How An Individual's Genetic Makeup Interacts With Nutrition, Smoking,

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Curr Cardiovasc Adventure Rep. Author manuscript; available in PMC 2011 Nov 1.

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PMCID: PMC3114454

NIHMSID: NIHMS254776

The Role of Genetics in Nicotine Dependence: Mapping the Pathways from Genome to Syndrome

James MacKillop

^one Section of Psychology, Academy of Georgia; Centre for Alcohol and Addiction Studies, Brownish Academy

Ezemenari Obasi

² Department of Counseling and Human Evolution Services, University of Georgia

Michael T. Amlung

³ Department of Psychology, University of Georgia

John E. McGeary

^four Substance Corruption Treatment Program; Providence Veterans Assistants Medical Center; Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital; Department of Psychiatry and Human Beliefs, Brown Academy

Valerie S. Knopik

^five Division of Behavioral Genetics, Department of Psychiatry, Rhode Island Hospital; Department of Psychiatry and Human Behavior, Chocolate-brown University

Abstract

Nicotine dependence continues to be a major public health trouble worldwide and there is unequivocal bear witness that genetics play a substantial role in its etiology. This review provides an overview of the testify for genetic influences and recent advances in the field. Traditional quantitative genetics studies have revealed nicotine dependence is heritable and molecular genetics studies are providing increasing evidence that the genes responsible for nicotine's pharmacokinetics and pharmacodynamics are specially important. Despite considerable progress, a number of meaning complexities and challenges remain. These include determining the specificity of genetic influences and clarifying the role of interactive contributions. One promising strategy for addressing these problems is an intermediate phenotype approach that attempts to identify the intervening proximal mechanisms that confer differential genetic adventure. Understanding these mechanisms may let more than precision in understanding genetic influences and may likewise place novel targets for intervention or prevention.

Keywords: Nicotine Dependence, Genetics, Smoking, Tobacco, Intermediate Phenotype, Endophenotype

Introduction

Cigarette smoking is the single largest crusade of preventable morbidity and mortality in the United States and the world [1]. Smoking is associated with increased hazard for lung cancer, eye disease, and chronic obstructive pulmonary disease and estimated to consequence in approximately 450,000 deaths annually in the United States solitary [2]. Reducing the prevalence of smoking via handling and prevention is a major international public health priority. For the bulk of smokers, tobacco use is specifically motivated by nicotine dependence, as nicotine is the principal compound responsible for tobacco reinforcement [3]. As such, agreement the causes of nicotine dependence is essential for decreasing the prevalence of smoking. Unequivocal evidence has demonstrated genetic factors play a substantial role in nicotine dependence, and this review provides an overview of the research in this area. Given the extensive body of work, the goal is not to be exhaustive but rather to synthesize the overall patterns of findings in humans. Nosotros use a peak-downwards arroyo, first reviewing evidence of the heritability of nicotine dependence and and then focusing on the specific sources of genetic influences. Finally, electric current challenges and the application of an intermediate phenotype approach as a promising strategy for progress are reviewed.

Quantitative Genetic Influences

Numerous quantitative genetic studies accept demonstrated a substantial genetic contribution to many aspects of smoking behavior and nicotine dependence. The quantitative approach incorporates family, adoption, and twin designs that capitalize on the comparison of relatives that differ in levels of genetic relatedness. For example, early twin studies simply compared cyclopedia of smoking behavior in monozygotic (identical) and dizygotic (congenial) twin pairs. More contempo approaches to twin analyses comprise statistical models that allow parameter estimation of genetic and environmental contributions to individual differences in the predisposition to smoking and related behaviors (for a review, meet Rose et al. [4••]). This genetic contribution, or heritability, is population and fourth dimension specific and tin can exist defined equally the proportion of the total phenotypic variance that is due to genetic effects. Heritability can reflect not only sampling variability, but likewise true variation due to multiple factors affecting smoking prevalence and the likelihood that a genetic predisposition can become manifest. Such factors might include nascency cohort, religiosity, family structure and status, parental smoking history, socioeconomic conditions, and availability of tobacco. Importantly, the heritability of the clinical phenotype of nicotine dependence remains consistent (~50%) beyond many studies, assessment measures, and cultures [4••], as does the heritability of volumetric tobacco consumption (eg, cigarettes per twenty-four hour period), which is also estimated at virtually l% [four••].

