Genes and Immunity (2002) 3, 220–224 2002 Nature Publishing Group All rights reserved 1466-4879/02 $25.00 www.nature.com/gene Polymorphism in the STAT6 gene encodes risk for nut allergy MM Amoli1, S Hand2, AH Hajeer3, KP Jones4, S Rolf4, C Sting5, BH Davies5 and WER Ollier1 1The Centre for Integrated Genomic Medical Research, Manchester University Medical School, Stopford Building, Oxford Road, Manchester M13 9PT, UK; 2Prince Charles Hospital, Merthyr Tydfil CF47 9DT, Wales UK; 3Department of Pathology and Laboratory Medicine (1122), King Fahad National Guard Hospital, PO Box 22490, Riyadh 11426, Kingdom of Saudi Arabia; 4University of Wales Institute Cardiff, Western Avenue, Cardiff CF5 2YB, Wales UK; 5Llandough Hospital, Penarth CF64 2XX, Wales, UK Nut allergy is an important and potentially life threatening food allergy with a prevalence of one in 150 children in the UK population. STAT6 (signal transducer and activator of transcription) is an important molecule in the induction and regulation of an allergic response, which maps to chromosome 12q in a region previously linked with total serum IgE concentration and atopy in different populations. We have examined the frequency of a single nucleotide polymorphism (SNP) in the 3ЈUTR region of STAT6 gene in 71 UK Caucasoid patients diagnosed with nut allergy and 45 atopic patients without nut allergy using PCR-RFLP and compared these with 184 UK healthy controls. The STAT6 G allele frequency was significantly increased in nut allergy patients compared with blood donor controls (P Ͻ 0.0001, OR = 2.9, 95% CI: 1.7–4.9), which was under a recessive model (GG vs GA+AA, P = 0.0001, OR = 3.2, 95% CI: 1.7–5.8) but not in atopic patients without nut allergy. The G allele was most frequent in the severe cases and GG homozygosity was associated with the increased risk of severe reaction (OR = 3.9, 95% CI: 1.9–8.3). We conclude that STAT6 3ЈUTR polymorphism is associated with susceptibility and severity in nut allergic patients in our population. Genes and Immunity (2002) 3, 220–224. doi:10.1038/sj.gene.6363872 Keywords: STAT6; polymorphism; nut allergy Introduction pathway used by IL-4 and IL-13 in IgE isotype switching and production of TH2 cytokines.10–12 In STAT6-deficient Nut allergy is a common food allergy and usually has an mice it has been observed that most IL-4-mediated func- early onset in childhood. It is frequently persistent and tions are reduced.10 Furthermore a study by Miyata et al13 1 life threatening due to the risk of anaphylactic shock. in STAT6-deficient mice demonstrated an absence of Almost 8% of children experience food allergy in the first eosinophilia and lung damage as a consequence of 2 3 years of life. According to population studies in the aeroallergen challenge. STAT6 also regulates the pro- UK the prevalence of peanut and/or tree nut allergy has duction of TH2-type cytokines by both CD4+ and CD8+ 1,3 been estimated as being one in 150 children and is the T cells, further indicating an important role of STAT6 in 4 cause of most fatal and near-fatal allergic reactions. The allergic responses.13 persistent and severe nature of nut allergy and also the It is assumed that IL-13, which has similar biological difficulty in avoiding nuts or nut products in foods activities to IL-4, can also account for the development through accidental ingestion followed by a potentially of an allergic response in the absence of IL-4 in the same fatal reaction attracts attention to this type of allergy as pathway, using STAT6 activation.14 an important clinical problem. The STAT6 gene has been mapped to chromosome TH2 type cytokines especially IL-4 have a major role 12q.15 We have recently identified a single nucleotide 5 in the induction and triggering of the allergic response. polymorphism (SNP) in the 3ЈUTR region of the STAT6 Although environmental factors are likely to play an gene16 and reported allele and genotype frequencies of important role in the development and specificity of an this polymorphism in a healthy UK population. In this allergic response, genetic factors also have been shown study we examined the hypothesis that STAT6 gene poly- 6 to be important. A region on chromosome 12q has been morphism may contribute risk for the development of shown to be linked with total serum IgE concentration nut allergy. and atopy in several different populations.7–9 STAT6 is a central molecule in the signal transduction Results Correspondence: Professor WER Ollier, The Centre for Integrated Gen- Patients characteristics omic Medical Research, Manchester University, Medical School, Stopford Building, Oxford