Functionally significant nicotine acetylcholine receptor subunit α5 promoter haplotypes are associated with susceptibility to lung cancer in Chinese

Abstract

BACKGROUND: Although recent genome-wide association studies have been conducted to reveal the relation between variations in the α5 nicotinic receptor subunit and lung cancer in European and American populations, to the authors' knowledge, no definite information on the role of nicotine acetylcholine receptor subunit α5 (CHRNA5) in lung cancer risk has been obtained in a Chinese population. METHODS: To test this possible association, a case-control study was conducted in 505 patients with lung cancer (cases) and a control group of 498 cancer-free individuals. RESULTS: Participants were screened for variations in the CHRNA5 promoter region by sequencing, and 2 common polymorphisms were selected at -1640 (reference single nucleotide polymorphism identifier rs3829787 cytosine to thymine [C→T]) and at -62 (rs3841324 insertion→deletion [ins→del]) from the transcription start site of the CHRNA5 gene. Haplotype analysis revealed that the 2 least frequent haplotypes (T/ins and C/del) were statistically protective against lung cancer (P =.0002 and P =.0094, respectively). Unexpectedly, the luciferase results indicated that these 2 protective haplotype constructs had the extremely opposite promoter activity in various cells: the T/ins haplotype had the highest activity and the C/del haplotype had the lowest activity. Surface plasmon resonance demonstrated that both minor alleles (T and del) decreased DNA binding affinity to nuclear extracts, which the authors presumed was responsible for the disparity in promoter activity. CONCLUSIONS: The current results indicated that the CHRNA5 gene with under-activated or over-activated promoter activity may be protective against lung cancer. These results indicated a new associated risk pattern between CHRNA5 promoter activity and susceptibility to lung cancer that implies a complex role of the CHRNA5 gene in lung cancer. Cancer 2011;. © 2011 American Cancer Society. The results from this study indicated a new associated risk pattern between nicotine acetylcholine receptor subunit α5 (CHRNA5) promoter activity and susceptibility to lung cancer that implies a complex role of the CHRNA5 gene in lung cancer. Together, the findings confirm CHRNA5 as a lung cancer susceptibility gene in the Chinese population. Copyright © 2011 American Cancer Society.