Perspective

The Pharmacogenomics Journal (2011) 11, 247–250; doi:10.1038/tpj.2011.3; published online 15 February 2011

Genetic testing for aldehyde dehydrogenase 2 deficiency in young adults

C S Hendershot1

1The Mind Research Network and Center on Alcoholism, Substance Abuse, and Addictions, University of New Mexico, Albuquerque, NM, USA

Correspondence: Dr CS Hendershot, The Mind Research Network and Center on Alcoholism, Substance Abuse and Addictions, University of New Mexico, 1101 Yale NE, Albuquerque, NM 87106, USA. E-mail: chendershot@mrn.org

Received 15 July 2010; Revised 7 January 2011; Accepted 20 January 2011; Published online 15 February 2011.

Keywords:

ALDH2; alcohol; acetaldehyde; genetic feedback; college students; University of California, Berkeley

Last May administrators at the University of California, Berkeley announced plans to offer voluntary genetic testing for incoming students. Over the summer ~5500 undergraduates received a DNA collection kit in the mail. More than 700 students responded by returning a saliva sample for the analysis of three common polymorphisms. The exercise, titled Bring Your Genes to Cal, was this year's iteration of Berkeley's On the Same Page program (http://onthesamepage.berkeley.edu), intended to provide incoming students with a shared didactic experience. Although the controversy generated by the project ultimately forced administrators to alter its scope, the resulting debate was useful in highlighting the challenges of inoculating public audiences to the topic of personalized genomics and instituting a framework for formal education in this area. Two particularly prominent issues raised by the project concern the need for genetic tests to be accompanied by complete and accurate clinical information, and the potential shortfalls of over-regulating access to personalized genetic test results.

The announcement of Bring Your Genes to Cal generated immediate criticism and opposition, which even included attempted legislation to block the project. Citing ethical and privacy concerns, a bill (AB 70) introduced by one California Assemblyman requested that the University refrain from making ‘unsolicited requests to submit to genetic testing’ and sought financial penalties equal to any expenditures related to the project. Following considerable public debate, the California Department of Public Health (CDPH) delivered the coup de grace by ruling in August that the critical component of the project—providing students with online access to individualized test results—could not proceed as planned. Although genetic feedback would have occurred on a voluntary, anonymous basis (and was approved by Berkeley's Institutional Review Board), the CDPH deemed that this approach required physician oversight and the use of a federally certified clinical laboratory. Instead of providing participants with individualized test results, project organizers resorted to presenting aggregated test results to students during a lecture in September. The three genetic variants selected for the project have functional significance for metabolism of lactose (LCT), folic acid (MTHFR) and alcohol (ALDH2). Given the population, it was obvious the latter would generate the most attention. The approach in focusing on ALDH2—as well as the CDPH ruling, which precluded Berkeley from communicating individual test results—each raise important issues concerning the delivery of personalized risk information based on common genetic variants.

ALDH2 encodes mitochondrial aldehyde dehydrogenase (ALDH2), the enzyme primarily responsible for the metabolism of acetaldehyde, an intermediary by-product of ethanol metabolism and established carcinogen.1 The ALDH2*2 allele, virtually exclusive to northeast Asian populations, encodes a functionally inactive variant of the ALDH2 enzyme that results in deficient acetaldehyde metabolism.2 Phenotypic correlates of ALDH2*2 include elevated blood and salivary acetaldehyde following alcohol consumption, heightened physiological responses to alcohol (including the characteristic skin flushing response) and reduced risk for heavy drinking and alcohol dependence.3, 4

In attempting to convey genetic test results to a lay audience the critical component is likely not molecular results, but interpretative clinical information. In this context, any information about phenotypic correlates of a given variant should be as accurate, complete and transparent as possible. In this respect the Berkeley project fell short. Publicly available descriptions of the project implied that the three genetic variants were selected on the basis of their associations with innocuous phenotypes; in fact, a project organizer explicitly described the variants as not disease-associated during a National Public Radio interview. Unfortunately, this characterization ignores a well-established finding: individuals with ALDH2*2 have significantly elevated risk for developing alcohol-related cancers. In addition to the documented association of ALDH2*2 with the risk for alcohol dependence, research spanning the last 15 years shows unequivocally that drinkers with the ALDH2*1/*2 genotype have significantly elevated risk for developing upper aerodigestive tract cancers, in particular squamous cell esophageal cancer.5, 6, 7, 8, 9, 10, 11 This association is documented at the meta-analytic level (Table 1), characterized by a clear dose-response pattern, significant when controlling for cigarette smoking, and substantiated by molecular evidence.5 Importantly, these findings are largely under-recognized and have yet to be widely translated in clinical interventions. Consequently, recent appeals have been made to heighten awareness among health care providers that alcohol-induced flushing is a biomarker for elevated cancer risk in individuals of northeast Asian descent.5 Although ALDH2*2 is specific to this population, the overall public health implications are substantial: individuals with ALDH2*2 are estimated to number 540 million worldwide and contribute disproportionately to the burden of alcohol-related disease.5 Alcohol use among ALDH2*2 carriers accounts for a substantial proportion of esophageal cancer cases in high-risk regions, and interventions to reduce drinking in this group could reduce disease incidence considerably.5, 9


Of particular relevance to the Berkeley project is that Asian–American college students with partial ALDH2 deficiency (ALDH2*1/*2 genotype) are potentially a high-risk subgroup.5 Despite the protective influence of ALDH2*2 on the risk for alcohol dependence, many ALDH2*1/*2 individuals engage in heavy drinking.3, 9 Additionally, the protective effect of ALDH2*2 can be mitigated by environmental conditions conferring greater risk for alcohol use.12 Anecdotal evidence suggests that some college students with ALDH2 deficiency use histamine antagonists to blunt alcohol-induced flushing, a practice likely to exacerbate health risks.5 Given clear evidence for increased cancer risk in drinkers with the ALDH2*1/*2 genotype, offering genetic feedback for ALDH2*2—particularly in a setting characterized by high rates of heavy drinking—necessitates inclusion of this information. However, public discussions on Bring Your Genes to Cal essentially ignored this issue (as well as the established association of ALDH2 with alcohol dependence). Ethical delivery of genetic test results hinges on providing complete and accurate information about known phenotypic correlates, especially because genotype results will be meaningless to a lay audience in the absence of interpretive information.

