A study that sequenced all genes encoding nicotinic receptor subunits has demonstrated that the low-frequency coding variants R37H in CHRNA3 and T375I and T91I in CHRNB4 decrease the risk for nicotine dependence among regular smokers (55). It further showed that the minor allele of each polymorphism increases the cellular response to nicotine (β4T375I p = 0.01, β4T91I p = 0.02, α3R37H p = 0.003), but the largest effect on in vitro receptor activity was seen in the presence of both CHRNB4 T91I and CHRNA3 R37H (p = 2 × 10−6), two SNPs in strong linkage disequilibrium in human populations (r2 = 0.89, n = 2,035 European Americans; r2 = 0.59, n = 710 African Americans).