Another strategy for examining the heritability of smoking behavior is to parse its chronology, examining both initiation and persistence. In a meta-analysis of 16 such studies, Li et al. [five] found both phenotypes were substantially heritable only also observed potentially meaningful sex differences. Across studies, the heritability of smoking initiation was 39% for men and 55% for women, whereas the heritability of smoking persistence was 59% for men and 46% for women. Thus, genetic influences appear to play a larger role for women in terms of starting to smoke and are more important for men when because smoking progression. However, a more than recent review that included several new studies with larger samples supported the testify of substantial genetic influences on both smoking initiation and persistence merely not sexual activity differences [4••]. Moreover, there is trivial show of mutual genetic effects that influence both initiation and persistence [vi], suggesting that in that location are genetic processes contributing to experimentation and initiation that are distinct from those influencing maintenance of a longstanding habit. There is likewise evidence of significant differences in heritability based on age. Specifically, genetic effects tend to be stronger as age increases [7], suggesting that ecology factors contribute early in life and genetic factors predominate later in life.

In sum, quantitative genetic studies take made, and keep to make, major contributions to our cognition of the genetic epidemiology of smoking behavior and nicotine dependence. There is a substantial genetic contribution to these behaviors that consistently accounts for roughly half of the phenotypic variance; all the same, there do appear to be meaningful differences in the genetic contribution beyond the lifespan. Further, whereas genetic factors significantly influence both smoking initiation and persistence individually, in that location is no evidence of a significant genetic contribution to the covariation betwixt these ii phenotypes.

Molecular Genetic Influences

Beyond evidence of latent condiment genetic effects, which provides no information about what specific genes are involved, there is an increasing understanding of the private molecular variants that confer risk for nicotine dependence. The nigh consistent evidence suggests that the genes responsible are those associated with differences in nicotine's pharmacokinetics (ie, metabolic capacity) and pharmacodynamics (ie, central nervous system neurotransmitter functionality). A model of these influences is presented in Effigy 1, including the master metabolic pathways, neurotransmitter systems, and a number of illustrative candidate genes.

A model of the office of genetics in nicotine dependence via alterations to nicotine'due south pharmacokinetics and pharmacodynamics

Using continuous arrows, the pharmacokinetic pathways (blue) reflect the metabolic transformations of nicotine that make up one's mind its cardinal and peripheral nervous arrangement bioavailability and the pharmacodynamic pathways (green) reflect nicotine'south molecular pharmacological effects on nicotinic acetylcholinergic receptors (nAChRs) and other neurotransmitter systems. Candidate genes (orange) and their points of putative influence are depicted using dashed arrows. Note that this is a simplified model of nicotine's pharmacokinetics and pharmacodynamics, and the candidate genes presented are illustrative examples, not an exhaustive list.

Genetic variation influencing nicotine pharmacokinetics

Nicotine'due south pharmacokinetics are relatively well understood. Approximately 75% of nicotine is metabolized into cotinine, which is itself partially metabolized into trans-3′-hydroxycotinine. In both cases, these conversions are catalyzed past liver cytochrome P450 enzymes (CYPs), primarily the CYP2A6 enzyme. The efficiency of this metabolic pathway varies considerably across individuals and is substantially influenced by genetic variation (for a review, see Mwenifumbo and Tyndale [8]). Twin studies signal approximately 60% of the variability in nicotine metabolism is attributable to genetic factors [9]. The major genetic contributor to variation in this pathway is the enzyme's eponymous cistron, CYP2A6, which is function of a cluster of six CYP genes and is highly polymorphic. The most common ("wild-type") allele is designated CYP2A6*i, and an array of other polymorphisms have been identified, including deletions, duplications, insertions, and single nucleotide polymorphisms (SNPs). The functional effects of many of these polymorphisms are unknown but a number of them essentially reduce enzymatic metabolism of nicotine and others increment nicotine metabolism. In terms of magnitude, CYP2A6 has major effects on metabolic capacity; individuals who are homozygous for the cistron deletion exhibit approximately 400% greater levels of nicotine, and possession of 1 decreased-activity allele has been found to exist associated with approximately 50% lower enzymatic activity [viii]. These differences are striking, merely there is also substantial variation amidst wild-type carriers [10], suggesting the importance of other sources of variation, genetic or otherwise.

