Cor a 9
Summary
Cor a 9 is a thermoresistant storage protein of the 11S globulin family, found in hazelnut (Corylus avellana). The allergenic acidic polypeptide chain of Cor a 9 possesses a molecular weight of 40 kDa. Cor a 9 sensitization among hazelnut-sensitized individuals has been described in Central, Southern and North-Western Europe as well as in the United States. Age-related variations in prevalence, with greater IgE-reactivity towards Cor a 9 in children than in adults, are reported. Cor a 9 possesses two important features: its ability to induce direct (primary) sensitization to hazelnut, as opposed to pollen-related sensitization, and its association with more severe clinical reactions (skin, respiratory, gastrointestinal, or even anaphylaxis). Determination of specific immunoglobulin E (sIgE) for Cor a 9 can serve as a predictive marker for clinical allergy to hazelnut with severe symptoms and could differentiate between sensitization and clinical allergy. However, the predictive ability of Cor a 9-sIgE was found to be lower than that of Cor a 14-sIgE. Combined assessment of Cor a 9 and Cor a 14 sensitization results in improved diagnostic accuracy for hazelnut allergy. Even though high sequence homology of Cor a 9 exists with several other 11S globulins, such as walnut, mustard, soybean, peanut, Brazil nut, almond, cashew nut, and pistachio, clinical cross-reactivity may not be present. Co-sensitization of Cor a 9 has been reported with 11S globulins like Jug r 4 (walnut) and Sin a 2 (mustard) as well as with 2S albumins like Jug r 1 and Ana o 2 (cashew nut).
Epidemiology
Worldwide distribution
Hazelnut allergy (Corylus avellana) is the most common tree nut allergy in Europe. According to a systematic review, this allergy accounts for about 17%-100% of the total tree nut allergies in Europe. Hazelnut allergy as well as sensitization are also frequent outside Europe, in countries such as India, Russia, Israel, Australia, Mexico and South Africa.
Cor a 9 is a seed storage protein of the 11S albumin family. In the EuroPrevall study conducted from 2005 to 2010 among 731 hazelnut-sensitized individuals in 12 European centers (central, eastern, north-western and southern countries), sensitization to Cor a 9 exhibited an overall prevalence of 9.9%. The highest prevalence was noted (18.2%-27.3%) in some cities of Central Europe (Prague [Czech Republic], Utrecht [The Netherlands], and Manchester [United Kingdom], Southern Europe (Madrid [Spain]) and North-western Europe (Reykjavik [Iceland]), while the prevalence in other cities of Central and Southern Europe was found to be <7%.
In the Netherlands, sensitization to Cor a 9 was found to be 35% in hazelnut-sensitized patients (81 children and 80 adults), while in Sweden among 220 hazelnut-allergic and asthmatic children (10-≤18 years) and young adults (>18-35 years), sensitization to Cor a 9 was 14.1% (31 out of 220). On the other hand, a study conducted in Turkey reported 72.5% (37 out of 51) prevalence of Cor a 9 sensitization, among hazelnut-sensitized children having a median age of 3.4 years.
Similarly, the prevalence of Cor a 9 among hazelnut-sensitized patients ranged from 48% to 59% in different regions of the United States (US). It was further noted that the prevalence rates decreased with increasing age.
Age-related variations in prevalence, with greater IgE-reactivity towards Cor a 9 in children than in adults, were reported in a few studies. In Belgium, sensitization to Cor a 9 was reported to be 80% in preschool children, 70% in school-age children and 43% in adults. Furthermore, 28% of infants with atopic dermatitis were also found to be sensitized to Cor a 9. A similar pattern was reported in a study conducted in Dutch children and adults, where sensitization to Cor a 9 was reported to be highest in pre-school children (65%), followed by school-going children (50%) and the adults (17%), showing severe reactions to hazelnut.
Clinical Relevance
Disease severity
Similar to other nut storage proteins, Cor a 9 possesses two important features: its ability to induce direct (primary) sensitization to hazelnut, as opposed to pollen-related sensitization, and its association with more severe clinical reactions (skin, respiratory, gastrointestinal [GI], or even anaphylaxis). As an example, the Europrevall study conducted among 731 hazelnut-sensitized individuals demonstrated a statistically significant association of Cor a 9 sensitization (p=0.025) with the prevalence of moderate-to-severe clinical presentations as stated above. In this study, Cor a 9 sensitization was present in 18.3% of patients with severe symptoms, 10.2% with moderate symptoms, and 7.2% with OAS. Also, the association of Cor a 9 sensitization with severe allergic reactions or anaphylaxis was found to be 71.4% in a study conducted among 227 children with severe allergic reactions or anaphylaxis. Similar data were collected in a study conducted in Belgium among 119 hazelnut-sensitized patients, with Cor a 9 sensitization significantly more prevalent in patients with generalized reactions (erythema, urticaria, angioedema, GI symptoms, and respiratory symptoms) as compared to patients with OAS (70% vs. 11%, p<0.05). In another study involving 220 hazelnut-allergic asthmatic patients, individuals displaying positive specific immunoglobulin E (sIgE) to Cor a 9 or Cor a 14 were found to report more generalized reactions, like GI symptoms or anaphylaxis as compared to those without Cor a 9 or Cor a 14 sensitization.
