Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial.

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.

Contribution of 30 Biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: The MONICA, risk, genetics, archiving and monograph (MORGAM) biomarker project

Background— Cardiovascular risk estimation by novel biomarkers needs assessment in disease-free population cohorts, followed up for incident cardiovascular events, assaying the serum and plasma archived at baseline. We report results from 2 cohorts in such a continuing study.
Methods and Results— Thirty novel biomarkers from different pathophysiological pathways were evaluated in 7915 men and women of the FINRISK97 population cohort with 538 incident cardiovascular events at 10 years (fatal or nonfatal coronary or stroke events), from which a biomarker score was developed and then validated in the 2551 men of the Belfast Prospective Epidemiological Study of Myocardial Infarction (PRIME) cohort (260 events). No single biomarker consistently improved risk estimation in FINRISK97 men and FINRISK97 women and the Belfast PRIME Men cohort after allowing for confounding factors; however, the strongest associations (with hazard ratio per SD in FINRISK97 men) were found for N-terminal pro-brain natriuretic peptide (1.23), C-reactive protein (1.23), B-type natriuretic peptide (1.19), and sensitive troponin I (1.18). A biomarker score was developed from the FINRISK97 cohort with the use of regression coefficients and lasso methods, with selection of troponin I, C-reactive protein, and N-terminal pro-brain natriuretic peptide. Adding this score to a conventional risk factor model in the Belfast PRIME Men cohort validated it by improved c-statistics (P=0.004) and integrated discrimination (P<0.0001) and led to significant reclassification of individuals into risk categories (P=0.0008).
Conclusions— The addition of a biomarker score including N-terminal pro-brain natriuretic peptide, C-reactive protein, and sensitive troponin I to a conventional risk model improved 10-year risk estimation for cardiovascular events in 2 middle-aged European populations. Further validation is needed in other populations and age groups.

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics

Objectives: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals.

Breast cancer genetics: Unsolved questions and open perspectives in an expanding clinical practice

Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine in women. Only 5-10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes, such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are likely to be of etiological importance in other families. This review addresses the current knowledge of breast cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology, prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer susceptibility may become widely available in the future, and has important ethical and management implications. (C) 2004 Wiley-Liss, Inc.

Genetics of narcolepsy and other major sleep disorders.

One third of the population is affected by a sleep disorder with a major social, medical, and economic impact. Although very little is known about the genetics of normal sleep, familial and twin studies indicate an important influence of genetic factors. Most sleep disorders run in families and in several of them the contribution of genetic factors is increasingly recognised. With recent advances in the genetics of narcolepsy and the role of the hypocretin/orexin system, the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth indepth investigation.

Life Insurance and Genetics: A Comparative International Overview

La possibilité d'utiliser l'information génétique dans le domaine de l'assurance vie a soulevé des discussions autour des politiques et des législations, et ce, au niveau international, régional et national. Dans certains pays offrant des services de santé universels, le débat sur la génétique et l'assurance vie a envisagé de possibles restrictions quant à l'utilisation de l’information génétique en matière d’assurance.

Physicians, genetics and life insurance

Par contraste avec de nombreux pays européens qui ont clarifié leur position vis-à-vis la génétique et l’assurance vie, le Canada en est encore à établir la sienne. Toute initiative en ce domaine doit être basée sur une compréhension des mécanismes de l’assurance vie, de la nature de l’information génétique, de l’historique du débat au sujet de la génétique et de l’assurance vie au Canada et, finalement, des raisons pour lesquelles un groupe de travail canadien a décidé de relever le défi.

Genetics and Life Insurance in Canada: Points to Consider

Par contraste avec de nombreux pays européens qui ont clarifié leur position vis-à-vis la génétique et l’assurance vie, le Canada en est encore à établir la sienne. Toute initiative en ce domaine doit être basée sur une compréhension des mécanismes de l’assurance vie, de la nature de l’information génétique, de l’historique du débat au sujet de la génétique et de l’assurance vie au Canada et, finalement, des raisons pour lesquelles un groupe de travail canadien a décidé de relever le défi.

The genetics of diabetes mellitus

Genes play an important role in the development of diabetes mellitus. Putative susceptibility genes could be the key to the development of diabetes. Type 1 diabetes mellitus is one of the most common chronic diseases of childhood. A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. The pathogenetic sequence leading to the selective autoimmune destruction of islet beta-cells and development of Type 1 diabetes involves genetic factors, environmental factors, immune regulation and chemical mediators. Unlike Type 1 diabetes mellitus, Type 2 diabetes is often considered a polygenic disorder with multiple genes located on different chromosomes being associated with this condition. This is further complicated by numerous environmental factors which also contribute to the clinical manifestation of the disorder in genetically predisposed persons. Only a minority of cases of type 2 diabetes are caused by single gene defects such as maturity onset diabetes of the young (MODY), syndrome of insulin resistance (insulin receptor defect) and maternally inherited diabetes and deafness (mitochondrial gene defect). Although Type 2 diabetes mellitus appears in almost epidemic proportions our knowledge of the mechanism of this disease is limited. More information about insulin secretion and action and the genetic variability of the various factors involved will contribute to better understanding and classification of this group of diseases. This article discusses the results of various genetic studies on diabetes with special reference to Indian population.