Possession of a decreased-action allele has been found to be by and large protective, with individuals existence less likely to smoke and, amid smokers, associations with lower cigarette consumption and greater probability of successful smoking abeyance [11, 12]. In addition, in a laboratory written report on smoking topography, individuals with decreased-activity alleles exhibited significantly lower puff volume and total puff volume, although non number of puffs [xiii]. Even so, a number of studies have not identified systematic differences based on CYP2A6 genotype, creating an overall blueprint of mixed findings (for a meta-assay, see Munafò et al. [fourteen]).

A second candidate in this pathway is CYP2B6, which also metabolizes nicotine in the liver, admitting less efficiently than CYP2A6 [8]. The office of CYP2B6 has not been extensively investigated, and the published studies on its relevance are mixed [15, 16]. Of note, a particularly interesting recent finding is that CYP2A6 and CYP2B6 genotype collaborate in relation to nicotine metabolism. A two-locus CYP2B6 haplotype has been associated with faster nicotine metabolism and was more than pronounced for individuals with decreased activity CYP2A6 genotypes [17]. This suggests CYP2B6 may be particularly of import for agreement variability in individuals with decreased CYP2A6 activity.

Although considerably less studied, there are other aspects of nicotine'south pharmacokinetics that may also be meaningfully affected by genetics. A small percentage of nicotine is metabolized into nicotine Due north′-oxide by flavin-containing monooxygenase 3 (FMO3) and excreted in urine. Moreover, individuals who are homozygous for the CYP2A6 gene deletion excrete about four times more nicotine this way [18], indicating an culling metabolic pathway. Considerable inter-private variability is evident in this pathway and a large number of polymorphisms accept been identified in the FMO3 gene, only no studies to date have investigated FMO3 genotype in relation to nicotine dependence. Finally, another process in nicotine metabolism is the glucuronidation of nicotine, cotinine, and trans-3′-hydroxycotinine to facilitate urinary excretion. Glucuronidation takes place via uridine-diphosphate glucuronosyltransferase enzymes (UGTs) and for which very high levels of variability in activeness are axiomatic [eight]. This is a 2nd alternative metabolic route for individuals who are homozygous for CYP2A6 deletions. The specific enzymes are UGT2B10 (nicotine and cotinine) and UGT2B7 (trans-3′-hydroxycotinine), and numerous polymorphisms in the UGT2B subfamily of genes accept been identified. Moreover, the UGT2B10*two allele has been associated with reduced nicotine and cotinine glucuronidation [19], making it a promising candidate.

Genetic variation influencing nicotine pharmacodynamics

The molecular pharmacology of nicotine'south psychoactive furnishings is via direct and indirect furnishings of nicotinic cholinergic receptor (nAChR) excitation (for a review, come across Benowitz [20]). Nicotine straight enhances cognitive functioning, such equally attention, learning, and retentiveness, via nAChR stimulation. In addition, nAChR excitation provokes burst firing in subcortical dopamine-secreting neurons that are part of the mesocorticolimbic DA pathway. The dynamic increment in dopamine is believed to be responsible for the reinforcing furnishings of nicotine and its addiction potential. Indeed, all addictive drugs commonly actuate this dopaminergic circuitry [21]. In improver to nAChR-mediated increases in dopamine, nicotine also augments dopamine release via glutamatergic, GABAergic, and opioidergic mechanisms. Over time, chronic nicotine exposure leads to neuroadaptive receptor upregulation and greater nicotine-elicited dopamine release, further strengthening dependence [twenty].

Genetic variation that contributes to functional differences within these circuits is both a logically plausible source of altered risk for nicotine dependence and 1 for which at that place is also considerable empirical evidence. The most robust findings to date have implicated variation in the genes that are responsible for nAChRs. Pharmacologically, nAChRs are composed of varying combinations of five α and β subunits. Functionally, nAChR subtypes vary widely, only the α4β2 nAChRs have a especially high analogousness for nicotine. Indeed, there is evidence that α4 subunit nAChRs are sufficient for nicotine reinforcement, tolerance, and sensitization [22], and functional neuroimaging has revealed that experiential satiation from smoking closely scales to α4β2 occupancy [23]. Moreover, a number of studies take institute that variation in CHRNA4, the α4 subunit gene, influences nicotine dependence [24••]. In addition, potentially of import genetic variation in cholinergic neurotransmission has been identified in a cluster of genes responsible for the α5, α3, and β4 nAChR subunits [25, 26]. One locus (rs16969968) in the α5 subunit gene, CHRNA5, appears to be specially of import, with a recent meta-analysis revealing a highly meaning association with smoking level in over 38,000 smokers (P < 10⁻³⁵) [27••].

