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Cited by 154Coagulation, Bradykinin, Polyphosphates, and AngioedemaRenin-Angiotensin System StudiesGenetic Associations and Epidemiology

A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor‐induced angioedema

Open access
Cilia La Corte, Amy L., Carter, Angela M., Rice, Gillian I., Duan, Qing Ling, Rouleau, Guy A, Adam, Albert, Grant, Peter J., Hooper, Nigel M.·2011·Human Mutation
DOI 10.1002/humu.21579
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Abstract

In a case control study of subjects with a history of ACEi-angioedema, haplotype ATG was significantly associated with ACEi-angioedema (OR 4.87 [1.78–13.35] p = 0.002). The ATG haplotype is functional and contributes to ACEi-angioedema through a reduction in APP.

Integrity signals

Registry

Crossref · 10.1002/humu.21579

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 24 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    Genetic factors contribute to 47.3% of variation in plasma APP activity in the Leeds Family Study, a healthy population.

    “we have shown in a well established and large family study representative of a healthy population, the Leeds Family Study [Freeman et al., 2002a[Freeman et al., , 2002b]], that genetic factors contribute to 47.3% of variation in plasma APP activity.”
    • Also stated in: § Discussion · boosted
      “the results of the present study reveal a major contribution of additive genetic factors in determining variance in plasma APP activity in healthy individuals.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Freeman et al., 2002a source

      The Abstract and Subject Recruitment sections describe a genetic study of healthy families recruited in Leeds, supporting the population and general genetic-contribution claim. But the Abstract assigns approximately 47% heritability to the FXIII complex, not plasma APP activity; the paper does not report the claimed 47.3% figure for APP activity. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Freeman et al., 2002b source
  • Findingown data

    None of the coding-region polymorphisms identified were associated with plasma APP activity.

    “None of the polymorphisms identified in the coding regions were associated with plasma APP activity and these polymorphisms were not studied further.”
    Quote in the paperSubstantial claim
  • Findingown data

    Haplotype ATG is associated with significantly lower plasma APP activity than haplotype CGG.

    “Haplotype ATG was associated with significantly lower plasma APP activity compared to haplotype CGG (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    The three 5' regulatory polymorphisms c.-2399C>A, c.-1612G>T, and c.-393G>A are significantly associated with plasma APP activity.

    “The three polymorphisms identified in the XPNPEP2 5 regulatory region were significantly associated with plasma APP activity”
    Quote in the paperSubstantial claim
  • Findingown data

    In a case-control study, haplotype ATG is significantly associated with ACE inhibitor-induced angioedema, with an odds ratio of 4.87 (95% CI 1.78-13.35) and P = 0.002.

    “In a case control study of subjects with a history of ACEi-angioedema, haplotype ATG was significantly associated with ACEiangioedema (OR 4.87 [1.78-13.35]P = 0.002).”
    Quote in the paperSubstantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 14
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    ACE accounts for about 70% of circulatory bradykinin degradation, and APP for about 30%.

    “ACE accounts for approximately 70% of the circulatory degradation of bradykinin, with aminopeptidase P (APP; MIM# 300145) contributing to approximately 30%”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Cyr et al., 2001 source

      The Results (p. 4) report that ACE accounts for 88 ± 6% of bradykinin metabolism in the serum of 116 healthy individuals, not approximately 70%. The Results (p. 5) assign 11 ± 5% to kininase I; the paper does not assign approximately 30% to APP. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Ersahin and Simmons, 1997 source
    • cites Prechel et al., 1995 source

  • May combine two claims.

    Premisecitation

    APP inactivates both bradykinin and des-Arg9-bradykinin, a role of major importance when ACE is inhibited.

    “Thus, APP inactivates bradykinin and des-Arg 9 -bradykinin [Turner and Cottrell, 2004], a role that is of major importance in the presence of ACEi [Cyr et al., 2001;Fryer et al., 2008;Kim et al., 2000].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Turner and Cottrell, 2004 source
    • cites Cyr et al., 2001 source
    • cites Fryer et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A soluble form of APP in blood plasma has the same properties as the membrane-bound isoform and likely arises from cleavage of its GPI anchor by phospholipases.

