Samani, Nilesh

    AU - Stewart, Paul M.

    AU - Wahlstrand, Bjorn

    AU - Webster, John

    AU - Palmer, Colin N. A.

    AU - Padmanabhan, Sandosh

    AU - Connell, John M.

    PY - 2013

    Y1 - 2013

    N2 - The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement

    AB - The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement

    KW - EXCRETION

    KW - GENOME-WIDE ASSOCIATION

    KW - CONSEQUENCES

    KW - cortisol

    KW - 11-BETA HYDROXYLASE

    KW - CYP11B1

    KW - CYP11B2

    KW - aldosterone

    KW - haplotypes

    KW - ALDOSTERONE SYNTHASE

    KW - METAANALYSIS

    KW - DAHL RAT

    KW - BLOOD-PRESSURE VARIATION

    KW - LINKAGE

    KW - hypertension

    KW - MUTATIONS

    KW - population

    UR - http://www.scopus.com/inward/record.url?scp=84871620553&partnerID=8YFLogxK

    U2 - 10.1161/HYPERTENSIONAHA.112.200741

    DO - 10.1161/HYPERTENSIONAHA.112.200741

    M3 - Article

    VL - 61

    SP - 232

    EP - 239

    JO - Hypertension

    JF - Hypertension

    SN - 0194-911X

    IS - 1

    ER -