Genes, Behavior, and the Social Environment Moving Beyond the Nature/Nurture Debate (2006) / Chapter Skim
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3 Genetics and Health
3 Genetics and Health
Pages 44-67
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From page 44... ...
This chapter focuses on what is known or theorized about the direct link between genes and health and what still must be explored in order to understand the environmental interactions and relative roles among genes that contribute to health and illness. GENETIC SUSCEPTIBILITY For more than 100 years, human geneticists have been studying how variations in genes contribute to variations in disease risk.
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From page 45... ...
Each of these approaches will be discussed below. In general, diseases with simple Mendelian patterns of inheritance tend to be relatively uncommon or frequently rare, with early ages of onset, such as phenylketonuria, sickle cell anemia, Tay-Sachs disease, and cystic fibrosis.
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From page 46... ...
. As opposed to the Mendelian approach, the second approach to studying how variations in genes contribute to variations in disease risk focuses on understanding the genetic susceptibility to diseases as the consequence of the joint effects of many genes, each with small to moderate effects (i.e., polygenic models of disease)
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From page 47... ...
The contributions of these factors have been shown to vary by age and population. When significant evidence of genetic involvement is established, the next step is to identify the responsible genes and the mutations that are associated with increased or decreased risk, using either genetic linkage analysis or genetic association studies.
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From page 48... ...
. Because the mode of inheritance is often not clear for common diseases, an alternative approach to classic linkage analysis was developed to capitalize on the basic genetic principle that siblings share half of their alleles on average.
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From page 49... ...
can detect polymorphisms occurring in 1 to 3 percent of the population with approximately 95 percent confidence. The Human DNA Polymorphism Discovery Program of the National Institute of Environmental Health Sciences' Environmental Genome Project is one example of the application of automated DNA sequencing technologies to identify SNPs in human genes that may be associated with disease susceptibility and response to environment (Livingston et al., 2004)
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From page 50... ...
GENE-ENVIRONMENT AND GENE-GENE INTERACTIONS The study of gene-environment and gene-gene interactions represents a broad class of genetic association studies focused on understanding how human genetic variability is associated with differential responses to environmental exposures and with differential effects depending on variations in other genes. To illustrate the concept of gene-environment interactions, recent studies that identify genetic mutations that appear to be associated with differential response to cigarette smoke and its association with lung cancer are reviewed below.
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From page 51... ...
there was a 5.2 time greater risk of lung cancer in nonsmokers and a 70 percent reduction of risk in the heavy smokers compared to individuals with no mutations. The protective effect of these genetic variations in heavy smokers may be caused by the differential increase in the activity of these protective genes stimulated by heavy smoking.
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From page 52... ...
and can prevent resources from being wasted. Variation in the DNA sequences associated with the regulation of a gene's expression are therefore likely candidates for understanding gene-environment interactions at the molecular level, since these variations will affect whether an environmental signal transduced to the nucleus will successfully bind to the promoter sequence in the gene and stimulate or repress gene expression.
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From page 53... ...
An Example of a Single-Gene Disorder with Significant Clinical Variability: Sickle Cell Disease3 Sickle cell disease refers to an autosomal recessive blood disorder caused by a variant of the -globin gene called sickle hemoglobin (Hb S)
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From page 54... ...
The process be gins shortly after conception when the yolk of the egg sac expresses genes that are responsible for the embryonic hemoglobin are deactivated, while the genes responsible for producing fetal hemoglobin in the liver are activated. Upon birth, the adult globin genes are activated and the bone marrow stem cells begin to produce adult hemoglobin and red blood cells (Rimoin et al., 2002)
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From page 55... ...
. There are two cardinal pathophysiologic features of sickle cell disease -- chronic hemolytic anemia and vasoocclusion.
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From page 56... ...
How that genetic variation is associated with particular disease risk is the focus of much current research. For common diseases such as CVD, hypertension, cancer, diabetes, and many mental illnesses, there is a growing appreciation that different genes and different genetic variations can be involved in different aspects of their natural history.
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From page 57... ...
It is well known that many social and behavioral factors ranging from socioeconomic status, job stress, and depression, to smoking, exercise, and diet affect cardiovascular disease risk (see Chapters 2, 3, and 6 for more detailed discussion of these factors)
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Researchers have provided a few well-established examples of differences in individual drug response that have been ascribed to genetic variations in a variety of cellular drug disposition machinery, such as drug transporters or enzymes responsible for drug metabolism (Evans and McLeod, 2003)
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New pharmacogenetic studies have indicated that these ADRs may be the result of genetic variations in serotonin transporter genes and cytochrome P450 genes. Further study and replication of these findings are necessary.
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From page 60... ...
Another key component of utilizing genetics to improve prevention and reduce disease is an understanding of the distribution of the genetic variations in the populations being served. GENETICS OF POPULATONS AS RELATED TO HEALTH AND DISEASE Human populations differ in their distribution of genetic variations.
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From page 61... ...
For example, the current population of the United States and much of North America is very diverse genetically as a consequence of the mixing of many people from many different countries and continents. A central reason for studying the origins and nature of human genetic variation is that the similarities and differences in the type and frequencies of genetic variations within and among populations can have a profound impact on studies that attempt to understand the influence of genes on disease risk.
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From page 62... ...
Another key consideration in understanding the relationship between genetic variations and measures of disease risk is the population differences in the correlations between genotype frequencies at different SNP locations. There are two common reasons why the frequency of an allele or genotype at a particular SNP could be correlated with the frequency of an allele or genotype for a different SNP.
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From page 63... ...
This phenomenon is called "population stratification" in epidemio logic studies investigating the effect of a genetic factor on disease, and it is a form of confounding. Population stratification refers to the presence of sub groups -- for example ethnic groups -- in the sample, which could potentially cause a spurious association between genetic variations and trait.
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From page 64... ...
Second, geneticists only recently have developed the knowledge base or methods needed to measure genetic variations and their metabolic consequences with sufficient ease and cost-effectiveness so that the large number of genes thought to be involved can be studied. With the completion of the Human Genome Project in 2003, many different scientific entities (e.g., the Environmental Genome Project and the International HapMap Consortium)
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From page 65... ...
The complex genetic and environmental architecture of multifactorial diseases is not easily detected or deciphered using the traditional statistical modeling methods that are focused on the estimation of a single overall model of disease for a population. For example, using traditional logistic regression methods it would be simply impossible to enter all the hundreds of genetic variations that are thought to be involved in CVD risk or in any of the other common disease complexes currently being studied.
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1999. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.
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2002. Characterization of apolipoprotein E genetic variations in Taiwanese association with coronary heart disease and plasma lipid levels.
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