Road, Manchester M13 9PT, UK. Table 1 shows characteristics of the nut allergic cohort E-mail: BillȰfs1.ser.man.ac.uk and the atopic volunteers. No such data are available for Received 10 December 2001; accepted 13 February 2002 the blood donor controls. The average age of the atopic STAT6 and nut allergy MM Amoli et al 221 Table 1 Characteristics of patients with nut allergy and atopic con- Table 3 STAT6 2964 G/A 3ЈUTR polymorphism allele and geno- trol groups type frequencies in nut allergy patients compared with atopic patients without nut allergy and healthy controls Controls Nut allergic Atopic patients Controls Nut allergy Atopic patients (n = 71) (n = 45) patients (without nut allergy) = = = Age (yrs) at the onset of atopy 3.2 ± 5.95 9.97 ± 6.78 (n 184) (n 71) (n 45) (mean ± s.d.) Age (yrs) at the onset of nut 9.7 ± 12.1 – GG 88 (48%)a,b 53 (75%)a 26 (58%)b allergy GA 78 (42%) 17 (24%) 16 (35%) Gender AA 18 (10%) 1 (1%) 3 (7%) Female 36 (51%) 30 (67%) G 254 (69%)c,d 123 (87%)c 68 (76%)d Male 35 (49%) 15 (33%) A 114 (31%) 19 (13%) 22 (24%) Family history of atopy n = 70 n = 42 Yes 52 (74%) 29 (69%) aP Ͻ 0.0001; bP = 0.4; cP Ͻ 0.0001 (OR 2.9, 95% CI: 1.7–4.9); dP = 0.2 No 18 (26%) 13 (31%) (OR 1.5, 95% CI: 0.7–2.8). Nut allergy severity Severe 46 (65%) – Moderate 18 (25%) – Mild 7 (10%) – mate of the true underlying relationship. The frequency of the G allele (76%) and GG homozygotes (58%) in atopic patients without nut allergy were increased com- pared with blood donor controls (69% and 48% controls was significantly higher than that of nut allergy respectively) but these differences did not achieve a level cases because of ethical issues relating to recruitment and of statistical significance. bleeding of children as age-matched controls. Most of the nut allergy patients had a history of severe symptoms of STAT6 genotype frequencies in severe nut allergy nut allergy. The percentage of patients who were skin cases prick test (SPT) and radio allergo-sorbent test (RAST) The nut allergy patients were divided to severe, moder- positive to different allergens are summarised in Table 2. ate and mild cases according to their reported reactions after the ingestion of nuts. The majority of cases in our STAT6 genotype frequencies in nut allergy patients cohort (65%) had previously experienced a severe reac- and control groups tion. The G allele was most frequent in the severe group The STAT6 G allele frequency was significantly increased (Table 4) and GG homozygosity was associated with the in the nut allergy patients compared with blood donor highest risk for a severe reaction (OR = 3.9, 95% CI: 1.9– controls (87% vs 69%, P Ͻ 0.0001, OR = 2.9, 95% CI: 1.7– 8.3). The STAT6 GG genotype was less associated with 4.9) (Table 3). STAT6 GG homozygosity was also signifi- mild/moderate reactions (P = 0.05, OR = 2.3, 95% CI: cantly increased in these patients compared with controls 1.0–5.5). using a recessive model (GG vs GA+AA, P = 0.0001, OR = 3.2, 95% CI: 1.7–5.8). Unfortunately no information Total and specific serum IgE level association with was available regarding the atopic status of these controls STAT6 polymorphism in different populations and previous studies suggest that the prevalence of There was no significant difference in mean total or spe- allergy to environmental allergens may be considerable.17 cific IgE level in patients with the GG genotype compared This suggest that using such controls would make it more with to those with other genotypes. When nut allergy and difficult to demonstrate a genetic association with atopy atopic patients were combined a small increase in median and any association found is likely to be an underesti- total serum IgE level was observed in patients carrying Table 2 Percentage of nut allergy patients with a positive skin prack test (SPT) and radio allergo-sorbent test (RAST) to nuts and other allergens. Mean scores have been given for SPT and RAST tested for each antigen SPT No. % Mean ± s.d. RAST No. % Mean ± s.d. Peanut 71 79 4.6 ± 3.3 Peanut 69 71 2.6 ± 1.9 Brazil nut 71 58 3.2 ± 4.1 Hazelnut 69 48 1.1 ± 1.2 Walnut 71 54 2 ± 2.6 Brazil nut 69 48 1.2 ± 1.4 Hazelnut 71 49 1.9 ± 2.1 Almond 69 32 0.5 ± 0.8 Pecan nut 71 78 2 ± 2.1 Pecan nut 68 32 0.8 ± 1.3 Cashew nut 71 39 1.6 ± 2.5 Cashew nut 69 34 0.7 ± 1.1 Almond 71 65 2.4 ± 1.9 Walnut 68 40 0.7 ± 1.2 Mite 69 91 4.3 ± 2.3 Grass 70 86 4.8 ± 2.8 Cat 69 69 3.3 ± 2.5 Apple 57 19 0.4 ± 0.9 Soy 57 42 0.9 ± 1.3 Birch 59 37 1.1 ± 1.9 Scores have been given based on measurement of 2 mm greater than the positive control for SPT and 2 units above the standard unit for RAST test.