The CDPH ruling—which effectively restricted Berkeley students from accessing results of genetic tests for which they had consented—also has important implications. Among the substantial minority (20–25%) of Berkeley undergraduates of northeast Asian descent, ALDH2*2 carriers might have learned important information about a genetic predisposition to alcohol-related health risks. Notably, initial evidence suggests that genetic feedback and risk information about ALDH2*2 can potentially lead to reductions in alcohol use among college students with the ALDH2*1/*2 genotype.13 However, these benefits would require that students receive relevant health-risk information; there was no evidence suggesting this information was included in the original plan to provide students with individualized test results. Following public comment on this issue by scientists from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the association of ALDH2 with cancer risk was ultimately referenced in the September lecture to students. However, students’ genotype results were presented in aggregate without mention of racial group differences in allele frequencies or health risks. In other words, students were not informed that health risks associated with ALDH2*2 should be an important consideration for many drinkers of northeast Asian descent, but are inconsequential for almost everyone else. (Incidentally, testing for ALDH2*2 is essentially irrelevant for those from other racial groups).

The apparent rationale for the CDPH ruling was that Berkeley's project did not fulfill the requirements of the Clinical Laboratory Improvement Amendments (CLIA), which stipulate that clinical and diagnostic genetic tests to be conducted in laboratories federally certified to meet specific quality standards. However, laboratories conducting genetic tests for research or educational purposes are technically exempt from CLIA regulations. Given that genotyping was conducted at a Berkeley research laboratory as part of a didactic exercise, the project arguably should not have been subject to CLIA regulations (a point stressed by Berkeley officials in communications with the CDPH). Moreover, the tests in question could not reasonably be characterized as diagnostic medical tests. Even the established association of ALDH2*2 with cancer risk is not deterministic, occurring by way of interaction with behavioral factors that influence relative disease risk. ALDH2*2 carriers can choose to reduce any risks by limiting their drinking (and cigarette smoking, which significantly exacerbates these risks). Concerns about Bring Your Genes to Cal also included speculation that ALDH2 testing would lead to increased alcohol use among individuals who test negative for ALDH2*2; this outcome has not been borne out empirically.13 Finally, although providing students with information related to cancer risk would have raised additional ethical concerns, including the possibility of psychological distress, initial evidence suggests that genetic feedback and risk information for ALDH2 is well tolerated by college students.13 It is important to note that inferences about increased cancer risk among ALDH2*2 carriers are ultimately not contingent on genetic testing; self-reported alcohol-induced flushing is a reliable proxy marker for ALDH2 deficiency.14 Genetic testing could nonetheless have ancillary benefits, including enhancing interest and engagement in health interventions or augmenting their motivational impact.

The emergence of the direct-to-consumer personal genomics industry (and recent developments around its impending federal regulation in the United States) makes this an opportune time to engage students in the debate on personalized medicine. Novel approaches like Berkeley's will help fulfill this goal. In this respect, it is critical that indiscriminant regulation over the access of genetic information not impinge on the ability to generate dialogue and promote public education on these issues.15 Ideally, any regulatory efforts should take into account the level of risk associated with a specific genetic variant and develop testing guidelines commensurate with those risks.16 Projects like the National Institutes of Health Genetic Testing Registry (GTR), expected to be available sometime in 2011 (http://www.ncbi.nlm.nih.gov/gtr), should help facilitate this goal. The GTR aims to provide a shared resource for researchers, consumers and health care providers to access information concerning the availability, indications, safety and clinical utility of various genetic tests. This and similar efforts will hopefully encourage greater transparency and public awareness about the clinical utility and predictive ability of such tests.

Ultimately, the events surrounding Bring Your Genes to Cal underscore the need for researchers and educators to develop novel approaches to engage students in the rapidly evolving dialogue on personal genomics while also minimizing legal and ethical concerns. Notably, as the Berkeley controversy played out, Stanford University also implemented a project that included optional genetic testing for students. A pilot summer course offered by the Stanford University School of Medicine, Personalized Medicine and Genomics, gave students the option to interpret their own genetic test results as a means of facilitating the course learning objectives. The approach taken by Stanford differed from Berkeley's in several ways: the course was offered to medical and graduate students and involved direct-to-consumer genetic testing companies, which use CLIA-certified laboratories. Students paid a nominal fee for testing and received baseline education before submitting DNA samples. Although the Berkeley and Stanford projects were each innovative, differences in their respective goals, approaches and outcomes will be instructive for similar efforts at education in personal genomics. In focusing specifically on ALDH2, Bring Your Genes to Cal also generated a unique opportunity to convey relevant health information to a subset of students and to enhance awareness of established but under-recognized health risks. These possibilities were ultimately unrealized. Future efforts to incorporate health risk information specific to ALDH2 in educational, primary care and brief intervention contexts could be important for reducing alcohol-related morbidity among individuals at increased genetic risk.

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Conflict of interest

The author declared no conflict of interest.

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