In a large genomewide association study to identify genetic factors that modify risk for lung cancer (LNCR2; 612052), Hung et al. (2008) found strong association of a single-nucleotide polymorphism in exon 5 of the CHRNA5 gene, rs16969968. This SNP results in the substitution of arginine for aspartic acid at the highly conserved codon 398 (D398N) of the CHRNA5 protein, located in the central part of the second intracellular loop. The SNP rs16969968 is in strong linkage disequilibrium with a SNP in the CHRNA3 gene (118503.0001) (Hung et al., 2008; Thorgeirsson et al., 2008). Wang et al. (2009) tested for cis-acting expression quantitative trait loci (eQTL) for nicotine dependence and lung cancer in the CHRNA5, CHRNA3, and CHRNB4 genes in human brain. Gene expression and disease association studies provided evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. The risk allele of rs16969968 primarily occurred on the low mRNA expression allele of CHRNA5. The nonrisk allele at rs16969968 occurred on both high and low expression alleles tagged by rs588765 within the CHRNA5 gene. When the nonrisk allele occurred on the background of low CHRNA5 mRNA expression, the risk for nicotine dependence and lung cancer was significantly lower compared to those with the higher mRNA expression. Wang et al. (2009) concluded that there are at least 2 distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by the D398N variant and variability in CHRNA5 mRNA expression. Hong et al. (2010) found a significant association (p = 0.020) between the D398N variant and smoking (188890) among 149 smokers and 148 nonsmokers (odds ratio of 1.84, p = 0.03 for 1 allele; odds ratio of 3.59, p = 0.032 for 2 alleles). The sample included individuals with psychiatric illnesses, which are associated with smoking; however, the D398N variant was not associated with psychiatric illness. Among 93 smokers and 79 nonsmokers who completed a functional MRI scan, smokers had significantly decreased functional connectivity between the dorsal anterior cingulate (dACC)-ventral striatum compared to nonsmokers, and the decrease was associated with the N389 risk allele. In addition, reduced connectivity of this circuit correlated with greater severity of nicotine addiction. Nonsmoker carriers of the N389 risk allele also showed reduced connectivity of this circuit, confirming a genetic effect independent of smoking status. Hong et al. (2010) postulated that variation in the nAChR alpha-4/beta-2/alpha-5 receptor may modulate dopamine release, which may regulate the reinforcing effects and addictive properties of nicotine. (less)

In a large genomewide association study to identify genetic factors that modify risk for lung cancer (LNCR2; 612052), Hung et al. (2008) found strong association of a single-nucleotide polymorphism in exon 5 of the CHRNA5 gene, rs16969968. This SNP results in the substitution of arginine for aspartic acid at the highly conserved codon 398 (D398N) of the CHRNA5 protein, located in the central part of the second intracellular loop. The SNP rs16969968 is in strong linkage disequilibrium with a SNP in the CHRNA3 gene (118503.0001) (Hung et al., 2008; Thorgeirsson et al., 2008). Wang et al. (2009) tested for cis-acting expression quantitative trait loci (eQTL) for nicotine dependence and lung cancer in the CHRNA5, CHRNA3, and CHRNB4 genes in human brain. Gene expression and disease association studies provided evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. The risk allele of rs16969968 primarily occurred on the low mRNA expression allele of CHRNA5. The nonrisk allele at rs16969968 occurred on both high and low expression alleles tagged by rs588765 within the CHRNA5 gene. When the nonrisk allele occurred on the background of low CHRNA5 mRNA expression, the risk for nicotine dependence and lung cancer was significantly lower compared to those with the higher mRNA expression. Wang et al. (2009) concluded that there are at least 2 distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by the D398N variant and variability in CHRNA5 mRNA expression. Hong et al. (2010) found a significant association (p = 0.020) between the D398N variant and smoking (188890) among 149 smokers and 148 nonsmokers (odds ratio of 1.84, p = 0.03 for 1 allele; odds ratio of 3.59, p = 0.032 for 2 alleles). The sample included individuals with psychiatric illnesses, which are associated with smoking; however, the D398N variant was not associated with psychiatric illness. Among 93 smokers and 79 nonsmokers who completed a functional MRI scan, smokers had significantly decreased functional connectivity between the dorsal anterior cingulate (dACC)-ventral striatum compared to nonsmokers, and the decrease was associated with the N389 risk allele. In addition, reduced connectivity of this circuit correlated with greater severity of nicotine addiction. Nonsmoker carriers of the N389 risk allele also showed reduced connectivity of this circuit, confirming a genetic effect independent of smoking status. Hong et al. (2010) postulated that variation in the nAChR alpha-4/beta-2/alpha-5 receptor may modulate dopamine release, which may regulate the reinforcing effects and addictive properties of nicotine. (less)