Is toll‐like receptor 6 or toll‐like receptor 10 involved in asthma genetics – or both?

The genetics of bronchial asthma is highly complex, approximately 70 genes having been implicated by genetic association studies so far. The identification of susceptibility genes for asthma is hampered by genetic heterogeneity, incomplete penetrance, high phenocopy rate, epistatic effects and interactions with environmental factors. Yet another complicating factor lies in the structure of the genome itself, as exemplified by recent association studies with toll like receptor (TLR) genes. The TLRs are involved in the innate immune system. They recognize so-called pathogen-associated molecular patterns (PAMPs) and initiate the production of various pro-inflammatory cytokines and chemokines. So far 10 different TLR have been identified in humans. Common polymorphisms within either TLR10 (1) and TLR6 (2, 3) have been independently found to be in association with bronchial asthma in different populations. However, it is important to realize that both genes are located at nomore than 58 kb distance on chromosome 4p14: thus, apparent association with one gene might just be determined by proximity to the other gene. In order to determine whether TLR10 or TLR6, or even both genes, are involved in asthma genetics, we performed genotyping of polymorphisms within both genes on asthmatics and controls by restriction fragment length polymorphisms. The asthmatic population included 322 children with doctordiagnosed asthma and proven bronchial hyperreactivity as defined as a fall in forced respiratory volume in one second by at least 15% on provocation with histamine or exercise using standard protocols. The controls were 270 randomly chosen individuals [for more details on population’s recruitment see (4)]. The study was approved by the local Ethic Committee. Two polymorphisms within TLR6 and seven within TLR10 were genotyped (see Table 1 for their identification numbers, as well as their position on chromosome 4 and within the respective gene). Thus, all three polymorphisms previously described in association with asthma were included in our study. The frequency of the polymorphisms in both populations is also shown in Table 1. Statistical analyses of single polymorphisms were conducted by the Armitage’s trend test as implemented in de Finetti. None of the polymorphisms showed associated with bronchial asthma (see Table 1 for the P-values). However, haplotype analyses spanning both genes by FAMHAP [see (4) for more information] revealed association with asthma (P 1⁄4 0.0065). The weak association might not be surprising due to the above mentioned complexity of asthma genetics. However, another finding might be important in regard to previous association studies: calculation of linkage disequilibrium (LD) between all polymorphisms by Arlequine revealed very tight LD. In fact, all polymorphisms in TLR6 and TLR10 previously found in association with asthma were in total LD in controls and asthmatics (P 1⁄4 0.00000 for all possible pairs). The strong LD between both genes as found by us is supported by a study on prostate cancer in the Swedish population. Here, partially different polymorphisms within both genes were typed, but again TLR6 and TLR10 polymorphisms were in tight LD (5). Finally, tight relation of both genes is demonstrated by recent data obtained within the International Hapmap Project (http:// www.hapmap.org). Thus, it is not possible to distinguish which one of the neighbouring genes (or perhaps even AL LERGY 2 0 0 6 : 6 1 : 6 4 9 – 6 5 1 • a 2006 THE AUTHORS • JOURNAL COMPILAT ION a 2006 BLACKWELL MUNKSGAARD • CONTRIBUT IONS TO THIS SECT ION WILL NOT UNDERGO PEER REVIEW, BUT WILL BE REV IEWED BY THE ASSOCIATE EDITORS •