Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema

doi:10.1016/j.jaci.2008.12.010

Journal of Allergy and Clinical Immunology

Volume 123, Issue 4, April 2009, Pages 906-910

https://doi.org/10.1016/j.jaci.2008.12.010 Get rights and content

Background

Recent studies reported a gain-of-function mutation in the gene encoding coagulation Factor XII (F12) among 5 German and French families with estrogen-associated angioedema who share a common ancestor. The role of this factor, additional pathways that might contribute to increased bradykinin levels, or both remain to be determined in other families with estrogen-dependent or estrogen-associated inherited angioedema.

Objective

The purpose of this study was to determine whether mutations in F12 and polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin I–converting enzyme (ACE), which have been associated with increased bradykinin levels, contribute to estrogen-dependent inherited angioedema in a large family of Italian origin.

Methods

We screened the coding regions of F12 and the gene encoding membrane-bound APP (XPNPEP2), for genetic variants in the 3 affected female subjects. In addition, we genotyped this family for the insertion/deletion polymorphism in the ACE gene, which accounts for variable ACE levels.

Results

The 3 affected female subjects all have the threonine-to-lysine (Thre328Lys) mutation, which is associated with higher Factor XII activity. In addition, they have at least one A allele of rs3788853 at the XPNPEP2 locus, which is associated with lower APP activity, and at least one I allele in ACE, which is associated with reduced ACE activity.

Conclusion

A missense mutation in F12 is present in the 3 affected female subjects of this family with estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower levels of both APP and ACE, the major enzymes responsible for bradykinin degradation. Thus, our study suggests that multiple genes might contribute to estrogen-dependent or estrogen-associated inherited angioedema and explain some of the observed heterogeneity.

Section snippets

Methods

DNA was extracted from blood samples of 29 members of a family of Italian origin with multiple cases of EDIA, which was previously described by Binkley and Davis.¹⁰Fig 2 shows a modified pedigree comparable with the earlier report, with several additional members who did not participate in the previous study (eg, spouses and children). Blood samples for the current investigation were collected in October 2007 from participants who now reside in Canada and represent a subset of the original

Results

Fig 2 shows that all 3 affected female subjects with a history of EDIA (II:2, II:7, and II:8) are heterozygous for Thr328Lys (c. 1032 C>A), a gain-of-function mutation in exon 9 of the F12 gene that has been previously described.11, 12 In addition, this family has 5 male carriers (III:5, III:19, IV:3, IV:5, and IV:7) and 1 female heterozygote (IV:6) with undetermined phenotype. At age 20 years, this female carrier has not demonstrated symptoms of EDIA, which is in keeping with the fact she has

Discussion

In this report we identify a gain-of-function mutation in F12 among 3 affected patients with EDIA in a previously well-characterized family.¹⁰ High estrogen levels, acting through an estrogen response element in the promoter region of F12, increase expression of the mutant Factor XII with a gain of function, which is thought to contribute to increased bradykinin levels and angioedema. Although this mutation has been documented in families from Germany and France,11, 12 we are the first to