    “A soluble form of APP is present in blood plasma, which has the same properties as the membrane-bound isoform [Ryan et al., 1992] and likely arises from cleavage of its glycosyl-phosphatidylinositol membrane anchor by phospholipases [Hooper et al., 1990;Hooper and Turner, 1989].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Ryan et al., 1992 source

      The Introduction (page unavailable) identifies guinea pig serum as a source of soluble aminoacylproline hydrolase. The Comment (page unavailable) says the serum and pig kidney enzymes appear to share some properties, but explicitly says their relationship is unclear; it does not establish that they have the same properties. The phospholipase-origin clause is attributed to other citations in the citing sentence, not to Ryan et al. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Hooper et al., 1990 source
    • cites Hooper and Turner, 1989 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    That smaller study also identified a QTL with peak LOD = 3.75 in the vicinity of the gene encoding APP (XPNPEP2).

    “this study also identified a QTL with peak LOD = 3.75 in the vicinity of the gene encoding APP (XPNPEP2) [Duan et al., 2005].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Duan et al., 2005 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The estimated heritability of plasma APP was 37.5 ± 26.5% in a smaller study of eight pedigrees selected on the basis of one family member with ACEi-angioedema and/or other anaphylactoid responses to ACEi.

    “This is similar to the estimated heritability of plasma APP of 37.5 ± 26.5% from a smaller study of eight pedigrees selected on the basis of one family member with ACEi-angioedema and/or other anaphylactoid responses to ACEi”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Duan et al., 2005 source

      The Variance-Component Linkage Analysis (p. 6) reports 37.5 ± 26.5% heritability for five pedigrees, not eight; its estimate for all eight is 33.6 ± 25.1%. The Participants section (p. 2) supports the description of how the eight families were selected. (LLM, conf=0.94)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    No consensus transcription factor binding sites or allele-specific differences were predicted for c.-393G>A or c.-1612G>T.

    “There was no consensus for transcription factors predicted to interact with the c.-393G>A or c.-1612G>T polymorphisms, nor were allele specific differences suggested.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Haplotypes CTG and CTA show significantly higher luciferase activity than CGG, but do not differ from each other.

    “Haplotypes CTG and CTA demonstrated significantly higher luciferase activity (P < 0.05) compared to haplotype CGG, but were not significantly different from each other.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The full-length XPNPEP2 upstream construct from -3,123 to -147 bp has promoter activity, showing about 10-fold higher luciferase activity than empty vector.

    “The full length construct (-3,123 to -147 bp) showed approximately 10-fold higher luciferase activity compared to the empty vector (pGL3 basic), demonstrating that this construct contained promoter activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The c.-2399C>A polymorphism is located in an enhancer region and is predicted to differentially bind HNF4.

    “The c.-2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The XPNPEP2 minimal promoter lies within the region from -338 bp to -147 bp.

    “reduced the luciferase activity down to a level comparable to the empty vector indicating that the minimal promoter was within this 191 bp fragment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The region around c.-2399C>A is predicted to bind HNF4 and COUP-TF by all three programs, and CHIP MAPPER predicts preferential HNF4 binding to the C allele.

    “the region surrounding the c.-2399C>A polymorphism was predicted to bind to HNF4 and Chicken Ovalbumin Upstream Promoter-Transcription Factor (COUP-TF) by each program, whilst both alleles were predicted to bind these transcription factors, CHIP MAPPER predicted preferential binding of HNF4 to the c.-2399C allele.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Haplotypes CTG and CTA do not significantly differ from CGG in plasma APP activity.

    “The plasma APP activity for haplotypes CTG and CTA did not significantly differ from haplotype CGG (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The association between XPNPEP2 haplotype and plasma APP activity does not differ by gender, plasma ACE, or oral contraceptive use.

    “The association between haplotype and plasma APP activity did not differ according to gender, plasma ACE, or oral contraceptive use (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The region between -2,502 to -2,238 harbors the c.-2399C>A polymorphism and putative binding sites for HNF4 and COUP-TF, and is important in transactivation of the XPNPEP2 promoter.

    “We have identified the region between -2,502 to -2,238, which harbors the c.-2399C>A polymorphism and putative binding sites for HNF4 and COUP-TF, as important in transactivation of the XPNPEP2 promoter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most common haplotype is CGG, with frequencies 0.64 in males and 0.59 in females.

    “the most common haplotype contained the more common allele for each of the polymorphisms (CGG; frequency in males 0.64, females 0.59).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The c.-1612G>T polymorphism is the most common, with T allele frequency 39.3% in females and 37.2% in males.

    “The c.-1612G>T polymorphism was the most common with the T-allele frequency being 39.3% and 37.2% in females and males, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The first key region, -388 bp to -147 bp upstream of the ATG, contained the proximal promoter and 117 bp of the 5' UTR as defined by Venema et al. 1997.

