Background:

We have previously reported an association between prenatal paracetamol exposure and asthma in ALSPAC and shown that this relation is modified by maternal antioxidant gene polymorphisms [1,2]. It was recently reported that the analgesic properties of paracetamol may be mediated by the transient receptor potential ankyrin-1 (TRPA1) channel [3]. Furthermore, animal studies have suggested that TRPA1 plays a role in airway inflammation in asthma [4] and, of relevance to our epidemiological observations, there is evidence that paracetamol can cause neurogenic inflammation in the airways through stimulation of TRPA1 [5]. Cigarette smoke induced neurogenic inflammation is also thought to be mediated by TRPA1 [6].

Aims:

To analyse the relation between maternal and child TRPA1 variants and asthma and lung function in ALSPAC and to explore interactions between TRPA1 and prenatal paracetamol and tobacco smoke exposure on childhood asthma and lung function in order to potentially strengthen causal inference and shed light on mechanisms.

Hypotheses:

1) Maternal and child TRPA1 genotype is associated with asthma and lung function in the offspring.

2) TRPA1 modifies the effects of prenatal paracetamol exposure on childhood asthma and of maternal smoking in pregnancy on childhood small airway function.

Analyses:

It has been proposed that TRPA1 alleles in ALSPAC could be inferred using SNP imputation; a list of 129 imputed SNPs has been generated (all SNPs except one which have been mentioned in the literature associated with pain phenotypes are included in this list) and the plan is to work with Dave Evans to see how best to analyse the data.

A DTA covering analysis of genetic data is already in place with QMUL.

NB: We have all other variables (maternal exposures, confounders and childhood atopic and respiratory outcomes) needed to carry out these analyses.

References:

1) Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton FD, Jones RW, Strachan DP, and the ALSPAC Study Team. Prenatal paracetamol exposure and risk of asthma and elevated IgE in childhood. Clin Exp Allergy 2005; 35:18-25.

2) Shaheen SO, Newson RB, Rose-Zerilli M, Ring SM, Holloway JW, Henderson AJ. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms and childhood asthma. J Allergy Clin Immunol 2010; 126: 1141-1148.

3) Andersson DA et al. TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid delta9-tetrahydrocannabiorcol. Nature Communications 2011; 2:551.

4) Caceres AI et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. PNAS 2009; 106: 9099-9104.

5) Nassini R et al. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J 2010; 24:4904-16.

6) Andre E et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated adehydes and the TRPA1 receptor in rodents. J Clin Invest 2008; 118: 2574-82.