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PubMedDate not supplied

Molecular genetics of age-related macular degeneration: current status.

Age-related macular degeneration (AMD), a multifactorial human disorder, is the most common cause of acquired visual impairment in people over the age 60. It is estimated to affect millions of individuals worldwide. Prevalence increases with age; among persons 75 years and older, mild, or early forms occur in nearly 30% and advanced forms in about 7% of the population. AMD has been associated both with environmental and genetic factors. However, the clinical heterogeneity, late age at onset, and complex etiology have confounded genetic studies of the disorder. Methods applicable to the study of single-gene and some complex disorders (i.e., linkage analysis, sib-pair analysis, transmission disequilibrium test, etc.) have had limited utility in elucidating the genetic components of the complex AMD trait. Recently, substantial progress has been made in determining the genetic basis of monogenic eye disorders. On a monthly basis mutations are identified in new genes responsible for some form of retinal degeneration. Most, if not all, of these genes become candidates for potential involvement in multifactorial disorders especially if the phenotypes of the early-onset Mendelian diseases they cause resemble later onset complex traits. Unfortunately, to date mutational analyses of the candidate genes in AMD patients to date have not yielded the highly anticipated information: statistically significant association of sequence variants with AMD. Whether this is due to the unsuccessful selection of the right candidate genes for the analysis, or the methods employed, or both, has to be elucidated. This review summarizes current knowledge of genetic research aimed at delineating the molecular genetic basis of age-related macular degeneration. Moreover, it attempts to offer some approaches for the future studies directed towards understanding the genetic components of this complex disorder.

Aging↗

PubMed1998

Genetic testing: can it predict the lived experience of individuals and families? A personal testimony.

An individual's and family's experience with a genetic disease is too complex and diverse to be totally predicted using genetic testing. Stigmatization and discrimination of gene carriers can occur if society chooses to utilize genetic technology to eliminate 'disease and disability' without accepting human variation and devoting any possible efforts for ameliorating the life of individuals faced with disabilities. In this paper I use Friedreich's ataxia (FA) to illustrate some ways in which a disease experience can differ from what is expected from textbook descriptions of a given condition. I describe the expected medical characteristics with FA and some of my own personal experience with the disease as well as that of my family.

Journal Article↗

PubMed2005

Use of genetic toxicology information for risk assessment.

Genetic toxicology data are used worldwide in regulatory decision-making. On the 25th anniversary of Environmental and Molecular Mutagenesis, we think it is important to provide a brief overview of the currently available genetic toxicity tests and to outline a framework for conducting weight-of-the-evidence (WOE) evaluations that optimize the utility of genetic toxicology information for risk assessment. There are two major types of regulatory decisions made by agencies such as the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA): (1) the approval and registration of pesticides, pharmaceuticals, medical devices, and medical-use products, and (2) the setting of standards for acceptable exposure levels in air, water, and food. Genetic toxicology data are utilized for both of these regulatory decisions. The current default assumption for regulatory decisions is that chemicals that are shown to be genotoxic in standard tests are, in fact, capable of causing mutations in humans (in somatic and/or germ cells) and that they contribute to adverse health outcomes via a "genotoxic/mutagenic" mode of action (MOA). The new EPA Guidelines for Carcinogen Risk Assessment [Guidelines for Carcinogen Risk Assessment, USEPA, 2005, EPA Publication No. EPA/630/P-03/001F] emphasize the use of MOA information in risk assessment and provide a framework to help identify a possible mutagenic and/or nonmutagenic MOA for potential adverse effects. An analysis of the available genetic toxicity data is now, more than ever, a key component to consider in the derivation of an MOA for characterizing observed adverse health outcomes such as cancer. We provide our perspective and a two-step strategy for evaluating genotoxicity data for optimal use in regulatory decision-making. The strategy includes integration of all available information and provides, first, for a WOE analysis as to whether a chemical is a mutagen, and second, whether an adverse health outcome is mediated via a mutagenic MOA.

Animals↗

PubMed2005

Racial differences in the use of BRCA1/2 testing among women with a family history of breast or ovarian cancer.

