Impact of delivery models on understanding genomic risk for type 2 diabetes.

BACKGROUND: Genetic information, typically communicated in-person by genetic counselors, can be challenging to comprehend; delivery of this information online--as is becoming more common--has the potential of increasing these challenges. METHODS: To address the impact of the mode of delivery of genomic risk information, 300 individuals were recruited from the general public and randomized to receive genomic risk information for type 2 diabetes mellitus in-person from a board-certified genetic counselor or online through the testing company's website. RESULTS: Participants were asked to indicate their genomic risk and overall lifetime risk as reported on their test report as well as to interpret their genomic risk (increased, decreased, or same as population). For each question, 59% of participants correctly indicated their risk. Participants who received their results in-person were more likely than those who reviewed their results on-line to correctly interpret their genomic risk (72 vs. 47%, p = 0.0002) and report their actual genomic risk (69 vs. 49%, p = 0.002). CONCLUSIONS: The delivery of personal genomic risk through a trained health professional resulted in significantly higher comprehension. Therefore, if the online delivery of genomic test results is to become more widespread, further evaluation of this method of communication may be needed to ensure the effective presentation of results to promote comprehension.

The potential impact of pharmacogenetic testing on medication adherence.

Poor medication adherence is a well-known problem, particularly in patients with chronic conditions, and is associated with significant morbidity, mortality and health-care costs. Multi-faceted and personalized interventions have shown the greatest success. Pharmacogenetic (PGx) testing may serve as another tool to boost patients' confidence in the safety and efficacy of prescribed medications. Here, we consider the potential impact (positively or negatively) of PGx testing on medication-taking behavior.

Primary care physicians' knowledge of and experience with pharmacogenetic testing.

It is anticipated that as the range of drugs for which pharmacogenetic testing becomes available expands, primary care physicians (PCPs) will become major users of these tests. To assess their training, familiarity, and attitudes toward pharmacogenetic testing in order to identify barriers to uptake that may be addressed at this early stage of test use, we conducted a national survey of a sample of PCPs. Respondents were mostly white (79%), based primarily in community-based primary care (81%) and almost evenly divided between family medicine and internal medicine. The majority of respondents had heard of PGx testing and anticipated that these tests are or would soon become a valuable tool to inform drug response. However, only a minority of respondents (13%) indicated they felt comfortable ordering PGx tests and almost a quarter reported not having any education about pharmacogenetics. Our results indicate that primary care practitioners envision a major role for themselves in the delivery of PGx testing but recognize their lack of adequate knowledge and experience about these tests. Development of effective tools for guiding PCPs in the use of PGx tests should be a high priority.

Survey of genetic counselors and clinical geneticists' use and attitudes toward pharmacogenetic testing.

Pharmacogenetic (PGx) testing aims to improve therapeutic outcomes through tailoring treatment based on a patient's genetic risk for non-response and/or an adverse event. Given their expertise, geneticists could facilitate the use of PGx testing; however, the preparedness and perceived role of the clinical genetics community is unclear. To assess the attitudes, preparedness, and perceived roles of geneticists in the delivery of PGx testing, we conducted a survey of 1500 randomly selected board-certified genetic counselors and clinical geneticists in the United States [response rate: 37.8% (n = 516)]. Twelve percent of genetic counselors and 41% of clinical geneticists indicated that they had ordered or coordinated patient care for PGx testing, a seemingly high proportion at this early stage of adoption. Almost all respondents had some education on pharmacogenetics, although only 28% of counselors and 58% of clinical geneticists indicated they felt well-informed about PGx testing. About half of counselors (52%) and clinical geneticists (46%) felt they would play 'some' role in the delivery of PGx testing; 17 and 19%, respectively, felt that they would play 'no' or 'a little' role. At this early stage of PGx testing, the role of geneticists and genetic counselors is unclear. However, their experience may aid in readying PGx testing and informing delivery strategies into clinical practice.

Survey of US public attitudes toward pharmacogenetic testing.

To assess public attitudes and interest in pharmacogenetic (PGx) testing, we conducted a random-digit-dial telephone survey of US adults, achieving a response rate of 42% (n=1139). Most respondents expressed interest in PGx testing to predict mild or serious side effects (73±3.29 and 85±2.91%, respectively), guide dosing (91%) and assist with drug selection (92%). Younger individuals (aged 18-34 years) were more likely to be interested in PGx testing to predict serious side effects (vs aged 55+ years), as well as Whites, those with a college degree, and who had experienced side effects from medications. However, most respondents (78±3.14%) were not likely to have a PGx test if there was a risk that their DNA sample or test result could be shared without their permission. Given differences in interest among some groups, providers should clearly discuss the purpose of testing, alternative testing options (if available) and policies to protect patient privacy and confidentiality.

Practical ethics: establishing a pathway to benefit for complex pharmacogenomic tests.

Pharmacogenomic tests offer a promising strategy to improve the safety and efficacy of drug treatment. Compelling examples, such as HLA-B*5701 testing to identify patients at risk for abacavir-associated hypersensitivity, are already changing clinical care. However, the level of evidence required to establish clinical utility is often the subject of debate. Determining the most efficient and effective pathway to benefit for a given test is therefore both a practical and an ethical concern.

Public perspectives on returning genetics and genomics research results.

BACKGROUND: The debate about returning research results has revealed different perspectives among researchers, participants and advisory groups with participants generally interested in obtaining their results. Given this preference, policies regarding return of individual research results may affect whether a potential subject chooses to participate in a study. Public attitudes, particularly those of African-Americans, toward this issue have been understudied. METHODS: In 2008-2009, we convened 10 focus groups in Durham, N.C. to explore attitudes about returning research results and how different policies might influence their likelihood to participate in genetic/genomic studies. Transcripts were complimented by a short anonymous survey. Of 100 participants, 73% were female and 76% African-American with a median age of 40-49 years. RESULTS: Although there was general interest in obtaining genetics research results, particularly individual results, discussants recognized many potential complexities. The option to obtain research results (individual or summary) was clearly valued and lack thereof was potentially a deterrent for genetic/genomic research enrollment. CONCLUSIONS: Providing the option to learn research results may help strengthen relationships between investigators and participants and thereby serve as a positive influencing factor for minority communities. Consideration of the broader implications of returning research results is warranted. Engaging diverse publics is essential to gain a balance between the interests and burdens of participants and investigators.

Public perspectives regarding data-sharing practices in genomics research.

BACKGROUND: Genomics research data are often widely shared through a variety of mechanisms including publication, meetings and online databases. Re-identification of research participants from sequence data has been shown possible, raising concerns of participants' privacy. METHODS: In 2008-09, we convened 10 focus groups in Durham, N.C. to explore attitudes about how genomic research data were shared amongst the research community, communication of these practices to participants and how different policies might influence participants' likelihood to consent to a genetic/genomic study. Focus groups were audio-recorded and transcripts were complemented by a short anonymous survey. Of 100 participants, 73% were female and 76% African-American, with a median age of 40-49 years. RESULTS: Overall, we found that discussants expressed concerns about privacy and confidentially of data shared through online databases. Although discussants recognized the benefits of data-sharing, they believed it was important to inform research participants of a study's data-sharing plans during the informed consent process. Discussants were significantly more likely to participate in a study that planned to deposit data in a restricted access online database compared to an open access database (p < 0.00001). CONCLUSIONS: The combination of the potential loss of privacy with concerns about data access and identity of the research sponsor warrants disclosure about a study's data-sharing plans during the informed consent process.

Factors influencing uptake of pharmacogenetic testing in a diverse patient population.

BACKGROUND: The successful integration of pharmacogenetic (PGx) testing into clinical care will require attention to patient attitudes. In this study, we aimed to identify the major reasons why patients would or would not consider PGx testing and whether these factors differed by race, socioeconomic and insurance status, and medical history. METHODS: We developed and conducted a survey within the adult patient population of the Duke Family Medicine Center. RESULTS: Of 75 completed surveys (65% African-American), 77% indicated they were 'very likely' or 'somewhat likely' to take a PGx test. Respondents who had experienced a side effect were significantly more likely to indicate they would take a PGx test and expressed greater interest in learning more about testing than those who had not. Drug safety and effectiveness were the major reasons to have PGx testing. Privacy concerns and lack of insurance coverage for testing were the major reasons to decline testing. CONCLUSIONS: We found no differences in interest in PGx tests by race or socioeconomic status, but found stronger interest from those with a history of side effects and private insurance. While the overall support of PGx testing is encouraging, greater reassurance of medical privacy and development of educational resources are needed.

The potential of a placebo/nocebo effect in pharmacogenetics.

Pharmacogenetic testing holds great promise to improve health outcomes and reduce adverse drug responses through enhanced selection of therapeutic agents. Since drug responses can be manipulated by verbal suggestions, it is of particular interest to understand the potential impact of pharmacogenetic test results on drug response. Placebo and nocebo-like effects may be possible due to the suggestive nature of pharmacogenetic information that a drug will or will not likely lead to improved health outcomes. For example, pharmacogenetic testing could provide further reassurance to patients that a given drug will be effective and/or cause minimal side effects. However, pharmacogenetic information could adversely affect drug response through negative expectations that a drug will be less than optimally effective or cause an adverse response, known as a nocebo-like effect. Therefore, a patient's perceived value of testing, their understanding of the test results, and the manner in which they are communicated may influence therapeutic outcome. As such, physicians should consider the potential effect of pharmacogenetic test results on therapeutic outcome when communicating results to patients. Studies are needed to investigate the impact of pharmacogenetic information of therapeutic outcome.

Distinct functions of two isoforms of a homeobox gene, BP1 and DLX7, in the regulation of the beta-globin gene.

Homeotic proteins are transcription factors that regulate the expression of multiple genes involved in development and differentiation. We previously isolated a cDNA encoding such a protein from the human leukemia cell line K562, termed Beta Protein 1 (BP1), which is involved in negative regulation of the human beta-globin gene. Sequence comparison revealed that BP1 is a member of the distal-less (DLX) family of homeobox genes and that it shares its homeodomain and 3' sequences with another DLX cDNA, DLX7. BP1 and DLX7 exhibit unique 5' regions, diverging at nucleotide 565 of BP1. We mapped this new distal-less family member BP1 to chromosome 17q21-22 by FISH and PCR, which is the same locus to which DLX7 has been mapped. These results strongly suggest that BP1 and DLX7 are isoforms (derived from the same gene). Since our previous data demonstrated that BP1 and DLX7 are frequently co-expressed, we determined whether DLX7 is also involved in the negative regulation of the beta-globin gene. Mobility shift assays demonstrated that both BP1 and DLX7 proteins, synthesized in vitro, bind to the same BP1 binding site. However, using transient assays, we showed that although BP1 represses activity of a reporter gene through either of two silencer DNA sequences upstream of the beta-globin gene, DLX7 did not show repressor activity against the beta-globin promoter. Further characterization of these apparent isoforms is of significance since they are jointly expressed in acute myeloid leukemia and in many leukemia cell lines.

BP1, a new homeobox gene, is frequently expressed in acute leukemias.

Aberrant expression of homeobox genes has been described in primary leukemia blasts. We recently cloned a new cDNA, BP1, which is a member of the homeobox gene family. BP1 expression was investigated in bone marrow samples from acute myeloid leukemia (AML), acute T cell lymphocytic leukemia (ALL) and pre-B cell ALL. Expression levels of two apparent isoforms of BP1, DLX7 and DLX4, were measured in the same samples. They are weakly if at all detectable in normal bone marrow, PHA-stimulated T cells or B cells. BP1 RNA was highly expressed in 63% of AML cases, including 81% of the pediatric and 47% of the adult cases, and in 32% of T-ALL cases, but was not found in any of the pre-B ALL cases. Coexpression of BP1, DLX7 and DLX4 occurred in a significant number of leukemias. Our data, including co-expression of BP1 with c-myb and GATA-1, markers of early progenitors, suggest that BP1 expression occurs in primitive cells in AML. Analysis of CD34+ and CD34- normal bone marrow cells revealed BP1 is expressed in CD34- cells and virtually extinguished in CD34+ cells. Ectopic expression of BP1 in the leukemia cell line K562 increased clonogenicity, consistent with a role for BP1 in leukemogenesis. The presence of BP1 RNA in leukemic blasts may therefore be a molecular marker for primitive cells and/or may indicate that BP1 is an important upstream factor in an oncogenic pathway.

Binding of HMG-I(Y) elicits structural changes in a silencer of the human beta-globin gene.

Proteins involved in repression of the human beta-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the beta-globin gene.