Pharmacogenetics Of Muscarinic Receptor Antagonists

Anticholinergic agents have shown efficacy in the treatment of chronic airway obstruction and have shown utility in the treatment of asthma. The M2 and M3 muscarinic receptor genes provide rational candidate genes, which might alter responses to muscarinic receptor antagonists. The M2 receptor gene (CHRM2) is located on chromosome 7q35-36 and several polymorphisms have been described within the CHRM2 gene, including two degenerate SNPs (1197T/C Thr-Thr, 976A/C Arg-Arg), a 3' UTR (1696T/A) SNP (55) and a CA repeat and C/A SNP in the promoter region (56). Functional effects have been described with different alleles of the promoter CA repeat in transfection studies, but no clinical studies have been performed to date. The M3 receptor gene (CHRM3) is located on chromosome 1q41-q44, and the coding region is contained within one exon. Several polymorphisms have been described including: — 708A/G, — 627G/C, — 513C/A, 492C/T, a CTTT repeat, and a GT repeat (57). Functional data are not currently available on these polymorphisms. In summary, therefore, the significance of individual polymorphism or haplotypes in determining the efficacy of anticholinergic therapy remains to be resolved. These genes are also likely to be of interest outside the area of respiratory disease, for example, in CNS disorders including endogenous depression.

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