Across cholinergic genes, a 2d logical target is genetic variation in the other neurotransmitter systems associated with nicotine'southward pharmacodynamics, such as the dopamine and endogenous opioid systems. In the outset case, dopamine is enzymatically broken downward past dopamine β hydroxylase and catechol-O-methyltransferase, which are encoded by the DBH and COMT genes, respectively. A number of studies take institute associations between polymorphisms in DBH and COMT and nicotine dependence or other smoking-related phenotypes [28, 29]. In addition, polymorphisms in or linked to the genes encoding the dopamine receptor subtypes take been associated with smoking status and motivation for cigarettes [30–33], as well as smoking cessation treatment consequence [34]. With regard to opioid neurotransmission, although there have been fewer studies, at that place is prove for associations between polymorphisms in the μ opioid receptor gene, OPRM1, and several smoking phenotypes, including initiation of smoking [35], the reinforcing value of smoking [36], and handling outcome [37].

The preceding genes and polymorphisms are by no means the only ones associated with nicotine dependence, only they reverberate the findings for which at that place is the greatest convergence of evidence. Many additional loci have as well been identified, especially in contempo studies using high-throughput genotyping technologies, such as genome-broad association studies. These studies tin can assess millions of polymorphisms at once and accept both supported the relevance of loci in the preceding systems and implicated a number of heretofore unidentified loci [38]. It is likewise of import to notation, withal, that there accept been many failures to replicate results, and there take even been significant findings in opposite directions, leading to an often conflicting and inconsistent literature [fourteen]. Moreover, where there are relatively reliable associations, the magnitudes of effects tend to be small. Equally such, there is footling evidence of a "nicotine-dependence gene" or fifty-fifty a pocket-sized number of high-touch on variants that largely explain its high heritability. Instead, risk for tobacco dependence appears to be conferred by a large number of genetic polymorphisms of relatively small magnitude furnishings, and even this estimation cannot be conclusive in low-cal of a number of persistent challenges.

Complexities and Challenges

There are a numerous complexities to understanding the genetics of nicotine dependence, just we focus on two of the almost pregnant problems, namely, ambiguity virtually the specificity of genetic influences and uncertainty about the extent to which interactive relationships play a function. These bug accept the potential to be the largest causes of inconsistency in the field and unraveling them will be necessary to make a total account of genetic influences.

In the offset instance, specificity refers to the extent to which genetic influences directly alter hazard for nicotine dependence but not other characteristics or conditions. A highly specific take a chance variant would only increase or decrease the probability of developing nicotine dependence, whereas a relevant but nonspecific variant might be tangentially related to nicotine dependence past altering risk for other variables that are probabilistically relevant to tobacco employ. Characterizing specificity is non just important for validly understanding the part of a given variant, but it is methodologically essential because nonspecific variants could introduce "tertiary variable" confounds (ie, unmeasured variables that are causally responsible for associations spuriously observed betwixt 2 other variables). From a statistical standpoint, this is a problem because the significance of an association study would depend on the frequency of the unmeasured variable. This would consequently be expected to generate mixed findings based on samples with dissimilar latent characteristics on the unmeasured variable and to underestimate the magnitude of the influence by inadvertently combining individuals for whom it is relevant and those for whom it is non. Moreover, it is likewise possible that a locus exist associated with an entirely unrelated variable. A prototypic instance of this is population stratification [39], which is a confounding of the phenotype of involvement with racial/indigenous status and, in plough, spurious associations with polymorphisms that also systematically vary by race or ethnicity.