CONTEXT: Given the current context of racial disparities in health and health care and the historical context of eugenics, racial disparities in the use of genetic susceptibility testing have been widely anticipated. However, to our knowledge there are no published studies examining the magnitude and determinants of racial differences in the use of genetic susceptibility testing. OBJECTIVES: To investigate the relationship between race and the use of BRCA1/2 counseling among women with a family history of breast or ovarian cancer and to determine the contribution of socioeconomic characteristics, cancer risk perception and worry, attitudes about genetic testing, and interactions with primary care physicians to racial differences in utilization. DESIGN, SETTING, AND PARTICIPANTS: Case-control study (December 1999-August 2003) of 408 women with a family history of breast or ovarian cancer, of whom 217 underwent genetic counseling for BRCA1/2 testing (cases) and 191 women did not (controls). Participants received primary care within a large health system in greater Philadelphia, Pa. MAIN OUTCOME MEASURES: Probability of carrying a BRCA1/2 mutation, socioeconomic characteristics, perception of breast and ovarian cancer risk, worry about breast and ovarian cancer, attitudes about BRCA1/2 testing, and primary care physician discussion of BRCA1/2 testing were measured prior to undergoing BRCA1/2 counseling for cases and at the time of enrollment for controls. RESULTS: African American women with a family history of breast or ovarian cancer were significantly less likely to undergo genetic counseling for BRCA1/2 testing than were white women with a family history of breast or ovarian cancer (odds ratio, 0.22; 95% confidence interval, 0.12-0.40). This association persisted after adjustment for probability of BRCA1/2 mutation, socioeconomic characteristics, breast and ovarian cancer risk perception and worry, attitudes about the risks and benefits of BRCA1/2 testing, and primary care physician discussion of BRCA1/2 testing (adjusted odds ratio for African American vs white, 0.28; 95% confidence interval, 0.09-0.89). CONCLUSIONS: Racial disparities in the use of BRCA1/2 counseling are large and do not appear to be explained by differences in risk factors for carrying a BRCA1/2 mutation, socioeconomic factors, risk perception, attitudes, or primary care physician recommendations. The benefit of predictive genetic testing will not be fully realized unless these disparities can be addressed.

Adult↗

PubMed2001

A genome-wide study of microsatellite instability in advanced gastric carcinoma.

BACKGROUND: Microsatellite instability (MSI) has been described in many human carcinomas, including gastric carcinomas (GCs). There are inconsistent findings regarding the association of MSI with various subsets of GC with specific clinicopathologic features. The objective of this study was to define MSI in advanced GC at a genome-wide level and to evaluate the clinical relevance of MSI in these patients. METHODS: Forty-one gastric adenocarcinomas with serosa invasion (T3) were analyzed at 59 loci that detected at least one site per arm of each autosome in human genome. The expression patterns of mismatch repair proteins hMLH1 and hMSH2 were examined by immunohistochemistry. Comparisons were made by categorizing tumors into three groups: tumors with MSI at multiple loci (at more than three loci), tumors with MSI at low level (at one to three loci), and microsatellite-stable (MSS) tumors. Clinical significance of MSI in advanced GC was evaluated. The relative rates of hypermutability of the 59 markers also were determined. RESULTS: A significant association was found between tumors with MSI at multiple loci and the expanding type of tumor growth by Ming's histologic classification (P = 0.001), whereas tumors with MSI at low level and MSS tumors are clinicopathologically indistinguishable. The 59 dinucleotide repeat markers displayed varying degrees of susceptibility toward genetic instability. The relative rates of hypermutability of these markers were consistent with a normal distribution pattern in which the frequency of unstable tumors detected at different chromosomal loci varied from 0% to 20%. CONCLUSIONS: The authors' results showed that advanced GC with MSI at multiple loci progress preferentially in an expanding mode, supporting the notion that high MSI tumors and low MSI/MSS tumors evolve through different genetic pathways. Thus, microsatellite testing may have clinical utility as a favorable prognostic marker.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Differential sensitivity of Chinese hamster V79 and Chinese hamster ovary (CHO) cells in the in vitro micronucleus screening assay.

