The DOI matches its Crossref record; 76 of the 77 references it cites were found in a registry or an index; 7 of the 24 sources its claims cite were checked for support.
A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor‐induced angioedema
Open accessAbstract
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.
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Claims the paper makes
7 of 24 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
What the sources say
- Partly supportedcites Freeman et al., 2002a sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites Freeman et al., 2002b source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Also stated in: § Discussion · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“None of the polymorphisms identified in the coding regions were associated with plasma APP activity and these polymorphisms were not studied further.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Haplotype ATG was associated with significantly lower plasma APP activity compared to haplotype CGG (Table 2).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The three polymorphisms identified in the XPNPEP2 5 regulatory region were significantly associated with plasma APP activity”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Heritability analysis indicated that 47.3% of variation in plasma APP activity was accounted for by additive genetic factors, after accounting for age, gender, and the oral contraceptive pill.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Determination of the Genetic Contribution to Variance in Plasma APP in Healthy Individuals
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Truncation of the construct from -2,502 bp to -2,238 bp reduced the luciferase activity by approximately threefold, indicating the presence of an enhancer within this region.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Functional Transcriptional Regulatory Elements
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Supershift analysis supports a differential interaction with HNF4 (Supp.Fig. S3).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > The Effects of XPNPEP2 Polymorphisms and Haplotypes on Gene Regulation
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“no qualitative allele specific differences in DNA:protein-binding complexes were observed for the c.-393G>A, c.-1612G>T, and c.-2399C>A polymorphisms (data not shown).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > The Effects of XPNPEP2 Polymorphisms and Haplotypes on Gene Regulation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“accounting for 1.7% (c.-393G>A), 0.5% (c.-1612G>T), and 8.4% (c.-2399C>A) of the variance in plasma APP activity when modeled individually”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 28
- Probably not a substantial claim. 14
- The quote only partly states this claim. 1
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“ACE accounts for approximately 70% of the circulatory degradation of bradykinin, with aminopeptidase P (APP; MIM# 300145) contributing to approximately 30%”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Introduction
What the sources say
- Disputedcites Cyr et al., 2001 sourceExperimental — accuracy not yet measured
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.
- Not checked — no full text of the sourcecites Ersahin and Simmons, 1997 source
- Not checked — no full text of the sourcecites Prechel et al., 1995 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Disputed
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Introduction
What the sources say
- Not checked — no full text of the sourcecites Turner and Cottrell, 2004 source
- Supportedcites Cyr et al., 2001 source
The Results (p. 6) report significant inverse correlations between APP activity and the half-lives of both bradykinin and des-Arg9-bradykinin in the presence of the ACE inhibitor enalaprilat. The paper also identifies APP as a pathway for metabolizing both peptides (p. 2), supporting the attributed importance of that role during ACE inhibition. (LLM, conf=0.88)
- Supportedcites Fryer et al., 2008 source
The Fryer et al. citation is attached to APP’s importance during ACE inhibition, not to the preceding statement about both substrates. The Discussion reports that, in rats with ACE inhibited, non-ACE breakdown of bradykinin is carried out predominantly by APP. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Introduction
What the sources say
- Partly supportedcites Ryan et al., 1992 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites Hooper et al., 1990 source
- Not checked — no full text of the sourcecites Hooper and Turner, 1989 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“this study also identified a QTL with peak LOD = 3.75 in the vicinity of the gene encoding APP (XPNPEP2) [Duan et al., 2005].”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
What the sources say
- Supportedcites Duan et al., 2005 source
The Discussion (p. 8) explicitly reports a QTL near XPNPEP2 with a LOD score of 3.75. The Introduction (p. 2) identifies XPNPEP2 as the gene encoding membrane-bound APP. (LLM, conf=0.94)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
What the sources say
- Partly supportedcites Duan et al., 2005 sourceExperimental — accuracy not yet measured
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)
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > The Effects of XPNPEP2 Polymorphisms and Haplotypes on Gene Regulation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Haplotypes CTG and CTA demonstrated significantly higher luciferase activity (P < 0.05) compared to haplotype CGG, but were not significantly different from each other.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Haplotype ATG Is Associated with Reduced Reporter Gene Activity
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Functional Transcriptional Regulatory Elements
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The c.-2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced the luciferase activity down to a level comparable to the empty vector indicating that the minimal promoter was within this 191 bp fragment.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Functional Transcriptional Regulatory Elements
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > The Effects of XPNPEP2 Polymorphisms and Haplotypes on Gene Regulation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The plasma APP activity for haplotypes CTG and CTA did not significantly differ from haplotype CGG (Table 2).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The association between haplotype and plasma APP activity did not differ according to gender, plasma ACE, or oral contraceptive use (data not shown).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the most common haplotype contained the more common allele for each of the polymorphisms (CGG; frequency in males 0.64, females 0.59).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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].”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
What the sources say
- Not checked — no full text of the sourcecites Venema et al., 1997 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Functional Transcriptional Regulatory Elements
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both of these regions lie within conserved areas between the human and mouse sequences (data not shown)”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Haplotypes AGG and CGA had frequencies of ≤ 1% and haplotypes AGA and ATA were not identified.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Twenty-five polymorphisms were identified and confirmed by sequencing (Supp.Table S3), nine of which were common (frequencies >3%).”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Determination of the Genetic Contribution to Variance in Plasma APP in Healthy Individuals
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we screened all the exons and 3-kb upstream of the initiator ATG codon of the XPNPEP2 gene for polymorphisms and identified 25 SNPs.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within the Leeds Family Study, these nine common polymorphisms and three rare nonsynonymous coding mutations were in Hardy Weinberg equilibrium”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the present study therefore confirms an association of this polymorphism with plasma APP and identifies two novel polymorphisms also associated with plasma APP.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Haplotype analysis in the Leeds Family Study identified six of the eight potential haplotypes.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Identification of Polymorphisms and Haplotypes Associated with Plasma APP Activity
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ATG haplotype is functional and contributes to ACEiangioedema through a reduction in APP.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Angiotensin I-converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life-threatening reaction, ACEi-angioedema.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In a logistic regression model adjusting for gender and country of origin”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > ACEi-Angioedema Patients Are More Likely to Possess the ATG Haplotype Compared to Control Subjects
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“therefore demonstrating for the first time that c.-2399C>A and c.-1612G>T are functional polymorphisms.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.
In the paper
“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].”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
What the sources say
- Not checked — no full text of the sourcecites Schrem et al., 2002 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Functional XPNPEP2 Promoter Haplotype Leads to Reduced Plasma Aminopeptidase P and Increased Risk of ACE Inhibitor-Induced Angioedema > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Reporter gene activity in HepG2 cells reflects XPNPEP2 promoter activity in vivo.
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.”
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
MinorThe 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.
“reduced the luciferase activity down to a level comparable to the empty vector indicating that the minimal promoter was within this 191 bp fragment.”
“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].”
Citations
Cites
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Self-citation
Flagged first, then by citations
1 of the 77 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 101–150 of 150
A Case of Prolonged Angioedema After Cardiac Surgery
(2019) · doi:10.1053/j.jvca.2019.12.025 · Cited by 4
Papapostolou, N., Gregoriou, S., Katoulis, A., & Makris, M. P. (2024) · Pharmaceuticals · doi:10.3390/ph17030360 · Cited by 6
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Metadata
- 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)
- 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
- bronze
- doi.org
- 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 › Hematology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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