Genetic Epidemiology Epidemiologic studies of risk factors for disease rely on population studies that measure disease prevalence or incidence and determine whether certain risk factors (e.g., genetic, environmental, social) are more prevalent in individuals with disease than those without. Genetic epidemiology is concerned with how genotypes and environmental factors interact to increase or decrease susceptibility to disease. Epidemiologic studies generally follow one of three different strategies: case- control, cross- sectional, and cohort design (see Box 1).

Box1. STRATEGIES USED IN GENETIC EPIDEMIOLOGY

Cohort and cross- sectional studies not only capture information on the relative risk conferred by different genotypes but, if they are random population samples, also provide information on the prevalence of the dis ease and the frequency of the various genotypes under study. A randomly selected cohort study, in particular, is the most accurate and complete approach, in that phenotypes that take time to appear have a better chance of being detected and scored; they are, however, more expensive and time consuming. Cross- sectional studies, on the other hand, suffer from underestimation of the frequency of the disease. First, if the disease is rapidly fatal, many of those with disease and carrying a risk factor will be missed. Second, if the disease shows age- dependent penetrance, some individuals carrying a risk factor will not be scored as having the disease. Case- control studies, on the other hand, allow researchers to efficiently target individuals, particularly with relatively rare phenotypes for which very large sample sizes would be needed in a cross- sectional or cohort study. However, unless a study is based on complete ascertainment of individuals with a disease (e.g., in a population register or surveillance program) or uses a random sampling scheme, a case- control study cannot capture information on the population prevalence of the disease.

Disease Association

A genetic disease association is the relationship in a population between a susceptibility or protective genotype and a disease phenotype. The susceptibility or protective genotype can be an allele (in either a heterozygote or a homozygote), a genotype at one locus, a haplotype containing alleles at neighboring loci, or even combinations of genotypes at multiple unlinked loci. Whether a disease association between genotype and phenotype is statistically significant can be determined from standard statistical tests, such as the chi- square test; whereas, how strongly associated the genotype and phenotype are is given by the odds ratio or relative risk. The relationship between some of these concepts is best demonstrated by means of a 2 × 2 table.

Clinical Validity and Utility

Finding the genetic contributions to health and disease is of obvious importance for research into underlying disease etiology and pathogenesis, as well as for identifying potential targets for intervention and therapy. In medical practice, however, whether to screen individuals for increased susceptibilities to illness depends on the clinical validity and clinical utility of the test. That is, how predictive of disease is a positive test, and how useful is it to have this information?

Clinical Validity

Clinical validity is the extent to which a test result is predictive for disease. Clinical validity is captured by the two concepts of positive predictive value and negative predictive value. The positive predictive value is the frequency with which a group of individuals who test positive have or will develop the disease. For mendelian disorders, the positive predictive value of a genotype is the penetrance. Conversely, the negative predictive value is the frequency with which a group of individuals who test negative are free of disease and remain so. When faced with a unique patient, the practitioner of individualized genetic medicine needs to know more than just whether there is an association and its magnitude (i.e., relative risk or odds ratio). It is important to know clinical validity (i.e., how well the test predicts the presence or absence of disease).

Susceptibility Testing Based on Genotype

The positive predictive value of a genotype that confers susceptibility to a particular disease depends on the relative risk for disease conferred by one genotype over another and on the prevalence of the disease. Fig. 1 provides the positive predictive value for genotype frequencies ranging from 0.5% (rare) to 50% (common), which confer a relative risk that varies from low (2-fold) to high (100- fold), when the prevalence of the disease ranges from relatively rare (0.1%) to more common (5%). As the figure shows, the value of the test as a predictor of disease increases substantially when one is dealing with a common disorder due to a relatively rare susceptibility genotype that confers a high relative risk, compared with the risk for individuals who do not carry the genotype. The converse is also clear; testing for a common genotype that confers a modest relative risk is of limited value as a predictor of disease.

Fig1. Theoretical positive predictive value calculations for a susceptibility genotype for a disease, over a range of genotype frequencies, disease prevalences, and relative risks for disease conferred by the genotype.