Both the V79 and CHO cell lines are routinely used in the in vitro MN screening assay for the detection of possible genotoxicants. The CHO cell line is the predominant cell line currently used in the genetic toxicology testing industry. However, some laboratories routinely utilize the V79 cell line since the in vitro MN screening assay was initially developed using V79 cells. Our laboratory has historically used the CHO cell line. Therefore, our laboratory was interested in comparing the two cell lines with regard to possible similarities or differences in MN induction sensitivity after exposure to cyclophosphamide (CPA) and mitomycin C (MMC), the two standard positive control chemicals routinely used in this assay. Three exposure conditions in the presence of CPA and MMC were examined in both cell lines. Replicate cultures of CHO cells in McCoy's 5A and V79 cells in both McCoy's 5A and E-MEM were established and treated with 5 microg CPA/ml (4h exposure with S9), 0.5 microg MMC (4h exposure without S9) and 0.5 microg MMC (24h exposure without S9). A total of 400 cytochalasin B-blocked binucleated cells and 200 consecutive cells were analyzed from each culture for MN and cell cycle kinetics, respectively. Analysis of the data demonstrated that CHO cells were up to approximately five-fold more sensitive to the induction of CPA- and MMC-induced MN than V79 cells. Both cell lines exhibited similar average generation times among identical exposure groups. Therefore, the difference in MN sensitivity cannot be attributed to possible differences in cell cycle kinetics and is possibly related to inherent cellular differences in the processing of and/or repair of CPA- and MMC-induced damage by V79 and CHO cells.

Animals↗

PubMedDate not supplied

Prevalence and clinical correlates of anti-phospholipid antibodies in South Africans with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence and clinical correlates of anti-phospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), lupus anti-coagulant (LA), anti-beta2-glycoprotein 1 (abeta2GP1), and anti-prothrombin (aPT) antibodies, in Black South African patients with systemic lupus erythematosus (SLE). METHODS: A cross-sectional study of 100 SLE patients in whom clinical characteristics, including features of the anti-phospholipid syndrome (APS), disease activity, and damage were documented, and sera tested for aCL, abeta2GP, and aPT of all isotypes, and LA. RESULTS: Positive aCL, abeta2GPI, aPT, and LA were found in 53, 84, 20, and 2 patients, respectively. Immunoglobulin (Ig)A aCL and IgG abeta2GPI were the commonest aCL (49.1%) and abeta2GPI (47%) isotypes, respectively. IgA abeta2GPI were associated with both a history of thrombosis alone (p<0.05) and a history of any clinical feature, thrombosis, and/or spontaneous abortion of the APS (p<0.05); IgA aCL were associated with a history of any clinical APS event (p<0.05); and abeta2GPI of any isotype were associated with a history of arthritis (p<0.001). CONCLUSION: Our findings provide further evidence that screening for abeta2GPI and IgA aCL isotypes may improve the risk assessment for APS in SLE patients of African extraction. Further prospective studies are warranted to determine the clinical utility of these tests and to elucidate the genetic basis for the increased IgA aPL response in SLE patients of African extraction.

Antibodies, Antinuclear↗

PubMed2000

Genetic diversity of beta-thalassemia mutations in Pakistani population.

BACKGROUND: beta-thalassemia is one of the most common inherited single gene disorder in Pakistan. It is characterized by reduced or absent beta-globin gene expression resulting in abnormal maturation and survival of red blood cells. Due to high prevalence of this disease in the local population, it has become important for the health care providers to encourage people to utilize laboratory facilities for carrier and prenatal genetic testing. OBJECTIVE: To study the frequency of beta-thalassemia mutations in Pakistani population. SETTING: A tertiary care teaching hospital. METHODS: Blood samples of 72 couples and chorionic villus (CV) biopsy specimen collected at the Aga Khan University Hospital, Karachi were tested by Amplified Refractory Mutation Systems (ARMS) for the 12 most common mutations in the beta-globin gene. RESULTS: Out of 72 chorionic villus biopsy specimen analyzed, 17 (23%) had mutations in both alleles of the beta-globin gene. Homozygosity was identified in 6 CV samples, whereas 11 CV specimens were diagnosed as double heterozygous. Almost 60% of the CV biopsies showed mutations in one allele and were diagnosed as carriers. IVSI-5 (G-C) was the most common mutation identified in this study. It was found in 53% of the subjects and was represented equally in all the ethnic groups except Pathans. Several regional and ethnic differences were observed in the distribution of common mutations, for example in Pathan families Fr 8-9 (+G) mutation was most prevalent. In addition, variation in the distribution of mutations was also observed between the Northern and the Southern regions. CONCLUSION: This study indicates that in Pakistan, the five most common mutations are IVS1-5 (G-C), IVS1-1 (G-T), Fr 41-42 (-TTCT) Fr 8-9 (+G) and deletion 619 bp. An important factor contributing to high incidence of thalassemia is the unawareness among people about the available diagnostic facilities for the prenatal diagnosis in Pakistan. Strict implementation of collective measures including carrier identification, genetic counseling and prenatal diagnosis are required for preventing beta-thalassemia in Pakistan.

