Genes and genetics explained - Better Health Channel
But it is only now that researchers are figuring out the relationship between diet, digestion and the effect on one's health and immune system. Traditionally, the process of gene discovery begins with a linkage. Particular interest has been shown in the relationship between 'race', ethnicity and health. There has been much discussion and debate about whether genetic .
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.
For example, there are likely to be genes whose variations are associated with a predisposition toward the initiation of disease and other genes or gene variations that are involved in the progression of a disease to a clinically defined endpoint.
Genetics and Health - Genes, Behavior, and the Social Environment - NCBI Bookshelf
Furthermore, an entirely different set of genes may be involved in how an individual responds to pharmaceutical treatments for that disease. There also are likely to be genes whose variability controls how much or how little a person is likely to be responsive to the environmental risk factors that are associated with disease risk. In many ways, we are only at the beginning the process of developing a true understanding of how genomic variations give rise to disease susceptibility.
Indeed many would argue that, without incorporating the equally important role of the environment, we will never fully understand the role of genetics in health. As progress is made through utilizing the new technologies for measuring biological variation in the genome, transcriptome, proteome, and metabonome, we are likely to have to make large shifts in our conceptual frameworks about the roles of genes in disease. Global patterns of genomic susceptibility are likely to emerge only when we consider the influence of the many interacting components working simultaneously that are dependent on contexts such as age, sex, diet, and physical activity that modify the relationship with risk.
For the most part, we are still at the stage of documenting the complexity, finding examples and types of genetic susceptibility genes, understanding disease heterogeneity, and postulating ways to develop models of risk that use the totality of what we know about human biology, from our genomes to our ecologies to model risk.
Cardiovascular Disease CVD The study of CVD can be used to illustrate the issues that are encountered in using genetic information in order to understand the etiology of the most common chronic diseases as well as in identifying those at highest risk of developing these diseases. CVD research has found many high-risk environmental agents and hundreds of genes, each with many variations that are thought to influence disease risk.
As the number of interacting agents involved increases, a smaller number of cases of disease will be found to have the same etiology and be associated with a particular genotype Sing et al. In attempting to sort out the relative contributions of genes and environment to CVD, a large array of factors must be considered, from the influence of genes on cholesterol e.
Please see Chapters 4 and 6 for further discussion of effects of social environment on CVD. 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 23and 6 for more detailed discussion of these factors.
First, how are the social factors embodied such that an interaction with a particular genotype can be associated with differential risk?
Pharmacogenetics It has been well established that individuals often respond differently to the same drug therapy. The drug disposition process is a complex set of physiological reactions that begin immediately upon administration. The drug is absorbed and distributed to the targeted areas of the body where it interacts with cellular components, such as receptors and enzymes, that further metabolize the drug, and ultimately the drug is excreted from the body Weinshilboum, At any point during this process, genetic variation may alter the therapeutic response of an individual and cause an adverse drug reaction ADR Evans and McLeod, It has been estimated that 20 to 95 percent of variations in drug disposition, such as ADRs, can be attributed to genetic variation Kalow et al.
Sensitivity to both dose-dependent and dose-independent ADRs can have roots in genetic variation. Polymorphisms in kinetic and dynamic factors, such as cytochrome P and specific drug targets can cause these individuals susceptibilities to ADRs.
While the characteristics of the ADR dictate the true significance of these factors, in most cases, multiple genes are involved Pirmohamed and Park, Future analyses using genome-wide SNP profiling could provide a technique for assessing several genetic susceptibility factors for ADRs and ascertaining their joint effects. One of the challenges to the study of the relationship between genetic variation and ADRs is an inadequate number of patient samples. To remedy this problem, Pirmohamed and Park have proposed that prospective randomized controlled clinical trials become a part of standardized practice to ultimately prove the clinical utility of genotyping all patients as a measure to prevent ADRs.
Here we review some of the current work in pharmacogenetics as an example of what might be expected to arise from rigorous study of the interaction between social, behavioral, and genetic factors. 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, With the knowledge that the HER2 gene is overexpressed in approximately one fourth of breast cancer cases, researchers developed a humanized monoclonal antibody against the HER2 receptor in hopes of inhibiting the tumor growth associated with the receptor.
Genotyping advanced breast cancer patients to identify those with tumors that overexpress the HER2 receptor has produced promising results in improving the clinical outcomes for these breast cancer patients Cobleigh et al. A therapeutic class of drugs called thiopurines is used as part of the treatment regimen for childhood acute lymphoblastic leukemia.
One in Caucasians has a genetic variation that results in low or nonexistent levels of thiopurine methyltransferase TPMTan enzyme that is responsible for the metabolism of the thiopurine drugs. If patients with this genetic variation are given thiopurines, the drug accumulates to toxic levels in their body causing life-threatening myelosuppression.
Assessing the TPMT phenotype and genotype of the patient can be used to determine the individualized dosage of the drug Armstrong et al. The family of liver enzymes called cytochrome Ps plays a major role in the metabolism of as many as 40 different types of drugs. Genetic variants in these enzymes may diminish their ability to effectively break down certain drugs, thus creating the potential for overdose in patients with less active or inactive forms of the cytochrome P enzyme.
Varying levels of reduced cytochrome P activity is also a concern for patients taking multiple drugs that may interact if they are not properly metabolized by well-functioning enzymes. Strategies to evaluate the activity level of cytochrome P enzymes have been devised and are valuable in planning and monitoring successful drug therapy.
Some pharmaceutical drug trials are now incorporating early tests that evaluate the ability of differing forms of cytochrome P to metabolize the new drug compound Obach et al. Some pharmacogenetics research has focused on the treatment of psychiatric disorders. With the introduction of a class of drugs known as selective serotonin re-uptake inhibitors SSRIspharmacological treatment of many psychiatric disorders changed drastically.
SSRIs offer significant improvements over the previous generation of treatments, including improved efficacy and tolerance for many patients. New pharmacogenetic studies have indicated that these ADRs may be the result of genetic variations in serotonin transporter genes and cytochrome P genes.
Further study and replication of these findings are necessary. If the characterization of the genetic variations is completed and is fully understood it would be possible to screen and monitor patients using genotyping techniques to create individualized drug therapies similar to those discussed above Mancama and Kerwin, A significant challenge to the development of individualized drug therapies is the often polygenic or multifactorial inherited component of drug responses.
Genes made Easy | East London Genes & Health
Isolating the polygenic determinants of the drug responses is a sizable task. This knowledge can aid in directing genome-wide searches for gene variations associated with drug effects and subsequent candidate-gene approaches of investigation.
It is not enough to show an association; characterization of the underlying biological mechanisms is an essential component of moving genetic findings into the area of risk reduction.
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.
This is a consequence of their historical patterns of mutation, migration, reproduction, mating, selection, and genetic drift. Inherited mutations typically occur during gametogenesis within a single individual and then can be passed on to offspring for many generations. Whether that mutation goes on to become a prevalent polymorphism i. The number of children in a family also influences the prevalence of the mutation, and this is often tied to environmental factors that impact fertility and mating patterns that influence the speed with which a private mutation becomes a public polymorphism.
There are well-known examples of what are called founder mutations in which this trajectory can be documented. For example, one particular district in what is Quebec Canada today was originally founded by only a few families from a particular French province. One of the founding fathers carried a 10kb deletion in his LDL receptor LDL-R gene that was passed down through the generations quickly and today is carried by 1 in French Canadians in northeastern Quebec.
This mutation is associated with familial hypercholesterolemia, and French Ca nadians have one of the highest prevalences of this disease in the world because of the small founding populations followed by population expansion Moorjani et al. There are also a number of examples where mutations that arise in an individual become more prevalent because of the selective advantage they impart on their carriers.
The best known example is the mutation associated with sickle cell anemia. The geographical pattern of this mutation strongly mirrors the geographical pattern of malarial infection. It has been molecularly demonstrated that individuals carrying the sickle cell mutation have a resistance to malarial infection.
Because many of the selection pressures that may have given rise to the current distribution of mutations in particular populations are in our evolutionary past, it is difficult to assess how much variation within or among populations is due to these types of selection forces.
Another major force in determining the distribution of genetic variations within and among human populations is their migration and reproductive isolation. According to our best knowledge, one of the most important periods in human evolution occurred approximatelyyears ago, when some humans migrated to other continents from the African basin and established new communities with relative reproductive isolation.
Genetic differences among people in different geographical areas have been associated with the concept of race for hundreds of years. Although race is still used as a label, the original concept of race as genetically distinct subspecies of humans has been rejected through modern genetic information. For numerous reasons, discussed in the section below, it is more appropriate to reconceptualize the old genetics of race into a more accurate genetics of ancestry.
In addition to distant evolutionary patterns of migration, more modern migration patterns also have had a profound effect on the genetics of populations. 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.
For example, some genetic variations, such as the apolipoprotein E protein polymorphisms, are found in every population and have very similar genotype frequencies around the world Wu et al. Other mutations such as the 10kb deletion in the LDL-R gene described above are more population-specific variations. Furthermore, from a statistical point of view, the effect of a genetic variation on the continuum of risk found in any population is correlated with its frequency.
For example, common genetic polymorphisms with frequencies near 50 percent cannot be associated with large phenotypic effects within a population because the genotype classes each represent a large fraction of the population and, since most risk is normally distributed, the average risk for a highly prevalent genotype class cannot deviate from the overall risk of the population to any large degree.
This correlation between genotype frequency and effect does not mean that common variations cannot be significant in their effects.
The statistical significance of an association between a genetic variant and a disease is a joint function of sample size and the size of the effect.
In addition, genetic research among populations that differ in their genotype frequencies can differ in their inferences about which polymorphisms have significant effects even if the absolute phenotypic effect is the same. See Cheverud and Routman for a more formal statistical explanation of this phenomenon and its impact on assessing gene-gene interactions.
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. When mutations arise, they occur on a particular genetic background, which creates a correlation with the other SNPs on the chromosome.
Second, the mixing of populations known as admixture that occurs typically through migration means that SNPs with population-specific frequencies will be correlated in a larger mixed sample. In this case, population stratification is the cause of the correlation, and there has been much genetic epidemiological research on this phenomenon and how to control for it.
Population stratification is thought to be a possible source of spurious genetic associations with disease see Box When the risk of disease varies between two ethnic groups, any genetic or environmental factor that also varies between the groups will appear to be related to disease. This new century has been characterized by huge advances in our understanding of Mendelian disorders with severe clinical outcomes.
However, the Men delian paradigm has failed to elucidate the genetic contribution to susceptibility to most common chronic diseases, which researchers know have a substantial genetic component because of their familial aggregation and studies that demonstrate significant heritabilities for these diseases.
Likewise, environmental and social epidemiological studies have been wildly successful in illuminating the role of many environmental factors such as diet, exercise, and stress on disease risk. However, these environmental factors still do not, by themselves, fully explain the variance in the prevalence of several diseases in different populations.
Researchers are only now beginning to study in earnest the potential interactions between the genetic and environmental factors that are likely to be contributing to a large fraction of disease in most populations.
There is much that can be done to incorporate measures of social environment into genetic studies and to also incorporate genetic measures into social epidemiological studies. Over the last two decades, progress in identifying specific genes and mutations that explain genetic susceptibility to common conditions has been relatively slow, for a variety of reasons. Any single genetic or environmental factor is expected to explain only a very small fraction of disease risk in a population.
Moreover, these factors are expected to interact, and other biological processes e. An accurate phenotypic definition of disease and its subtypes is crucial to identifying and understanding the complexities of disease-specific genetic and environmental causes.
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 inmany different scientific entities e. At present, the largest dataset on human variation is being generated by the International HapMap Project, 4 which is genotyping millions of SNPs on individuals from 4 geographically separated sites from around the world.
The International HapMap Project has greatly increased the number of validated SNPs available to the research community to be used to study human variation and is producing a map of genomic haplotypes in four populations with ancestry from parts of Africa, Asia, and Europe. In addition, high-throughput methods of genotyping large numbers of SNPs thousands in large epidemiological cohorts are only now becoming available see above.
Unfortunately, high-throughput methods of measuring the environment have not kept a similar pace. For many studies of common disease, a rate-limiting step to increasing our understanding will continue to be the difficult and costly measurement of environmental factors.
Finally, progress also has been hampered because of a lack of adequate investment in developing new methods of analysis that can incorporate the high-dimensional biological reality that we can now measure. 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. Beyond the obvious issues of power and overdetermination in such a large-scale model, we also do not know how to model or interpret interactions among many factors simultaneously or how to incorporate the rare, large effects of some genes relative to the common, small effects of others.
New modeling strategies that take advantage of advances in pattern recognition, machine learning, and systems analysis e. The field of human genetics, like many other disciplines, is in transition, and there is much to be gained by joining forces with a wide range of other disciplines that are focused on improving prevention and reducing the disease burden in our populations. Genetic polymorphisms and disease. New England Journal of Medicine.
Testing for population subdivision and association in four case-control studies.
Genes made Easy
American Journal of Human Genetics. PMC ] [ PubMed: The same thing can happen with diseases—they can be passed down from one family member to another. In most cases, diseases or other problems do not have one single cause. They come from a combination of your genes, your choices, and your environment. How Do Genes Cause Problems? Most genes we get from our parents are copies that work the same way they do in our parents.
But sometimes, a gene is not a perfect copy. Changes in genes are called mutations, and everyone has some. Some mutations work better than the original, and many make no difference at all.
Some mutations cause problems. There is a group of rare diseases caused by mutations in one gene at a time. These are called single-gene disorders. But most common diseases are caused by a combination of gene changes, lifestyle choices, and your environment.
They may cause problems for you, such as skin cancerbut you cannot pass them to your children. Why Do Mutations Cause Disease?
When the genes that instruct the making of proteins have mutations and do not work properly, whole systems in the body can have problems. These upsets can be caused in a number of ways. A new copy of your genes is made in every new cell that your body creates throughout your life. If those copies have mistakes, this can cause problems.
- How do genes impact health and disease?
- Genes and genetics explained
- 02. Genetics and Human Health: A Primer
For example, some gene changes can make you more likely to get cancer. Your environment can also directly cause changes to DNA inside your cells. For example, the sun damages DNA in the cells that are exposed to it, and if the damage goes unrepaired, these gene changes will be copied as your body creates new cells. This is not quite right. When we describe genes that cause disease, we are really talking about a gene that has a genetic mutation.
The gene should help create a normal, healthy state, but a mutation of that gene can cause problems. Even when your genes are not copied perfectly, they will usually still function correctly, or at least well enough that you will not notice a problem. Only a small number of mutations cause a genetic disorder. Sometimes, your body can repair the gene to help protect itself from disease. Mutations can sometimes even have a positive effect, such as resistance against disease, although this is rare.