Unfortunately, it is often an implicit supposition that there is a relatively high level of specificity between genetic factors and nicotine dependence, but there is a strong empirical basis for a large portion of genetic heritability to come from indirect influences. First, from a purely epidemiologic standpoint, nicotine dependence is comorbid with a number of psychiatric atmospheric condition, such every bit depression, schizophrenia, and substance use disorders [xl], which are also genetically influenced and would be expected to indirectly affect motivation to fume. 2nd, twin studies take identified large nonspecific genetic furnishings on substance use disorders and conduct disorder/antisociality [41] and shared genetic effects on licit substance utilize (tobacco and alcohol) [42]. Third, every bit noted in a higher place, all addictive drugs activate the mesocorticolimbic dopamine pathway [21], and nAChRs are both highly expressed in this pathway and serve in a modulatory capacity [20], suggesting that genetically mediated sensitivity within this system may not be specific to hazard for nicotine dependence. Finally, in that location are a number of parallel behavioral characteristics across types of substance dependence, such as impulsivity and reactivity to drug stimuli, and there is evidence these are influenced by mutual genetic variants [32, 43]. Thus, indirect genetic pathways may contribute to contradictory findings across studies and ambiguity well-nigh the level of specificity of genetic influences represents both a meaning gap in knowledge and a serious methodologic claiming.

The second major claiming pertains to understanding the role of interactive relationships in genetic risk for tobacco dependence. The majority of studies primarily examine independent associations betwixt ane or a small number of polymorphisms and a smoking-related phenotype. However, genetic influences may be conferred as a result of a number of different interactive relationships. At the simplest level, genetic influences may non pertain to genotypes, but rather haplotypes (ie, common combinations of proximal variants that are inherited together) [44]. In such cases, if the other variants comprising the haplotype are not assessed, a latent unmeasured source of error is again introduced. As well, there may as well be gene–gene interactions (ie, epistasis) between loci that are independently related to nicotine dependence [17]. Possession of multiple alleles that confer greater risk by small amounts may multiplicatively increase the probability of nicotine dependence (ie, based on non-additive interactions, a person's total genetic gamble may be greater than sum of its parts). Across the level of the genome, more than complex interactions include those betwixt genetic variables and nongenetic (environmental) variables, such as developmental events (eg, historic period of initiation [45]) and the influences of acute experiential states, such as stress, craving, withdrawal, and negative affect [46]. A skillful case of these multiple sources of complexity is axiomatic in a contempo study of the CHRNA5-A3-B4 factor cluster in relation to nicotine dependence and other smoking-related phenotypes [26]. In this case, a haplotype-based analysis was more sensitive than examining SNPs individually, revealing both risk and protective combinations, and the associations with nicotine dependence were only significant in individuals who began smoking at an early historic period.

A farther complication is that there is increasing evidence that epigenetic processes contribute to addiction [47], and nicotine dependence in particular [48]. Epigenetic mechanisms are cellular level modifications to genetic material based on environmental exposures (eg, diet, chronic stress, drug exposure) that alter subsequent transcriptional activeness. Rather than static independent influences, genetic variants may need only to be associated with initial aspects of nicotine exposure or other events, differentially initiating a pour of subsequent furnishings. Interestingly, in that location is growing evidence that epigenetic markers tin can be passed down across generations and significantly affect offspring wellness [49]. Thus, modest private variant findings may need to be explored in the context of epigenetics.

Taken together, like the ambiguities relating to specificity, it is both plausible and probable that the pathways from genome to syndrome are not a event of independent and additive furnishings, simply interactive and recursive processes, reflecting much more circuitous dynamics than are typically examined. These relationships may in turn explicate the observed inconsistencies in the literature.

Understanding Genetic Influences via an Intermediate Phenotype Arroyo

To a large extent, the preceding challenges reflect the common problem of a express understanding of the proximal function that a genotype (or haplotype) has in either increasing or decreasing the probability of nicotine dependence. Although major technological advances take been made in terms of genotyping, the well-nigh common phenotypes continue to be clinical endpoints, such as nicotine dependence. Presence of a diagnosis or the level of dependence may exist useful for describing a clinical syndrome and advice amid clinicians, but may non be useful genetic phenotypes. This may be because a diagnosis or total index of symptoms is not highly informative almost the disorder's underlying pathophysiology and motivational processes. Further, there are numerous pathways and symptom permutations that tin lead to nicotine dependence and the syndrome may be considerably downstream from genome-level variation, making it an important clinical endpoint but an excessively diffuse phenotype.