Adult↗

PubMed2025

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Humans↗

PubMed2005

Facilitating family communication about predictive genetic testing: probands' perceptions.

The responsibility of informing relatives that predictive genetic testing is available often falls to the proband. Support is required during this process, however the perceived utility of genetic counseling and other strategies to facilitate communication have not been explored. We investigated the experiences of 12 individuals with hereditary nonpolyposis colorectal cancer (HNPCC) in a semistructured telephone interview. Respondents informed their immediate family about the availability of genetic testing, however many more-distant relatives were not directly informed. Respondents were mostly satisfied with the way they told family members about testing and had mixed views about the usefulness of genetic counseling. Gender differences were observed, with most men expressing a need for guidance or support in communicating to relatives. Letters and booklets were thought to enhance the quality of information but the provision of further aids is unlikely to increase the number of relatives made aware of predictive testing by the proband.

Adult↗

PubMed1998

Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption.

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F2 mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F2 and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements.

Alcohol Drinking↗

PubMed2004

Are genetic self-tests dangerous? Assessing the commercialization of genetic testing in terms of personal autonomy.

Should a growing market for genetic self-tests be welcomed or feared? From the point of view of personal autonomy the increasing availability of predictive health information seems promising. Yet it is frequently pointed out that genetic information about future health may cause anxiety, distress and even loss of "life-hopes." In this article the argument that genetic self-tests undermine personal autonomy is assessed and criticized. I contend that opportunities for autonomous choice are not reduced by genetic information but by misperceptions and misunderstandings of the results of genetic tests. Since the interpretation of genetic information is sometimes distorted by the information provided about the genetic products, more attention should be given to deceitful marketing that overblows the utility of genetic products. Yet personal autonomy is reduced neither by genetic tests nor by genetic information and there is consequently no compelling case for the conclusion that genetic self-tests should be prohibited.

Decision Making↗

PubMed1997

Clinical molecular genetic testing.

Recent advances in human molecular genetics are rapidly producing clinical genetic tests for a variety of conditions. In addition to tests for rare genetic disorders, tests for common illnesses with mixed genetic and environmental etiologies are being developed. While practice guidelines for test utilization are being developed, many physicians would benefit from additional knowledge about the design and limitations of these tests. This article reviews the genetic background necessary to understand linkage-based and direct mutations tests and discusses some of the issues physicians must consider when selecting an appropriate test for a given clinical situation.

Genetic Techniques↗

PubMed2005

Impact of genetic testing on complex diseases.

OBJECTIVE: Wide applications for genetic testing in the clinical care of complex diseases have been discussed. However, it has never been quantified to what extent genetic testing could eventually be useful in the clinical care of common disorders. We aimed to quantify the theoretically possible utilization in common ischemic stroke, an example of a complex disease. METHODS: We computed the possible impact of genetic testing on risk assessment, secondary prevention and prognosis of ischemic stroke. This was done for hypothetical genotypes with different frequencies and effects. RESULTS: To apply pharmacogenetic secondary prevention based on a genotype with a frequency of 10% and 33% risk reduction, 204 subjects would have to be screened and 110 given genotype specific treatment for 1 year, in order to prevent one recurrent stroke, compared with standard therapy. The application of genetic testing seems to be less promising in risk assessment and the assessment of prognosis of common ischemic stroke. CONCLUSIONS: The highest impact of genetic testing on clinical practice of stroke will be in the areas of secondary prevention. Given the weak effects of reported susceptibility genotypes, it is theoretically unlikely that genetic screening will be used for the assessment of risk or prognosis of a complex disorder, except for Mendelian types of disease.

