Joint statistical analyses of the two loci, or haplotype analyses, that mark both these biologic mechanisms demonstrate that the amino acid change and varying levels of RNA expression independently contribute to nicotine dependence. The variant CHRNA5 (D398N), which greatly increases the risk for nicotine dependence, lung cancer, and COPD, primarily occurs on the background of low mRNA expression of CHRNA5. The lower mRNA expression of CHRNA5 along with the non-risk allele of rs16969968 is protective for nicotine dependence and lung cancer. These functional receptor data, gene expression results, and genetic analyses point to the nicotinic receptor genes, and specifically the α5 nicotinic receptor subunit gene, as the most likely gene altering the risk for nicotine dependence, lung cancer, and COPD.
