In the UK, 2% of the adult population carry adrenaline due to prior anaphylactic reactions [2
]. The genes for Atopy, bronchial hyperresponsiveness, and asthma are being recognised and form a polygenetic pattern of inheritance but there are no links between individuals with anaphylaxis and any specific “allergy genes” [36
]. Current research is examining food allergy and conformational and sequential antibody-antigen binding sites [37
]. This may ultimately confirm a difference in IgE binding which may affect levels of histamine release and the manifestation of these reactions.
Our study demonstrates a link between ACE genotype and anaphylaxis to food, venom, and drugs, particularly for reactions that include cardiovascular collapse and severe angioedema. Here the genotype is ID and II relative to HC. These two genotypes share similar ACE activity and AI and AII plasma levels and physiological responses [14
] and are therefore likely to behave in a similar manner clinically in response to hypotension and BK metabolism [12
]. The AACVS pattern of symptoms would be very consistent with low levels of ACE activity, producing both inadequate or delayed A2 generation to prevent hypotension and impaired BK metabolism that could facilitate angioedema [11
Few patients with the DD genotype were found in the anaphylactic group, and most of those manifested cutaneous and respiratory symptoms only, which are least likely to be associated with reduced ACE activity and more likely to be related to histamine effects [11
]. The CRA group only represented 23% of the total group and so may be subject to bias.
The atopic group is smaller than the other groups and so may lack sufficient power to examine fully its relationship with healthy controls. Atopics do show an increased ID genotype population although this was not significant (P = 0.14), but may suggest that they lie somewhere between HC and anaphylaxis and warrants further investigation.
Niedoszytko et al. [38
] examined angiotensinogen (MM/MT) and ACE gene (I/D) polymorphisms in 107 patients with Grades III and IV anaphylaxis to insect venom and 113 controls. They found no difference in ACE genotypes between subjects and controls. Neither could they relate it to the conventional grades of anaphylaxis. In addition they identified polymorphisms in the angiotensinogen gene M235T resulting in low levels of angiotensinogen in 29.9% of subjects compared with 17% of controls (P
= 0.02). In grade IV anaphylaxis this frequency increased to 39% (P
= 0.001, odds ratio 2.5). Since this is the substrate for renin to generate AI this could be an important additional genetic factor in anaphylaxis.
Our serum ACE levels appear to reflect the genotype findings, with HC and atopics being similar, but anaphylaxis showing significantly lower levels especially for the AACVS subdivision. These findings fit well with those of Summers et al. [27
] who examined serum ACE levels in patients with tree/nut allergy. He found that mean ACE levels above 47
mmol/L were not associated with pharyngeal oedema, while serum ACE levels <37
mmol/L were a risk factor for pharyngeal oedema but not asthma. He suggested that since ACE levels are stable in adult life and independent of age or sex, they reflect genetic inheritance.
In women of reproductive age it is now understood that oestrogen protects against cardiovascular disease due to the inhibitory effects of oestrogen upon mRNA synthesis of ACE [39
]. This protective effect contributes to the hypotension of pregnancy as oestrogen levels climb and is lost at menopause when serum ACE levels rise unless inhibited by the use of hormone replacement therapy [40
]. This could suggest that premenopausal women effectively “inactivate a “D” gene,” through their oestrogen effects on ACE synthesis, rendering themselves more ACE deficient than men for the same genotype [39
]. This could offer one explanation as to why adult premenopausal women show an increased anaphylaxis rate compared to men; an observation which is lost after menopause.
Anaphylaxis research in rodents suggests that platelet activating factor (PAF) is involved in cardiovascular collapse in murine models of anaphylaxis which can be prevented by PAF antagonists [43
]. In PAF knockout mice, no hypotension or death in anaphylaxis occurs. PAF levels have been measured in man, and are reduced immediately following anaphylaxis [45
], but other data indicates that these levels are normal if measured away from the event. PAF maybe acting through endothelial nitric oxide (eNO), when mediating its hypotensive effect in anaphylaxis [4
]. eNO is now of interest in murine models of anaphylaxis, where chronic blockade of eNO increases expression of mRNA for renin, ACE, and AI receptors in the aorta, with the risk of hypertension [47
]. In man eNO is involved in regulation of the microcirculation but has links with RAS, BK, and renal function [6
]. Activation of RAS enhances eNO production, giving vasodilator effects on the microcirculation to protect against the vasoconstrictor effects of AII [31
]. Oestrogens have been shown to increase eNO levels and protect the circulation leading to the better renal function and resistance to renal injury observed in women [7
]. Basal AII levels exert a tonic effect on the circulation which reduces eNO [8
]. This may suggest that individuals with DD genotypes, and therefore higher basal levels of AII, would be more protected from the risk of cardiovascular collapse via eNOS and PAF in anaphylaxis [15
]. This may not be true for ID and II genotypes especially in premenopausal women, where the presence of oestrogen reduces basal AII levels giving higher levels of BK and eNOS. Vitamin D has effects on renin levels and several publication suggest a link to allergy, anaphylaxis, and Epi-Pen prescription [29
]. Renin synthesis is lowered by vitamin D at the mRNA level and is suggested to be cardioprotective in this way [30
]. Lowering levels of renin would theoretically reduce its enzymatic activity and AI generation which may reduce eNOS productions. This observation is probably minimised in our study, since nearly all subjects had vitamin D insufficiency, although the atopics and anaphylaxis groups had the lowest levels. Further work in this area would be of interest.