The present analysis identified common variants in CHRNB2
associated with nausea severity at 21 days of use of varenicline for smoking cessation. The presence of the minor allele in these variants is associated with reduced levels of reported nausea. The prevalence of the CHRNB2
minor alleles ranges from 6.6% to 24.5% in this treatment seeking sample. For the rs2072660 minor allele (C), allele frequencies of 0.21, 0.23, 0.29 and 0.54 are observed in HapMap29
samples JPT, CEU, CHB and YRI, respectively, suggesting that approximately 50% of individuals with Caucasian and East Asian ancestry, and about 15% of individuals with West African ancestry are without the rs2072660 nausea-reducing genotypes observed in this study (rs2072661 and rs4292956 are not genotyped in as many HapMap samples but have lower MAF in those samples that have been genotyped).
Ehringer and colleagues reported a relation between one of the CHRNB2
SNPs examined here (rs2072660) and feelings of dizziness or nausea (tobacco sensitivity) shortly after smoking initiation in 1068 young adults aged 17-21 years10
. The direction of the association noted by Ehringer et al
was the same as that seen here. That is, the minor allele of this SNP was associated with lower levels of sensitivity to tobacco to the first few cigarettes.
In additional studies of CHRNB2
promoter and 3′UTR variants, Ehringer et al30
assessed association with dizziness after the first few cigarettes in 1600 ever-smokers in the COGEND sample, and Hoft et al31
assessed association with subjective physical effects (including dizziness and nausea) following cigarette smoking in a controlled laboratory environment in a sample of 316 adult daily smokers. While Ehringer et al
did not observe association of CHRNB2
SNPs with dizziness in the COGEND sample, Hoft et al
report association of a CHRNB2
promoter variant (rs2072659) with physical effects. S
ignificant association with sweating, heart pounding and nausea (three of six components of the physical effects score) were identified in post-hoc
In contrast, Conti et al
reported rs2072660 and rs2072661 significantly associated with the likelihood of abstinence and the severity of withdrawal symptoms in a placebo-randomized trial of bupropion therapy for smoking cessation, with the minor alleles inversely associated with abstinence and positively associated with severity of withdrawal symptoms11
. Another investigation showed the major allele of rs2072660 to be associated with an increased number of days of abstinence following treatment with nicotine patch32
. Etter et al33
, on the other hand, found no association between variation in this SNP and nicotine dependence or smoking behavior. A number of other papers have also reported null associations between variation in CHRNB2
3′UTR variants and nicotine dependence34-37
or smoking behaviors38, 39
. The rare variant analyses at CHRNB2
values ranging from 0.06 to 0.44. Thus, the possible contribution from rare variants at CHRNB2
to 21 day nausea severity requires further study, e.g., resequencing of additional samples and/or in silico
assessment of rare variant function.
While animal models of nausea have been difficult to establish for a variety of reasons including a lack of definitive knowledge of neural circuitry for nausea in humans40
, conditioned taste aversion (CTA) paradigms may be one potential model to study the aversive effects of drugs at high doses. Studies involving wild type and CHRNB2
knockout mice revealed that while nicotine produced CTA in both genotypes, the magnitude of the effect was less in the mutant mice, thereby implicating the CHRNB2
subunit in the taste aversion effects of nicotine41
Nausea in humans can be generated peripherally by toxic materials within the lumen of the gut from which abdominal vagal afferents project to the dorsal brainstem via the nucleus tractus solitarius (a structure in the brainstem that receives inputs from visceral sensations including taste) and/or the area postrema (a structure in the medulla that controls nausea and vomiting). Accumulating data indicate that small intestinal (myenteric) neurons in the intestinal (enteric) nervous system possess not only somatodendritic nAChRs, which mediate cholinergic transmission between neurons, but also presynaptic nAChRs. Myenteric motor neurons express a large number of nAChR subunits including α3, α5, α7, β2 and β48
which comprise the nAChRs upon which varenicline exerts action.40
Nausea in humans can also be generated centrally as a consequence of the absorption of toxic materials (including drugs) with direct actions on the area postrema.40
It is possible that varenicline results in nausea as a consequence of its agonist effects on presynaptic α4 and α6-containing receptors involved in the regulation of dopamine release in the striatum42
. Although nausea and emesis have been observed in Parkinson's patients taking dopaminergic agonists43
, the precise pathway by which this might occur is unknown9
. A recent paper describing the results of a randomized clinical trial of the potent α4β2 neuronal nicotinic agonist, ABT-594, in the context of the management of pain associated with diabetic peripheral neuropathy44
, found that treatment emergent adverse events (including nausea, dizziness, and vomiting) were very high and three to four times more common than that seen in the placebo condition. These authors concluded that this profile is consistent with that seen for α4β2 agonists as a drug class and that the CHRNB2
subunit, in particular, could partner with other alpha subunits to form a functional receptor that influences autonomic ganglia. Because nicotine has a high affinity for α4β2 receptors, it is interesting to note here that nausea and dizziness are also commonly reported following smoking of the first cigarette in naïve individuals who later become smokers 45-47
Implications for the pharmacogenetic management of varenicline-related nausea
There is evidence that not completing approved cessation pharmacotherapy is associated with relapse to smoking48
. The present analysis revealed that the experience of nausea early in the recommended course of treatment with varenicline impacted negatively a number of indicators of adherence and outcome later in the course of treatment. These indicators include smaller proportion of varenicline pills taken, fewer total days taken the pills, increased chances of complete discontinuation, and an increased chance of relapse at 12 weeks. These results suggest that the early identification of risk for nausea and preemptive treatment could further maximize the clinical effectiveness of varenicline.