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The effect of estrogen-containing birth control pills on the constituents of bradykinin expression in plasma
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Hereditary angioedema with C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal disorder presenting with recurrent angioedema. Estrogen-containing medications trigger angioedema in some patients, and conversely, progesterone may decrease attack frequency. The mechanism by which estrogen may exacerbate angioedema in HAE-C1INH is not well characterized.
Our aim was to investigate the link between estrogen and bradykinin constituents to better understand the specific underlying triggers that may exacerbate angioedema in patients with HAE-C1INH.
As estrogen is contraindicated for patients with HAE-C1INH, females without a history of angioedema were recruited to evaluate whether estrogen-containing oral contraceptive pills (OCPs) alter plasma protein levels of bradykinin, cleaved high-molecular-weight kininogen (cHK), and activated factor XII (FXIIa). Blood (plasma) was collected before initiation of OCP administration and 3 months thereafter. High-molecular-weight kininogen (HK) was measured by ELISA and FXIIa and cHK were analyzed by Western blot analysis.
A total of 12 adult females without HAE-CINH (aged <40 years) had a median baseline plasma HK level of 33,976 ng/mL. After 3 months of OCP therapy, their median HK level increased to 38,202 ng/mL. With OCPs, there was also a significant increase in level of FXIIa protein (P <.01), as well as an increase in cHK protein level.
This preliminary study, performed in females without HAE-C1INH, suggests that estrogen may exacerbate angioedema by increasing the production of cHK and FXIIa.
The Expanding Spectrum of Mutations in Hereditary Angioedema
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Citation Excerpt :
Although there have been no prospective studies evaluating response to therapy between these groups, it is likely that such relationships will be found because only 2 of the genes (F12 and KNG1) involve the contact system whereas another involves the fibrinolytic system (PLG), and 2 involve the vascular system (ANGPT1 and MYOF). Furthermore, associations between single nucleotide polymorphisms in the aminopeptidase gene (XPNPEP2) and F12-46C/T with disease severity of HAE-FXII have been suggested.65,66 HAE-C1-INH and HAE-nC1-INH are ultrarare disorders, making pharmacogenomic associations very difficult to prove.
The evolution in the knowledge of rare genetic diseases such as hereditary angioedema (HAE) has increased at a parallel pace with the development of new molecular tools. The deficiency of C1 inhibitor (C1-INH) has been recognized as the main cause of HAE (HAE-C1-INH) since the 1960s, but the discovery of the wide spectrum of mutations affecting the C1-INH gene (SERPING1) was possible only from the late 1980s, when Sanger sequencing became available and more accessible worldwide. Nevertheless, the involvement of other genes in HAE was discovered only in 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. In the last 3 years, advanced next-generation sequencing techniques allowed the identification of mutations in 5 new genes being associated with HAE and normal C1-INH: ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate-glucosamine 3-O-sulfotransferase 6). The knowledge provided by the new era of genomic studies was pivotal in the discovery of mutations in new genes responsible for this complex pathogenesis. Genomics advances promise a better understanding of unknown mechanisms leading to HAE, the establishment of new molecular targets for novel therapeutic agents, and personalized treatment.
International Consensus on the Use of Genetics in the Management of Hereditary Angioedema
2020, Journal of Allergy and Clinical Immunology: In Practice
Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.
A cost-effective algorithm for diagnosis of hereditary angioedema with normal C1 inhibitor: Applying molecular approach to clinical practice
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Laboratory Approaches for Assessing Contact System Activation
2017, Immunology and Allergy Clinics of North America
Differential Diagnosis of Chronic Urticaria and Angioedema Based on Molecular Biology, Pharmacology, and Proteomics
2017, Immunology and Allergy Clinics of North America
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Similarly, hereditary angioedema without urticaria has historically been categorized as “type 1” resulting from a defect in the C1 inhibitor protein level, “type 2” resulting from a defect in protein function with normal or near normal C1 inhibitor protein levels, and “type 3” resulting from the disease without detected abnormal C1 inhibitor protein levels or function.5 The term “type 3” has also sometimes been used to denote a specific form of estrogen-sensitive familial urticaria that in some ethnic groups is associated with a specific abnormality in the factor XII protein.24–29 However, most clinicians who see significant numbers of patients with chronic angioedema encounter patients who do not fall neatly into any of these groups.

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: Supported by the Canadian Institute of Health Research (G.A.R.) and the Allergy, Asthma and Immunology Society of Ontario (K.B.). Q.L.D. was supported by the Heart and Stroke Foundation of Canada.

: Disclosure of potential conflict of interest: K. Binkley has received research support from the Research Institute for Fragrance Materials. The rest of the authors have declared that they have no conflict of interest.

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Immune deficiencies, infection, and systemic immune disordersGenetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Transfus Apheresis Sci

J Allergy Clin Immunol

Am J Med

Lancet

J Allergy Clin Immunol

Biochem Biophys Res Commun

Am J Hum Genet

Immunopharmacology

Peptides

Am J Hum Genet

Kidney Int

Atherosclerosis

Am J Hypertens

J Allergy Clin Immunol

Transfus Apheresis Sci

Immune deficiencies, infection, and systemic immune disorders
Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema