Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects.
BACKGROUND
The human cholinergic receptor muscarinic-1 (CHRM1) is widely distributed in the lungs. In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation. The CHRM1 gene is located on chromosome 11q13, which is one of the candidate loci for asthma and atopy.


OBJECTIVE
To determine the role of the CHRM1 gene polymorphisms in asthma.


METHODS
We studied nine single-nucleotide polymorphisms (-18379G > A, -9697C > T, -6965T > C, -4953A > G, +267A > C, +1353C > T, +3970C > G, +5418C > G, and +5455G > T) in a case-control study using 326 patients with asthma and 333 healthy control subjects. We also examined functional consequences of the -9697C > T and -4953A > G polymorphisms at the regulatory region using an mRNA reporter assay.


RESULTS
Two common single-nucleotide polymorphisms (-9697C > T and -4953A > G) were associated with asthma. The odds ratio for the TT homozygotes at the -9697C > T polymorphism was 0.29 compared with the CC homozygotes (95% confidence interval, 0.12-0.73; p = 0.008), and the odds ratio for the GG homozygotes at the -4953A > G polymorphism was 1.86 compared with the AA homozygotes (95% confidence interval, 1.04-3.34; p = 0.038). Haplotype analysis showed that the -9697T/-6965T/-4953A haplotype was associated with a lower risk of asthma (p = 0.00055) and the -9697C/-6965T/-4953G haplotype was associated with an increased risk of asthma (p = 0.020). The -9697T/-4953A haplotype was also associated with lower luciferase activity in vitro compared with the -9697C/-4953G haplotype.


CONCLUSIONS
This study, together with an in vitro functional study, suggests that the CHRM1 gene is an important susceptibility locus for asthma on chromosome11q13.
Maeda
Yukiko
Y
First Department of Medicine, Hokkaido University Graduate School of Medicine, N-15 W-7, Kita-Ku, Sapporo 060-8638, Japan.
Hizawa
Nobuyuki
N
Jinushi
Eisei
E
Honda
Ayumi
A
Takahashi
Daisuke
D
Fukui
Yoshinobu
Y
Konno
Satoshi
S
Shimizu
Tadamichi
T
Shimizu
Hiroshi
H
Yamaguchi
Etsuro
E
Nishimura
Masaharu
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D043643:Receptor, Muscarinic M1 / Q000235:genetics*; D011976:Receptors, Muscarinic / Q000235:genetics*
C086088:CHRM1 protein, human; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic