Genomics & Health Impact Update
The Office of Public Health Genomics (OPHG) provides updated and credible information on how genomic information and family health history can improve health and influence policy and practice. We highlight news and information on the use of genomic tests and other applications, including family health history, in clinical and public health practice and programs, along with relevant data, policy, and legislation. We hope the update is informative to practitioners, policy makers, consumers, and researchers. Please send your comments to: email@example.com.
Thursday, May 12, 2011 Volume 26 Number 19
New Genomics and Health Impact Blog
In the Genomics and Health Impact blog, we will offer comments from a public health perspective on genomic research and programs conducted by CDC and other institutions around the world. We will not provide individual medical advice or endorse specific commercial products. We encourage respectful comments and dialogue.
- The newest report “Generating Evidence for Genomic Diagnostic Test Development – Workshop Summary” based on the November 2010 workshop from the Institute of Medicine’s Roundtable on Translating Genomic-Based Research for Health has been released.
- Multiple State Genetics Programs have collected population-based genomic data using state surveillance systems which have been posted by Oregon State.
- The second issue of the GAPPNet Quarterly Newsletter has been posted on the GAPPNet website.
Clinical utility gene card for: fragile X mental retardation syndrome, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Jacquemont S, et al. Eur J Hum Genet 2011 May
New guidelines for cardiovascular genetic testing, EurekAlert, May 6
Educational needs about cancer family history and genetic counseling for cancer risk among frontline healthcare clinicians in New York city. Sussner KM, et al. Genet Med 2011 May
International Thalassemia Day was May 8th. To find out more about thalassemia, please visit the CDC Feature.
British health authorities criticize medical laboratory tests for consumers, Dark Daily, May 6
Ethnic, Racial and Cultural Identity and Perceived Benefits and Barriers Related to Genetic Testing for Breast Cancer among At-Risk Women of African Descent in New York City. Sussner KM, et al. Public Health Genomics 2011 May
Genetic susceptibility testing for beryllium: Worker knowledge, beliefs, and attitudes. Silver K, et al. Am J Ind Med 2011 May
A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast Cancer. Christos Hatzis, PhD; Lajos Pusztai, MD, DPhil; et al. JAMA. 2011;305(18):1873-1881.
Genomic test shows promise as predictor of chemotherapy response, survival for women with invasive breast cancer, Medical News Today, May 11
Polygenic susceptibility to prostate and breast cancer: implications for personalised screening. Pashayan N, Duffy SW, Chowdhury S, et al. Br J Cancer. 2011 Apr 5.
Genetic risk information can improve cancer screening, PHG Foundation, May 11
Public Perspectives on Returning Genetics and Genomics Research Results. O'Daniel J & Haga SB. Public Health Genomics 2011 May
Breast cancer multi-gene tests compared, Medical News Today, May 6
No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Sibbing D, Koch W, Massberg S, et al. Eur Heart J. 2011 Apr 28.
New study refutes role of PON1 gene in clopidogrel treatment, Medscape, May 5 [by free subscription only]
CDC authors are indicated in bold
Diallyl sulfide protects against ultraviolet B-induced skin cancers in SKH-1 hairless mouse: analysis of early molecular events in carcinogenesis. Cherng JM, Tsai KD, Perng DS, Wang JS, Wei CC, Lin JC. Photodermatol Photoimmunol Photomed. 2011 Jun;27(3):138-146.
Kyasanur forest disease virus alkhurma subtype in ticks, Najran Province, Saudi Arabia. Mahdi M, Erickson BR, Comer JA, Nichol ST, Rollin PE, Almazroa MA, Memish ZA. Emerg Infect Dis. 2011 May;17(5):945-7.
Reevaluation of the taxonomic status of recently described species of Enterococcus: evidence that Enterococcus thailandicus is a senior subjective synonym of "Enterococcus sanguinicola", and confirmation of Enterococcus caccae as a species distinct from Enterococcus silesiacus. Shewmaker PL, Steigerwalt AG, Nicholson A, Carvalho MD, Facklam RR, Whitney A, Teixeira LM. J Clin Microbiol. 2011 May 4.
Prenatal Programming and Toxicity II (PPTOX II): role of environmental stressors in the developmental origins of disease. Darney S, Fowler B, Grandjean P, Heindel J, Mattison D, Slikker W. Reprod Toxicol. 2011 Apr;31(3):271.
Control for confounding in case-control studies using the stratification score, a retrospective balancing score. Allen AS, Satten GA. Am J Epidemiol. 2011 Apr 1;173(7):752-60.
Impact of HPV assay on observed population prevalence. Unger ER, Steinau MS, Lin JM, Patel SS, Swan DC. Diagn Mol Pathol. 2011 Apr 28.
Initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants. Fogel J, Li Q, Taha TE, Hoover DR, Kumwenda NI, Mofenson LM, Kumwenda JJ, Fowler MG, Thigpen MC, Eshleman SH. Clin Infect Dis. 2011 Apr;52(8):1069-76.
Military veterans genomics research project launched, PHG Foundation, May 9
International study of the human genome, Medical News Today, May 6
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"An international panel of experts from The Heart Rhythm Society and the European Heart Rhythm Association issued new guideline recommendations for all health care professionals about cardiovascular genetic testing at the Heart Rhythm Society's 32nd Annual Scientific Sessions.
Silvia G. Priori, MD, PhD, a leader in the field of inherited cardiovascular diseases and director of the Cardiovascular Genetics Program at NYU Langone Medical Center, was co-lead author of the HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. The complete guidelines will be published in the August 2011 issue of the HeartRhythm Journal and Europace."
This study investigated the educational needs of frontline healthcare clinicians about cancer family history and genetic counseling for cancer risk.
We conducted a voluntary, anonymous survey among (1) general medicine clinicians, (2) obstetrics/gynecology clinicians, and (3) nurse practitioners at Mount Sinai School of Medicine in New York City.
A total of 143 clinicians completed the survey (response rate 81%). The majority of clinicians (77.5%) reported regularly completing family histories on cancer risk for their patients, but only 1.7% considered themselves "experts" in interpreting risk to make prevention, screening, and treatment recommendations. Numerous barriers to cancer family history collection were noted. More than half (55.8%) reported referring patients to genetic counseling, although only 14.3% reported confidence in their ability to make appropriate referrals. The majority reported that they would apply genetic counseling for cancer risk in their practice if they had the skills (84.9%). There was some variability found regarding specialty.
Despite widespread use of family histories for cancer risk, barriers remain to appropriate cancer risk management among frontline healthcare clinicians. Development of educational training programs to assist clinicians with collection of cancer family history information, interpretation, and appropriate referral along with teaching direct application of a modified form of genetic counseling for low-medium risk patients and referral of patients at genetic risk is warranted."
"After seven years of unexplained infertility, Ann Najdek-Andrada finally had a son, a baby boy who seemed as perfect as she’d always imagined.
But that fantasy was shattered when Gianni was two weeks old. That’s when the call came saying the child had tested positive for cystic fibrosis — and that it would take nearly four months to find out for sure."
"It’s not just in the United States that Direct-to-Consumer (DTC) medical laboratory tests are coming under criticism, as reported in recent weeks by Dark Daily. Two prominent organizations in the United Kingdom (UK) have issued reports with serious criticisms of what are known as “Do-It-Yourself” (DIY) clinical laboratory tests in that country."
Background: Due to disparities in the use of genetic services, there has been growing interest in examining beliefs and attitudes related to genetic testing for breast and/or ovarian cancer risk among women of African descent. However, to date, few studies have addressed critical cultural variations among this minority group and their influence on such beliefs and attitudes. Methods: We assessed ethnic, racial and cultural identity and examined their relationships with perceived benefits and barriers related to genetic testing for cancer risk in a sample of 160 women of African descent (49% self-identified African American, 39% Black-West Indian/Caribbean, 12% Black-Other) who met genetic risk criteria and were participating in a larger longitudinal study including the opportunity for free genetic counseling and testing in New York City. All participants completed the following previously validated measures: (a) the multi-group ethnic identity measure (including ethnic search and affirmation subscales) and other-group orientation for ethnic identity, (b) centrality to assess racial identity, and (c) Africentrism to measure cultural identity. Perceived benefits and barriers related to genetic testing included: (1) pros/advantages (including family-related pros), (2) cons/disadvantages (including family-related cons, stigma and confidentiality concerns), and (3) concerns about abuses of genetic testing. Results: In multivariate analyses, several ethnic identity elements showed significant, largely positive relationships to perceived benefits about genetic testing for breast and/or ovarian cancer risk, the exception being ethnic search, which was positively associated with cons/disadvantages, in general, and family-related cons/disadvantages. Racial identity (centrality) showed a significant association with confidentiality concerns. Cultural identity (Africentrism) was not related to perceived benefits and/or barriers. Conclusions: Ethnic and racial identity may influence perceived benefits and barriers related to genetic testing for breast and/or ovarian cancer risk among at-risk women of African descent. Genetic counseling services may want to take into account these factors in the creation of culturally-appropriate services which best meet the needs of this heterogenous population."
The primary purpose of newborn screening for hemoglobinopathies is the presymptomatic diagnosis and early treatment of sickle cell disease. Hemoglobinopathy traits detected on the newborn screening provide an opportunity for genetic counseling of families regarding the trait and information that may impact reproductive decisions of the parents. We describe the results of a study to determine the impact of newborn screening and genetic counseling on the lives of families in which an abnormal hemoglobin trait had been identified.
From June 2003 to December 2009, families of children with trait attending a clinic visit and receiving professional genetic counseling were asked to participate in a semistructured follow-up survey regarding their experience and the impact of genetic counseling on their families.
Of the 300 patients seen in clinic during the specified time period, 209 consented to be recontacted and 114 have completed the survey. Eighty-five percent of responders reported knowing that the newborn screen had been performed, but only 55% understood the purpose of newborn screening. When asked about the effect of finding out that trait was present in their baby, 19% reported feeling guilty or upset, whereas 4% believed that their partner blamed them for the child's results. That genetic counseling was found to be beneficial was indicated by the fact that 99% reported that their questions were answered, 82% reported feeling less anxious, and 78% discussed the trait with their partner after the appointment.
Genetic counseling after newborn screening relieves anxiety, provides knowledge, facilitates dialog within families and between partners about hemoglobinopathy trait, and was seen as a positive experience for the majority of responders.
We sought to gain insight into workers' knowledge, beliefs, and attitudes on the subject of testing for genetic susceptibility to beryllium.
Five focus groups were held with 30 current and former beryllium workers and nine family members. Audio recordings were transcribed and assessed by hierarchical coding using an inductive approach.
Some workers were unclear about the distinction between genotoxicity and heritability. A key finding is that they perceived the benefits of a positive test result to be related to enhanced autonomous decision-making. The major concern cited by participants was potential abuse of genetic information by employers. Complete financial separation of a prospective testing entity from the employer was seen as crucial.
A window of opportunity exists to create regional partnerships for translational research on genetic susceptibility testing. Such partnerships would involve labor, management, public health scientists, primary care professionals, and other stakeholders. They would be critical to identifying testing strategies that maximize worker autonomy along with the public health advantages of genetic testing.
Context Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.
Objective To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.
Design, Setting, and Patients Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)–negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline–based regimens (then endocrine therapy if estrogen receptor [ER]–positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.
Main Outcome Measures Distant relapse–free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).
Results Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.
Conclusion A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.
Background:We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone.Methods:We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively).Results:Compared with screening men based on age alone (aged 55-79: 10-year absolute risk 2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk 2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases.Conclusion:Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.
"What this study set out to do:
To model a personalised screening strategy for breast and prostate cancer based on genetic risk and age, and compare it with a screening strategy based on age alone."
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."
"Two multi-gene tests designed to predict the risk of disease progression and response to chemotherapy in breast cancer produce broadly similar results for high- and low-risk patients, but do not always agree in their predictions for those at intermediate risk, a new analysis shows."
Aims In clopidogrel-treated patients undergoing coronary stenting, high on-treatment platelet reactivity was linked to a higher risk of stent thrombosis (ST). Platelet response to clopidogrel is significantly influenced by genetic factors. Recently published findings showed a highly significant impact of a common polymorphism (Q192R) within the paraoxonase-1 (PON1) gene on clopidogrel treatment efficacy but no influence of the CYP2C19*2 genetic variant as previously demonstrated. The aim of this study was to assess the impact of the PON1 Q192R genotype in parallel to that of CYP2C19*2 on the antiplatelet effect of clopidogrel and the risk of ST in clopidogrel-treated patients. Methods and results In 1524 patients undergoing percutaneous coronary intervention, ADP-induced platelet aggregation was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was investigated by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST vs. an early ST-free control cohort (n = 1439). For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (P = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (P < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (P = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (P = 0.019). Conclusion The PON1 Q192R genotype did not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacted on both antiplatelet effect of clopidogrel and risk of coronary ST."
"A new study has refuted previous data suggesting that PON1 gene polymorphisms are involved in the activation of clopidogrel .
The study, published online April 28, 2011 in the European Heart Journal, found that PON1 polymorphisms did not influence platelet response to clopidogrel or the risk of stent thrombosis in clopidogrel-treated patients, whereas the CYP2C19*2 genotype had an impact on both antiplatelet effect of clopidogrel and risk of coronary stent thrombosis."
Background: Diallyl sulfide (DAS) has been shown to have a preventive effect against various cancers. Aims and objectives: We evaluated the protective effects of DAS in regression of ultraviolet B (UVB)-induced skin tumor formation in SKH-1 hairless mice and its underlying early molecular biomarkers. Methods: We examined the efficacy of DAS in UVB light-induced skin lesion in SKH-1 hairless mice and the associated molecular events. Results: Mice irradiated with UVB at 180 mJ/cm(2) twice per week elicited 100% tumor incidence at 20 weeks. The topical application of DAS before UVB irradiation caused a delay in tumor appearance, multiplicity, and size. The topical application of DAS before and immediately after a single UVB irradiation (180 mJ/cm(2) ) resulted in a significant decrease in UVB-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells, together with an increase in p53 and p21/Cip1-positive cell population in the epidermis. Simultaneously, DAS also significantly inhibited nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. Conclusions: The protective effect of DAS against photocarcinogenesis is accompanied by the down-regulation of cell-proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-κB, and of inflammatory responses involving COX-2, PGE2, and NO, and up-regulation of p53, p21/Cip1 to prevent DNA damage and facilitate DNA repair."
To the Editor: The lineage of Kyasanur Forest disease virus (KFDV) found in the Kingdom of Saudi Arabia is commonly referred to as Alkhurma hemorrhagic fever virus (AHFV). This virus was first isolated from a specimen collected in 1994 from a butcher living in Makkah Province, who was hospitalized for a hemorrhagic fever from which he died (1). The virus was assigned to the genus Flavivirus on the basis of reactivity with genus-specific monoclonal antibodies and sequencing of a fragment of the nonstructural 5 (NS5) gene, which showed >89% identity with KFDV. Ten other cases were confirmed among patients who had leukopenia, thrombocytopenia, and elevated liver enzymes. Observations of patients in the original study or in a subsequent analysis (2) suggested that Alkhurma hemorrhagic fever (AHF) disease was associated with contact with blood from infected animals, bites from infected ticks, or the drinking of raw milk. However, the exact mode of transmission to humans has still not been fully elucidated. More recently, AHFV RNA was detected in a single pool of sand tampans (Ornithodoros savignyi, soft ticks), collected in western Saudi Arabia (3), which suggests a link with these ticks."
Several of the more recently proposed new species of Enterococcus are nearly identical based on 16S rDNA sequence analysis and phenotypic traits. In the present study, DNA-DNA reassociation experiments, in conjunction with sequencing of the 16S rRNA and rpoB genes, provided evidence that "Enterococcus sanguinicola" and Enterococcus thailandicus actually represent the same species. In contrast, Enterococcus caccae and Enterococcus silesiacus, two other species with nearly identical 16S rRNA gene sequences were confirmed as separate species."
The stratification score for a case-control study is the probability of disease modeled as a function of potential confounders. The authors show that the stratification score is a retrospective balancing score and thus plays a similar role in case-control studies as the propensity score plays in prospective studies. The authors further show how standardization using the stratification score can be used to compare the distributions of exposures that would be found among case and control participants if both groups had the same distribution of confounding covariables. The authors illustrate these results using data from a genome-wide association study, the GAIN (Genetic Association Information Network) study of schizophrenia among African Americans (2006-2008)."
Type-specific surveillance of human papillomavirus (HPV) has been proposed as an early indicator of vaccine impact. Longitudinal comparison of HPV typing results requires stable assays with high type-specific reproducibility. Assays are evolving and the impact of even minor changes in the assay format may be difficult to anticipate. We initiated a population-based study of HPV with the prototype line blot (PLB) assay. These reagents were replaced by the research use only Linear Array (LA) HPV Genotyping kit. The assays are similar in principle and earlier comparisons found increased sensitivity and detection of more types per sample with LA; however, in samples from women with cervical abnormalities, the overall concordance was good. Slight changes in sensitivity may be more significant in samples from a general population with lower viral loads in the samples. Residual extracts from 3001 self-collected vaginal swabs from women in the general US population originally tested with PLB were retested with LA. With LA, all the samples were hybridized. PLB hybridization was restricted to samples with probable amplicon in gel electrophoresis. For HPV detection, the agreement between the 2 assays was 78.6% (κ=0.55) with a positive concordance of 52.8%. However, this masks the observation that repeat testing with LA led to the detection of HPV in nearly twice as many samples. Agreement improves if comparison was restricted to the samples hybridized. These results emphasize that assay comparisons should consider the clinical-epidemiologic context of sample collection. Studies designed to examine temporal trends in type-specific prevalence should archive residual material to permit retesting if assays change."
Background. The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis. Methods.We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests. Results.Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003). Conclusions.postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use."
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