Further, sensitization to Cor a 9 was found to be associated with the presence of clinical allergy to hazelnut. This could be seen from few studies conducted in the Netherlands (n= 38), Denmark (n=155) and the US (n=42) that showed higher Cor a 9 sensitization in hazelnut challenge (double-blind placebo-controlled food challenge [DBPCFC])-positive patients than in challenge negative individuals. However, in a Turkish pediatric cohort, Cor a 9 sensitization was similarly frequent in hazelnut-sensitized children passing (19/26, 73.1%) or failing (18/25, 72%) an oral challenge.
Cross-reactive molecules
Clinical cross-reactivity may be expected among homologous seed storage proteins, such as 2S albumins, 7S globulins, 11S globulins or oleosins as they may share common IgE epitopes or due to sequence or structural similarity. Co-sensitization of Cor a 9 with the 2S albumins Jug r 1 (walnut) or Ana o 3 (cashew nut) may be present as observed in a study conducted among 10,503 hazelnut-sensitized individuals in the US. Moderate co-sensitization was reported between Cor a 9 and Jug r 1 of walnut (correlation coefficient=0.5) and Ana o 3 of cashew nut (correlation coefficient=0.5).
A study conducted on 13 walnut and/or hazelnut-allergic patients revealed that walnut allergy or serological reactivity to walnut may place the patients at potential risk of developing hazelnut allergy due to cross-reactivity between their seed storage proteins i.e., Cor a 9, Cor a 14 and Jug r 1. Further, co-sensitization of Cor a 9 with the 11S globulin of walnut (Jug r 4) was also observed in another study among 10 Jug r 4-sensitized subjects with walnut allergy.
Cor a 9 and peanut 11S globulin Ara h 3 are not found to be significantly cross-reactive, as demonstrated in a study investigating peanut and hazelnut molecular profiles in 114 hazelnut-allergic patients, of whom 48% were also confirmed as peanut-allergic. Co-sensitization between Cor a 9 and Ara h 3 was virtually absent in hazelnut-allergic patients without peanut allergy, however, reached up to ~10% in peanut-allergic patients with no hazelnut allergy, and to even 30% in patients with both hazelnut- and peanut-allergy.
Furthermore, 11S globulins of mustard (Sin a 2) and hazelnut (Cor a 9) were reported to be cross-reactive in a study conducted among 34 mustard-allergic patients.
Diagnostics
Disease Severity
Determination of sIgE for Cor a 9 can serve as a prediction marker for clinical allergy to hazelnut with severe symptoms which holds true even in regions with less birch pollen-sensitization as reported by a study conducted on 82 individuals in Finland.
The predictive capacity of Cor a 9 determination was confirmed by DBPCFC test conducted on 8 children. The specificity and sensitivity of IgE estimation to differentiate between sensitization and clinical allergy were found to be 72% and 100%, respectively. Another study in Denmark reported the specificity and sensitivity of Cor a 9-sIgE to be 82.7% and 62.9%, respectively. However, Cor a 9-sIgE was also found in some hazelnut-tolerant individuals. Thus, it was suggested that Cor a 9-sIgE may be less specific than Cor a 14-sIgE. Furthermore, the predictive ability of Cor a 9-sIgE was best observed at a cut-off value of 1.0 kUA/L as reported in a meta-analysis involving 8 studies. However, it was suggested that rather than an independent test, the predictive ability of Cor a 9-sIgE could be enhanced by combining it with Cor a 14-sIgE and thus alleviate the risk of misclassifying patients.
Exposure
The main route of exposure is through ingestion.
Cross-Reactivity
Clinical cross-reactivity or co-sensitization may be expected among different 11S globulins owing to high sequence identity or similarity. However, such structural or sequence homology may not necessarily translate into clinical cross-reactivity.
Cor a 9 shares significant sequence homology with other 11S globulins such as Jug r 4 of walnut (63%), Ara h 3 of peanut (67%), Sin a 2 of mustard (66%) as well as Gly m 6 of soybean, Ana o 2 of cashew nut, Ber e 2 of Brazil nut, Pru du 6 of almond and Pis v 2 of pistachio (46-70%).
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