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PubMed2006

Review article: genetic susceptibility and application of genetic testing in clinical management of inflammatory bowel disease.

The volume of research undertaken on the genetic susceptibility of inflammatory bowel disease (IBD) has been tremendous, and over 10 chromosomal regions have been identified by genome-wide scanning. Fine-mapping approaches and candidate gene studies have already led to the identification of several susceptibility genes, including CARD15 (NOD2), DLG5, novel organic cation transporter (OCTN) 1 and 2, and CARD4 (NOD1). The CARD15 gene is the most understood at present and explains around 20% of the genetic predisposition to Crohn's disease. Although the clinical implications of genetic testing are limited at present, genetic research has advanced our understanding of the clinical heterogeneity and the complex interactions between genetic and environmental risk factors in IBD. Genes also interfere with the metabolism of drugs and may influence the clinical response and drug-related toxicity. Ultimately, researchers and clinicians aim to personalize medicine based on a patient's genotype, although azathioprine (thiopurine methyltransferase polymorphisms) is the only drug to date where pharmacogenetics has shown clinical relevance in IBD. In the future, it is anticipated that genetic markers will be implemented in an integrated molecular diagnostic and prognostic approach to managing our patients.

Colitis, Ulcerative↗

PubMed2004

Quantitative genetics of sexually dimorphic traits and capture of genetic variance by a sexually-selected condition-dependent ornament in red junglefowl (Gallus gallus).

We studied the quantitative genetics of sexually selected traits in a captive population of red junglefowl (Gallus gallus L.) using a multi-generational 'animal model' approach. We found significant heritability of mass, tarsus length (both strongly sexually dimorphic), residual mass, and male comb (a fleshy head ornament) length. Residual mass has a genetic correlation between the sexes smaller than unity and so could show partially independent responses to selection in the two sexes. In males, tarsus length and mass were not genetically correlated, and this produced a negative genetic correlation between tarsus length and residual mass. The male red junglefowl's comb, an ornament influencing female choice, is highly condition dependent. We show that expression of this ornament is heritable, however, and shows strong genetic correlation with a condition index, residual mass. Because residual mass is partly influenced by various aspects of condition, it appears that comb size has 'captured' genetic variability in condition.

Analysis of Variance↗

PubMed2006

Genetic testing, genetic information, and the role of maternal-child health nurses in Israel.

PURPOSE: To examine the rate of genetic testing, the characteristics of those who had these tests, and to examine the public's openness to the possibility of expanding nurses' roles in maternal-child health (MCH) clinics to include providing genetic information. DESIGN: The study was conducted in nine MCH clinics in the central district of Israel. All women attending the clinics during 1 week were requested to complete the questionnaire. The sample consisted of 361 participants. FINDINGS: A high rate of genetic testing (80.4%) was shown. Higher education, being secular, and native-born Israeli predicted testing performance. Half of the tested participants reported that they did not understand the test results and were interested in receiving explanations regarding these results. Forty-four percent of respondents were interested in receiving genetic information from an MCH nurse. CONCLUSIONS: A high rate of genetic testing performance was reported. The public reported lack of information regarding genetic tests and their results. An appropriate setting for providing this information is the maternal-child health clinics.

Adult↗

PubMed2000

Genetic erosion in northern marginal population of the common wild rice Oryza rufipogon Griff. and its conservation, revealed by the change of population genetic structure.

In order to monitor genetic erosion within the northern marginal population of common wild rice Oryza rufipogon Griff. from Dongxiang, Jiangxi Province, China, allozyme diversity encoded by 22 loci was analyzed electrophoretically from all the existing subpopulations in 1980, 1985 and 1994. The sample collected from the nine large subpopulations in 1980 showed the highest levels of genetic diversity (A = 1.27, P = 18.20%, Ho = 0.042 and He = 0.049) and a slight deviation from Hardy-Weinberg expectation (F = 0.143), the sample from five moderate ones in 1985 displayed medium levels of genetic diversity (A = 1.14, P = 13.60%, Ho = 0.008 and He = 0.049) and a great deviation from Hardy-Weinberg expectation (F = 0.837), and the sample from two small ones in 1994 demonstrated the lowest levels of genetic diversity (A = 1.09, P = 9.10%, Ho = 0.000 and He = 0.043) and the largest deviation from Hardy-Weinberg expectation (F = 1.000). The results not only documented the genetic erosion stemmed from the extinction of the subpopulations, but also revealed the drastic change of the population genetic structure due to the reduction of the population. Finally, some conservation strategies for the population are proposed.