    “The first in the region of -388 bp to -147 bp upstream of the ATG contained the proximal promoter in addition to 117 bp of the 5 UTR as defined by [Venema et al., 1997].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Venema et al., 1997 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The enhancer and minimal promoter regions identified are located in areas conserved between human and mouse XPNPEP2 sequences.

    “The relative positions of the enhancer and minimal promoter regions identified by the nested deletion analysis were located in areas of conservation between the human and the mouse sequences (data not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Both of these regions lie within conserved areas between the human and mouse sequences.

    “Both of these regions lie within conserved areas between the human and mouse sequences (data not shown)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Haplotypes AGG and CGA have frequencies at or below 1%, and AGA and ATA were not identified.

    “Haplotypes AGG and CGA had frequencies of ≤ 1% and haplotypes AGA and ATA were not identified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Haplotypes ATG, CTA, and CTG have frequencies greater than 4% in the Leeds Family Study.

    “The other haplotypes observed with frequencies greater than 4% were ATG (frequency in males 0.15, females 0.20), CTA (frequency in males 0.18, females 0.14), and CTG (frequency in males 0.04, females 0.06).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Twenty-five polymorphisms were identified in XPNPEP2, nine of which were common with frequencies above 3%.

    “Twenty-five polymorphisms were identified and confirmed by sequencing (Supp.Table S3), nine of which were common (frequencies >3%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The second key region, -2,502 bp to -2,238 bp, demonstrated approximately 2.2-fold greater luciferase activity than the -388 bp to -147 bp region containing the proximal promoter, indicating a potential transcriptional enhancer.

    “The second occurred in the region -2,502 bp to -2,238 bp, which demonstrated approximately 2.2-fold greater luciferase activity than the -388 bp to -147 bp region containing the”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean plasma APP activity in the Leeds Family Study was 0.20 nmol/min/ml (95% CI 0.06-0.65), with a range of 0.02-0.73 nmol/min/ml.

    “The mean (±95% CI) plasma APP activity in the study was 0.20 (0.06-0.65) nmol/min/ml with a range of 0.02-0.73nmol/min/ml.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Screening all exons and 3-kb upstream of the initiator ATG codon of XPNPEP2 identified 25 SNPs.

    “we screened all the exons and 3-kb upstream of the initiator ATG codon of the XPNPEP2 gene for polymorphisms and identified 25 SNPs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The nine common polymorphisms and three rare nonsynonymous coding mutations were in Hardy-Weinberg equilibrium.

    “Within the Leeds Family Study, these nine common polymorphisms and three rare nonsynonymous coding mutations were in Hardy Weinberg equilibrium”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The present study confirms an association of c.-2399C>A with plasma APP and identifies two novel polymorphisms also associated with plasma APP.

    “the present study therefore confirms an association of this polymorphism with plasma APP and identifies two novel polymorphisms also associated with plasma APP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Haplotype analysis identified six of eight potential haplotypes in the Leeds Family Study.

    “Haplotype analysis in the Leeds Family Study identified six of the eight potential haplotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The ATG haplotype is functional and contributes to ACE inhibitor-induced angioedema through a reduction in APP.

    “The ATG haplotype is functional and contributes to ACEiangioedema through a reduction in APP.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    ACE inhibitors are commonly prescribed for hypertension and can cause a rare but potentially fatal angioedema reaction.

    “Angiotensin I-converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life-threatening reaction, ACEi-angioedema.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brown et al., 1996 source
    • cites Leenen et al., 2006 source
    • cites Vleeming et al., 1998 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The logistic regression model for ACEi-angioedema adjusted for gender and country of origin.

    “In a logistic regression model adjusting for gender and country of origin”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The c.-2399C>A polymorphism and the ATG haplotype are functional and significantly reduce transactivation of the XPNPEP2 promoter, potentially through a mechanism involving differential HNF4 binding.

    “Furthermore, we have demonstrated for the first time that the c.-2399C>A polymorphism and the ATG haplotype are functional and significantly reduce transactivation of the XPNPEP2 promoter, potentially through a mechanism involving differential HNF4 binding.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.

  • May combine two claims.

    Interpretationreasoning

    Polymorphisms in the 5' regulatory region influence the transcriptional regulation of XPNPEP2, resulting in decreased cellular expression and consequently decreased plasma levels of APP.

    “These results therefore suggest that the polymorphisms in the 5 regulatory region influence the transcriptional regulation of XPNPEP2 resulting in decreased cellular expression, and consequently decreased plasma levels, of APP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    A common ATG haplotype in the XPNPEP2 5' regulatory region accounts for a greater proportion of the variance in plasma APP and a greater increased risk for ACEi-angioedema than the c.-2399C>A polymorphism alone (4.9-fold compared with 3.0-fold increased risk, respectively).

    “We have identified a common ATG haplotype in the XPNPEP2 5 regulatory region, which accounts for a greater proportion of the variance in plasma APP and a greater increased risk for ACEi-angioedema than the c.-2399C>A polymorphism alone (4.9-fold compared with 3.0-fold increased risk, respectively)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The c.-2399C>A and c.-1612G>T polymorphisms are functional.

    “therefore demonstrating for the first time that c.-2399C>A and c.-1612G>T are functional polymorphisms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HNF4 is a zinc finger protein expressed in the liver, kidney, and intestine, known to participate in the regulation of several genes involved in glucose, cholesterol, and fatty acid metabolism and in the synthesis of blood coagulation factors.

    “HNF4 is a zinc finger protein expressed in the liver, kidney, and intestine, which is known to participate in the regulation of several genes involved in glucose, cholesterol, and fatty acid metabolism and also in the synthesis of blood coagulation factors [Schrem et al., 2002].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schrem et al., 2002 source

  • May combine two claims.

    Interpretationown data

    A functional haplotype in the XPNPEP2 5' regulatory region is associated with reduced plasma APP activity and increased risk for ACEi-angioedema.

    “In conclusion, we have identified and characterized a functional haplotype in the XPNPEP2 5 regulatory region that is associated with reduced plasma APP activity and increased risk for ACEi-angioedema.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.
37 of 37

  • The paper relies on this without support.

    The HepG2 cell line is a valid model for XPNPEP2 transcriptional regulation in the tissues relevant to ACE inhibitor-induced angioedema.

    “Constructs were transiently transfected into HepG2 cells using FuGENE6 (Roche).”
    “In trans-activation experiments, HepG2 cells were cotransfected with 0.4 μg reporter construct and 0.1 μg hepatic nuclear factor-4 (HNF4) expression vector”

  • The paper relies on this without support.

    The Angioedema Study cases and controls are representative of the broader population at risk for ACE inhibitor-induced angioedema.

    “The Angioedema Study: consisted of 34 participants from Canada, Belgium, and the United States who had a history of ACEiangioedema or ACEi-induced anaphylactoid reactions and 127 control samples, matched for gender and country of origin.”

  • The paper relies on this without support.

    The Leeds Family Study sample is representative of healthy individuals for estimating the genetic contribution to plasma APP activity.

    “The Leeds Family Study: consisted of 537 subjects from 89 pedigrees (average of six subjects per family) from 133 households.”

  • The paper relies on this without support.

    Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.

    “suggesting these regions may be important for transcriptional regulation of XNPEP2 expression in vivo.”
    “demonstrating for the first time that c.-2399C>A and c.-1612G>T are functional polymorphisms.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The minimal promoter has two reported boundaries

    Minor

    The results identify the minimal promoter as extending from −338 to −147 bp, but the discussion places its upstream boundary at −388 bp. Those boundaries differ by 50 bp.

1 of 1

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Related

Authors
Cilia La Corte, A. L., Carter, A. M., Rice, G. I., Duan, Q. L., Rouleau, G. A., Adam, A., Grant, P. J., & Hooper, N. M.
Affiliations
  • University of Leeds (GB)
  • McGill University (CA)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • Université de Montréal (CA)
Corresponding author
Hooper, Nigel M.
ORCID
Venue
Human Mutation
Publisher
Wiley
Published
2011-09-12
Volume
32
Issue
11
Pages
1326-1331
ISSN
1059-7794 (ISSN-L)
DOI
10.1002/humu.21579
OpenAlex
W2038331078
Semantic Scholar
00e2999e2998ccdf31e93b0ff6c5956f18405ae5
Cited by
154
References
77
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2023: 9 · 2021: 15 · 2020: 12 · 2019: 12 · 2018: 19 · 2017: 16 · 2016: 22 · 2015: 18 · 2014: 14 · 2013: 3 · 2012: 7
FWCI
4.04
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1450 d)
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • University of Cincinnati
  • CSL Behring
  • British Heart Foundation (PG/02/106/14434, FS/02/058/14378)
Topics
  • Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
aminopeptidase P, ACE inhibitor-induced angioedema, promoter haplotypes, genetic polymorphism, enhancers, bradykinin metabolism, plasma enzyme activity, genetic susceptibility
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Aminopeptidases, Angioedema, Angiotensin-Converting Enzyme Inhibitors, Female, Haplotypes, Humans, Male, Middle Aged, Pedigree, Promoter Regions, Genetic, Regulatory Elements, Transcriptional

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