Aged↗

PubMed1998

Psychosocial predictors of interest in prenatal genetic screening.

The purpose of the study was to identify psychosocial predictors of interest in prenatal genetic testing. Analysis of data from 886 responses in the 1996 Louisville Metropolitan Survey indicate that factors such as demographic characteristics and scores on health locus of control that predict utilization of other preventive health care are less applicable to predicting attitudes toward genetic testing. Regression analyses indicated that political orientation, identification with religion, and attitudes against abortion predicted less favorable responses to a question about prenatal genetic testing. Abortion attitudes were particularly strong indicators of respondents' stated interests in testing. The findings have practical implications in terms of promoting preventive health care. Personal values may lead individuals to believe that prenatal testing leads to the intention of abortion.

Abortion, Induced↗

PubMed2003

DNA microarray for discrimination between pathogenic 0157:H7 EDL933 and non-pathogenic Escherichia coli strains.

The primary technique currently used to detect biological agents is based on immunoassays. Although sensitive and specific, currently employed immunoassays generally rely on the detection of a single epitope, and therefore often cannot discriminate subtle strain-specific differences. Since DNA microarrays can hybridize hundreds to thousands of genomic targets simultaneously and do not rely on phenotypic expression of these genetic features for identification purposes, they have enormous potential to provide inexpensive, flexible and specific strain-specific detection and identification of pathogens. In this study, pathogenic Escherichia coli O157:H7-specific genes, non-pathogenic K12-specific genes, common E. coli genes, and negative control genes were polymerase chain reaction-amplified and spotted onto the surface of treated glass slides. After labeled bacterial cDNA samples were hybridized with probes on the microarray, specific fluorescence patterns were obtained, enabling identification of pathogenic E. coli O157:H7 and non-pathogenic E. coli K12. To test the utility of this microarray device to detect genetically engineered bacteria, E. coli BL21 (a B strain derivative with antibiotic resistance gene, ampR) and E. coli JM107 (a K12 strain derivative lacking the gene ompT) were also employed. The array successfully confirmed the strain genotypes and demonstrated that antibiotic resistance can also be detected. The ability to assess multiple data points makes this array method more efficient and accurate than a typical immunoassay, which detects a single protein product.

Colony Count, Microbial↗

PubMed1995

An improved Escherichia coli-Rhodococcus shuttle vector and plasmid transformation in Rhodococcus spp. using electroporation.

The genetic studies of metabolically diverse Rhodococcus spp. have been hampered by the lack of a system of introducing exogenous DNA. The authors improved an existing Escherichia coli-Rhodococcus shuttle vector (pMVS301) by removing much of the DNA not needed for replication and adding a multicloning site. This improved vector (pBS305) is 7.9 kb in length. Its ability to transform Rhodococcus was tested using electroporation parameters optimized for introduction of pMVS301 into Rhodococcus. Transformation efficiencies as high as 10(5) cfu micrograms-1 DNA were obtained although efficiencies varied depending on the Rhodococcus strain tested. The improved vector pBS305 offers great utility for genetic studies of Rhodococcus because its small size enables movement of large inserts of DNA into Rhodococcus, it has multicloning sites, contains a highly selective thiostrepton marker, and can be replicated in both E. coli and Rhodococcus.

DNA, Bacterial↗

PubMed1980

Identification and mapping of a second proline permease Salmonella typhimurium.

In this paper we demonstrate the existence of a second proline permease, gene proP, in Salmonella typhimurium. Uptake assays demonstrate that this second proline permease has 5 to 10% the uptake rate of the putP permease, the cell's major proline permease, when assayed at 20 microM proline. Genetic mapping by Hfr and P22-mediated genetic crosses placed the second proline permease gene at 92 min on the S. typhimurium genetic map, near the genes for melibiose utilization. F'-mediated complementation tests indicated that Escherichia coli also has the proP gene.

Chromosome Mapping↗