DNA, Plant↗

PubMed1997

Evolutionary dynamics of genetic variation in Epstein-Barr virus isolates of diverse geographical origins: evidence for immune pressure-independent genetic drift.

The question whether immune pressure exerted by cytotoxic T lymphocytes (CTLs) can influence the long-term evolution of genetically stable viruses such as Epstein-Barr virus (EBV) has generated considerable scientific interest, primarily due to its important implications for the overall biology of the virus. While arguing for a role of CTLs in the evolution of viruses, it is important to differentiate between genetic variation in virus and immune recognition of these variant virus by CTLs. To assess the role of genetic selection in the long-term evolution of EBV, we have analyzed a large panel of type 1 EBV isolates from African, Southeast Asian, Papua-New Guinean (PNG), and Australian Caucasian individuals. Seven different regions of the EBV genome, which include nine CTL epitopes restricted through a range of HLA class I alleles, were sequenced and compared. Although numerous nucleotide changes were identified within these isolates, comparison of synonymous and nonsynonymous substitutions in the CTL epitope indicated that the genetic variation was generated mostly independently of immune selection pressure. Surprisingly, an inverse correlation between genetic variation within certain CTL epitopes and the frequency distribution of HLA alleles that present the CTL epitopes was seen, suggesting that the evolutionary pressures on the CTL epitopes of the virus may be toward their conservation rather than their inactivation. Furthermore, molecular evolutionary genetic analysis of nucleotide sequences revealed that viral isolates from PNG are evolving as a lineage distinct from isolates from African, Southeast Asian, and Australian Caucasian individuals.

Amino Acid Sequence↗

PubMed1986

Genetic structure of the population with rheumatoid arthritis in north east England: a genetic approach to define different subtypes.

Clinically and immunologically rheumatoid arthritis (RA) is possibly a heterogeneous disorder. Despite numerous efforts clearer definition of this heterogeneity has been of limited success. Measurements of rheumatoid factor (RF) and antinuclear antibodies (ANA) by conventional methods define subpopulations of patients with RA and in a few recent studies an association of human leucocyte antigens (HLA) undoubtedly indicates the immunogenetic differences in the susceptibility of RA patients with different status of autoantibodies. The studies on a few isolated non-HLA genetic markers in RA are controversial. To understand the role of genetic factors in susceptibility 24 single gene characters other than HLA were investigated in 225 patients with RA classified by humoral status (presence or absence of RF and ANA) into three groups and in 104 healthy control individuals from the north east of England. Locus by locus comparison suggested associations of MN, Lewis, and Bf system with RF positive patients. Although the associations with MN and Lewis blood groups require further investigations, the involvement of the Bf locus is in agreement with the immunological component of the disease suggested by HLA associations and it could be due to the phenomenon of linkage disequilibrium. Measures of genetic distance applied to the subpopulations of patients with RA, divided according to the presence or absence of humoral factors, suggest that RF+ ANA+, RF- ANA-, and RF+ ANA- subgroups are distinct genetic diseases, each affecting a different subsection of the population which is genetically distinct. Such genetic heterogeneity may suggest a different pathogenetic mechanism for each of these subpopulations of rheumatoid arthritis.

Antibodies, Antinuclear↗

PubMed2004

Genetics of LDL particle heterogeneity: from genetic epidemiology to DNA-based variations.

Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles. This work is an attempt to summarize the growing evidence of genetic control on LDL particle heterogeneity with the aim of providing a concise overview in one read.

Animals↗

PubMed1989

Genetic support groups: a continuum of genetic services.

Genetic counseling for parents of children with a genetic disorder is only the beginning of needed support services. One important member of the health team is the genetic support group. Within a genetic support organization, individuals and families discover that they are not alone and that they can be helped by others affected by similar genetic diagnoses. Ideally, a strong partnership between the support group members and interested health professionals will enable the organization to meet its goals. Networks, such as the Alliance of Genetic Support Groups, can help member organizations become a unified force without taking away their individual agendas.

Genetic Counseling↗

PubMed2005

Atherosclerosis: from genetic polymorphisms to system genetics.

It is generally considered that the genetics of atherosclerosis and its complications involves a large number of genes with common alleles having weak effects on disease risk but possibly interacting with each other and with non-genetic factors. In such a complex system, absence of marginal effects (effects of polymorphisms considered one at a time) is insufficient to exclude the implication of a polymorphism on disease risk. Investigating polymorphisms and even genes one by one is no longer appropriate. It is necessary to focus on biological systems and integrate the contribution of genetic as well as non-genetic factors and their interactions. Hopefully, system genetics will ultimately improve our understanding of the genetic architecture of complex traits.

Animals↗

PubMed2001

Effect of race, genetic population structure, and genetic models in two-locus association studies: clustering of functional renin-angiotensin system gene variants in hypertension association studies.

Previous genetic association studies have overlooked the potential for biased results when analyzing different population structures in ethnically diverse populations. The purpose of the present study was to quantify this bias in two-locus association studies conducted on an admixtured urban population. We studied the genetic structure distribution of angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen methionine/threonine (M/T) polymorphisms in 382 subjects from three subgroups in a highly admixtured urban population. Group I included 150 white subjects; group II, 142 mulatto subjects, and group III, 90 black subjects. We conducted sample size simulation studies using these data in different genetic models of gene action and interaction and used genetic distance calculation algorithms to help determine the population structure for the studied loci. Our results showed a statistically different population structure distribution of both ACE I/D (P = 0.02, OR = 1.56, 95% CI = 1.05-2.33 for the D allele, white versus black subgroup) and angiotensinogen M/T polymorphism (P = 0.007, OR = 1.71, 95% CI = 1.14-2.58 for the T allele, white versus black subgroup). Different sample sizes are predicted to be determinant of the power to detect a given genotypic association with a particular phenotype when conducting two-locus association studies in admixtured populations. In addition, the postulated genetic model is also a major determinant of the power to detect any association in a given sample size. The present simulation study helped to demonstrate the complex interrelation among ethnicity, power of the association, and the postulated genetic model of action of a particular allele in the context of clustering studies. This information is essential for the correct planning and interpretation of future association studies conducted on this population.

Alleles↗

PubMed2000

[Genetics of human obesity: results from genetic epidemiology studies].

Obesity is a complex disease resulting from the interaction between a variety of genetic and environmental factors. Research conducted over the past 20 years in the field of genetic epidemiology has contributed to increase our understanding of the genetic basis of obesity. It is now clearly established that overweight and obesity aggregate in families. Studies have shown that the prevalence of obesity is 2 to 8 times higher in families of obese individuals than in the population at large and that the familial risk increases with the severity of obesity. The heritability of the various obesity phenotypes varies considerably depending on the phenotype under study, the nature of familial data and the methods used to compute heritability estimates. Heritability estimates tend to be highest when derived from twin studies (50% à 80%) while they are the lowest when derived from adoption studies (10% à 30%). Several studies have reported the presence of major gene effects for body mass index, body fat and abdominal visceral fat. Finally, there is increasing evidence that shared genetic factors could play a role in determining the covariation between obesity and its major co-morbidities, including blood pressure, insulin resistance, diabetes and dyslipidemia. This genetic covariation is however moderate and accounts for a smaller percentage of the variance compared to the genetic effects reported for each of the phenotypes studied independently.

Adipose Tissue↗

PubMed1999

Potential usefulness of preimplantation genetic diagnosis in the control and prevention of genetic diseases.

Prenatal diagnosis of molecular mutations can be of immense value, since diagnosis followed by genetic counselling provides the most appropriate approach to genetic diseases control and prevention. However, ethical, psychosocial and religious considerations hamper adoption of prenatal diagnosis in communities where termination of a pregnancy may not be acceptable. Recently, preimplantation genetic diagnosis has attracted considerable interest. This involves in vitro fertilization, followed by genetic disorder diagnosis using polar bodies or cells extracted from a blastomere stage. The normal blastomere is implanted in the womb and pregnancy proceeds naturally. If an abnormality is diagnosed, the blastomere is not implanted, thus preventing pregnancy with the affected fetus. This paper outlines the potential usefulness of preimplantation genetic diagnosis in the control and prevention of genetic disease in our part of the world.

Attitude to Health↗

PubMed2004

[Active screening for genetic pathology in newborns. II. Genetic counseling and prenatal diagnosis in high risk families].

Active screening for genetic pathology over a period of 12 years (1990-2001) involved examination of 29629 newborns at the Clinic of Obstetrics and Gynaecology. Congenital anomalies were detected in 1244 cases (live-, stillbirths and terminated pregnancies) which gives an average incidence rate of 42.0 per 1000 among the studied population. Chromosomal abnormalities were diagnosed in 70 cases (5.6%), single gene conditions--in 164 cases (13.2%), multifactorially determined conditions--in 449 cases (36.1%). The total genetic contribution of all recognized cases with genetic conditions was 54.9% (683 cases). Genetic counseling was provided to 560 out of 1244 (45%) couples who given births to affected children. During that period prenatal diagnosis was performed on 110 (44%) pregnancies and most of them (90%) ended successfully (healthy child was born). Our strategy for identifying CD by active screening enabled us to provide more accurate genetic counselling and prenatal diagnosis for genetic diseases. Screening of newborn population is likely to be an effective and necessary service.

Bulgaria↗

PubMed1991

Genetic discrimination: the use of genetically based diagnostic and prognostic tests by employers and insurers.

Genetic discrimination is detrimental to public health programs, as well as to society generally. Advances in genetic testing and screening, accelerated and prompted by the Human Genome Initiative, increase society's ability to detect and monitor chromosomal differences. These technologies and their resulting genomic data will enhance medical science, but may also encourage discrimination. Although few employers or insurers currently utilize genetic screening, testing or data, rising employee benefit costs and market forces create powerful incentives for usage. Current municipal, state and federal laws, including the Americans with Disabilities Act (ADA), may not sufficiently protect employees and insureds from genetic discrimination. While municipal and state protections should not be overlooked, the ADA's sweeping scope may currently provide the most comprehensive safeguard. Federal laws banning discrimination on the basis of race or sex might also successfully redress some forms of genetic discrimination. Genetic technologies' advent necessitates efforts to rectify state and federal statutory coverage gaps, strictly regulate employers and produce comprehensive guidelines regarding its use.

Persons with Disabilities↗

PubMed1989

The economics of clinical genetics services. III. Cognitive genetics services are not self-supporting.

We investigated the amount of time required to provide, and the charges and reimbursement for, cognitive genetics services in four clinical settings. In a prenatal diagnostic center, a mean of 3 h/couple was required to provide counseling and follow-up services with a mean charge of $30/h and collection of $27/h. Only 49% of personnel costs were covered by income from patient charges. In a genetics clinic in a private specialty hospital, 5.5 and 2.75 h were required to provide cognitive services to each new and follow-up family, respectively. The mean charge for each new family was $25/h and for follow-up families $13/h. The amount collected was less than 25% of that charged. In a pediatric genetics clinic in a large teaching hospital, new families required a mean of 4 h and were charged $28/h; follow-up families also required a mean of 4 h, and were charged $15/h. Only 55% of the amounts charged were collected. Income from patient charges covered only 69% of personnel costs. In a genetics outreach setting, 5 and 4.5 h were required to serve new and follow-up families, respectively. Charges were $25/h and $12/h, and no monies were collected. In all clinic settings, less than one-half of the total service time was that of a physician, and more than one-half of the service time occurred before and after the clinic visit. In no clinic setting were cognitive genetics services self-supporting. Means to improve the financial base of cognitive genetics services include improving collections, increasing charges, developing fee schedules, providing services more efficiently, and seeking state, federal, and foundation support for services.

Costs and Cost Analysis↗

PubMed1984

Quantitative genetics and the evolution of ontogeny. II. Genetic and environmental correlations among age-specific characters in randombred house mice.

In this study, phenotypic, genetic, maternal and residual environmental correlations among all pairs of six ages (17, 24, 31, 38, 45 and 52 days) were calculated for each of five morphometric characters (body weight, head length, trunk length, trunk circumference, and tail length) in ICR randombred house mice. The maternal correlations between ages averaged nearly unity for all characters, and the overall level (and integration, I) of the genetic correlations (mean level = 0.82, mean I = 0.85) was greater than that for the residual environmental correlations (mean level = 0.26, mean I = 0.32). The patterns of the phenotypic and genetic correlations were similar, with the highest correlations being between contiguous ages and a relatively smooth decrease in correlations for increasingly distant ages. Nearly all of the genetic covariation among ages was explained by the first (average = 86%) and second (average = 14%) components derived from principal components analysis of the genetic correlations. Genes with basically equal pleiotropic effects presumably generated the first component, genes with different effects among ages the second component. From the patterns of genetic correlations, it is predicted that direct selection on any given age would result in a moderate, positive response at most other ages, with more change in the height relative to the shape of the growth curve for each characteristic.

Aging↗

PubMed1997

Simultaneous genetic chemoprotection of normal marrow cells and genetic chemosensitization of breast cancer cells in a mouse cancer gene therapy model.

Repeated exposures to high doses of chemotherapy are often required to eradicate solid tumors. The success of such high-dose therapy is often limited by the myelosuppressive and toxic effects of these drugs on bone marrow cells and by the intrinsic resistance of the cancer cells to chemotherapy. To test ways of using genetic modification of somatic cells to circumvent both of these problems, we first genetically modified normal bone marrow cells with multidrug resistance-1 (MDR-1) cDNA retroviral vectors to render these cells more resistant to p-glycoprotein-transported agents. Experiments conducted previously in a mouse model in our laboratory (E. G. Hanania et al., Cancer Gene Ther., 2: 251-261, 1995; E. G. Hanania and A. B. Deisseroth, Cancer Gene Ther., 1: 21-25, 1994), which involve transplantation of mouse marrow cells modified with the human MDR-1 cDNA, showed that the majority of the marrow cells of these animals were resistant to repetitive administration of myelotoxic doses of Taxol, a MDR-1-transported drug. Next, to test the effects of genetically modifying marrow cells to make them resistant to chemotherapy, and genetically modifying tumor cells to make them more sensitive to chemotherapy, a mouse breast cancer cell line was transfected with a plasmid expression vector that contained a wild-type p53 chemosensitization transcription unit. Others have shown that restoration of the p53 gene can lead to decreased proliferation, reduced tumorigenicity, and increased sensitivity to chemotherapy-induced apoptosis. In this animal model, the simultaneous use of both chemoprotection and chemosensitization vectors, which provided protection of the normal cells to the chemotherapy and at the same time sensitized the tumor cells to the toxic effects of the chemotherapy, resulted in levels of in vivo tumor reduction that were not possible when either genetic chemoprotection of marrow cells or chemosensitization of tumor cells was used alone. These data should be of interest to those who are studying ways of using genetic modification to improve the outcome of established chemotherapy treatment programs for solid tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2024

Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

Humans↗