One way to address this is an intermediate phenotype, or "endophenotype", approach, which attempts to characterize genetic influences by identifying intervening mechanistic processes (ie, the intermediate phenotypes or endophenotypes) that are responsible for a genetic variant'southward local influence on a disorder [50]. By focusing on more than narrowly defined phenotypes that are associated with both genetic and clinical variation, this approach attempts to identify the proximal influences of take a chance-conferring and risk-preventing polymorphisms. Moreover, a focus on intermediate phenotypes has the potential to simultaneously place the pathophysiologic and motivational mechanisms underlying the disorder, dissimilar the relatively opaque phenotype of diagnosis. Given the considerable phenotypic heterogeneity and limited show of large-magnitude single factor influences, this approach has considerable promise for clarifying the relationships betwixt specific genes and nicotine dependence.

The objective of an intermediate phenotype approach is to map the chance pathway (positive or negative) from the genome to the clinical syndrome. This requires characterizing the part of genetic variation at multiple levels of analysis, from the level of transcription and the intra-/intercellular functionality to emergent alterations of brain/body systems and, finally, proximal intermediate phenotypes that straight influence the clinical phenotype (Table 1). Broadly speaking, each of these levels reflects an important phenotype, but the level of proximal intermediate phenotypes is especially of import. These reflect processes that are sufficient (directly or indirectly) for explaining increases or decreases in motivation for nicotine. A recent written report provides an excellent example and recapitulates the important levels of analysis. Every bit illustrated in Table 1, Hutchison et al. [24••] establish that a specific allele in the α4 nAChR gene CHRNA4 was associated with significantly greater transcriptional action in vitro, significantly greater smoking-induced reward in a human laboratory epitome, and significantly greater nicotine dependence every bit a clinical phenotype. Thus, the study provides show that the polymorphism is functional at the level of transcription, that its functionality affects smoking reward (a motivationally relevant proximal intermediate phenotype), and this in plow affects the level of nicotine dependence. Applying this arroyo more broadly has the potential for fully agreement the office of an individual variant and in plow investigating its individual and interactive roles with other genetic and ecology factors.

Tabular array 1

Mapping genetic take chances from genome to syndrome using an intermediate phenotype approach

Level of assay	Observed variation	Example: Hutchison et al. [24••]a,b
Genome	Polymorphism	G →A SNP (rs6122429)
Intra-/Intercellular milieu	Transcription/biochemical	GG = ↑ binding
Physiologic system (trunk/brain)b	System/network	GG = ↑ a4* NAChR/DA activity (putative)
Proximal intermediate phenotype	Motivational	GG = ↑ smoking reward
Clinical	Presence/severity	GG = ↑ nicotine dependence/smoking

Although its application to nicotine dependence is relatively new, a number of potentially useful intermediate phenotypes accept emerged. These include tobacco-specific phenotypes, such as master and secondary motives for smoking [26], relative value of tobacco [36], and smoking topography [13], and indirect phenotypes, such as cue-elicited peckish [32] and impulsivity [43]. Shifting the phenotypic focus to motivationally relevant intermediate phenotypes that connect genetic variation and clinical variation has a number of potential advantages. A focus on intermediary genetic processes putatively increases the precision and validity of understanding how genetic risk is transmitted and may clarify interactive pathways that are typically disregarded. A mechanistic understanding of a polymorphism's role would contribute to agreement the boundary conditions of its influence (ie, for whom and nether what conditions it is relevant). Finally, from an practical standpoint, intermediate phenotypes have the potential to be useful clinical targets for intervention or prevention.

Conclusions

At that place accept been major advances in understanding the role of genetics in nicotine dependence. The condition is conspicuously heritable and has been found to be associated with a large number of individual genetic polymorphisms. Still, inconsistent findings and typically modest magnitude associations reveal the significant challenges posed to fully understanding genetic influences. Mapping these influences from individual loci to nicotine dependence, and in particular employing an intermediate phenotype approach, is a promising strategy for shedding low-cal on a number of the extant challenges. In plow, a meliorate understanding of the mechanisms of genetic run a risk and protection has great promise for improving prevention and treatment.

Acknowledgments

This review was partially supported past the following grants: National Institutes of Health (NIH) - K23 AA016936 (JM); NIH - R03 DA027481 (EMO, JM); NIH - P30 DA027827 (EMO, JM), NIH - R01 DA023134 (VSK). The authors are grateful for the research assist of Anna Harrell, BS, and Shannen Malutinok, MSW, MPH.

Footnotes

Disclosure

No potential conflicts of involvement relevant to this article were reported.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114454/

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