One possibility could be to provide an inexpensive test for genotyping relevant nAChR
variants prior to the onset of taking varenicline to personalize therapy. Those with CHRNB2
minor alleles could receive the standard course of treatment with the usual rate of titration to the full dose (1mg bid). Those with CHRNB2
major alleles could: 1) be encouraged to consistently take varenicline with food and water; 2) receive a more extended course of titration from the lower to the higher sustained dose (perhaps up to two weeks); 3) remain at the lower dose for the entire course of treatment; or 4) in cases of extreme sensitivity, be prescribed a concomitant therapeutic agent to reduce nausea such as a 5-hydroxytryptamine receptor 3 (HTR3
) or neurokinin receptor 1 (NK1R
. At this stage of knowledge, however, randomized, prospective pharmacogenetic trials are needed to determine the effectiveness of such approaches to the preemptive management of nausea and whether doing so results in desired clinical outcomes (decreased stopping of the medication, improved adherence, and higher overall quit rates).
Potential limitations of the study include its reliance on self-report for medication adherence and smoking outcomes. Because this open-label study was conducted in a real-world setting and utilized telephone and mailed data collection methods, more intensive monitoring was not feasible. The direct inquiry of the experience of nausea at each follow-up is different than the method used to assess side-effects in a standard clinical trial, and could result in a higher frequency than previously reported. Finally, DNA samples were not obtained from all members of the COMPASS study. While there were no differences in reported nausea severity at 21 days between those who did and did not provide a biospecimen for genotyping, those who did so were significantly older than those who did not. Since nausea severity at 21 days was associated negatively with age (younger participants reported higher nausea), it is likely that the strength of the observed associations between nausea and correlates (genetic and otherwise) was attenuated.
The possibility that nausea is directly produced by agonism of CHRNB2
receptors by varenicline will need to be confirmed through analysis of gene-nausea associations in another clinical trial setting. Moreover, other plausible explanations of the association observed here exist will also need to be examined. It is possible, for example, that variation in CHRNB2
enhances the nausea associated with smoking abstinence even in the absence of varenicline, although, at present, there is insufficient evidence to view nausea as a specific abstinence effect49
. This could be examined in a clinical trial arm that involves behavioral counseling paired with placebo medication. While the occurrence of nausea is much lower for other smoking cessation medications such as nicotine replacement therapy and bupropion (approximately 10% of users50, 51
), the specificity of the association could also be determined by examination of the gene-nausea association in the presence of these medications. A second possibility that will require further research is that CHRNB2
variation contributes to nausea in individuals who smoke while also taking varenicline. Laboratory studies of the effects of varenicline in the presence and absence of concurrent smoking could be conducted under controlled conditions to examine this hypothesis. A number of side effects, in addition to nausea, have been reported following use of varenicline. Any one or combination of these could result in lower levels of patient adherence to the recommended regimen, thereby reducing varenicline's overall effectiveness in clinical settings. Because varenicline is one of the most effective medications currently available for smoking cessation when taken as prescribed
, further investigation of the relation between the complete side effect profile and its subsequent impact on adherence is warranted.