We will illustrate the use of the 2 × 2 table in assessing the role of susceptibility alleles in a common disorder, colorectal cancer. Shown in the following Box are data from a population- based study of colorectal cancer risk conferred by common variant in the APC gene that changes isoleucine to lysine at position 1307 of the protein (p.Ile1307Lys). This variant has an allele frequency of ~3.1% among those of Ashkenazi Jewish ancestry, which means that ~1 in 17 such individuals is a heterozygote (and 1 in 1000 are homozygous) for the allele. The prevalence of colon cancer among this population is 1%. The common p.Ile1307Lys variant confers a 2.4- fold increased risk for colon cancer relative to individuals without the allele. However, the small positive predictive value (≈2%) means that an individual who tests positive for this allele has only a 2% chance of developing colorectal cancer. If this had been a cohort study that allowed complete ascertainment of everyone in whom colorectal cancer was going to develop, the penetrance would, in effect, be only 2%.

Clinical Utility

The clinical utility of a test is more difficult to assess than clinical validity because it has different meanings for different people. In its narrowest sense, the clinical utility of a test is that the result is medically actionable; that is, the result will change medical care for an individual and, as a consequence, will improve the outcome of care, both medically and economically. At the other end of the spectrum is the broader definition as any piece of information an individual might wish to have, for any reason, including simply for the sake of knowing.

In a person who tests positive for the APC Ile1307Lys allele, how does a positive predictive value of 2% translate into clinical utility for medical practice? (see Box 2) One critical factor is a public health economic one: can the screening be shown to be cost effective? Is the expense of the testing outweighed by improving health outcomes while reducing health care costs, dis ability, and loss of earning power? In the example of screening for the APC p.Ile1307Lys allele in those of Ashkenazi ancestry, more frequent screening or the use of different approaches to screening for colon cancer may be effective. Screening methods (occult stool blood testing vs fecal DNA testing, or sigmoidoscopy vs full colonoscopy) differ in expense, sensitivity, specificity, and potential for hazard; deciding which regimen to follow has important implications for the person’s health and health care costs.

Box2. THE P.ILE1307LYS ALLELE OF THE APC GENE AND COLON CANCER

Even with demonstrable clinical validity and action able clinical utility, to demonstrate that testing improves health care is not always straightforward. For example, 1 in 200 to 1 in 250 individuals of European ancestry are homozygous for a p.Cys282Tyr variant in the HFE gene associated with hereditary hemochromatosis: a dis order characterized by iron overload that can silently lead to extensive liver damage and cirrhosis. A simple intervention – regular phlebotomy to reduce total body iron stores – can prevent hepatic cirrhosis. The susceptibility genotype is common, and 60 to 80% of p.Cys282Tyr homozygotes show biochemical evidence of increased body iron stores. This suggests that screening would be a reason able and cost- effective measure to identify asymptomatic individuals who should undergo further testing and, if indicated, the institution of regular phlebotomy. However, most p.Cys282Tyr homozygotes (>90– 95%) remain clinically asymptomatic, leading to the argument that the positive predictive value of HFE gene testing for liver disease in hereditary hemochromatosis is too low to justify population screening. Nonetheless, some of these largely asymptomatic individuals do have signs of clinically occult fibrosis and cirrhosis on liver biopsy, indicating that the Cys282Tyr homozygote may actually be at a higher risk for liver disease than previously thought. Thus, some argue for population screening to identify individuals in whom regular prophylactic phlebotomy should be instituted. The clinical utility of such population screening remains controversial and will require additional research to determine the natural his tory of the disease and whether the silent fibrosis and cirrhosis seen on liver biopsy represent the early stages of a progressive illness. As of 2019, guidelines recommend screening of transferrin levels to look for any cause of iron overload, rather than HFE testing, due to the very low penetrance.

APOE testing in Alzheimer disease (AD) is another example of the role of a careful assessment of clinical validity and clinical utility in applying genetic testing to individualized medicine. Heterozygotes for the ε4 allele of the APOE gene are at two- to three-fold increased risk for development of AD, compared with individuals without an APOE ε4 allele. APOE ε4/ ε4 homozygotes are at eight-fold increased risk. An analysis of both the clinical validity and clinical utility of APOE testing, including calculation of the positive predictive value for asymptomatic and symptomatic individuals, is shown in Table 1.

Table1. Clinical Validity and Utility of APOE Population Screening and Diagnostic Testing for Alzheimer Disease

As can be seen from these positive predictive values for asymptomatic people aged 65 to 74 years, a single ε4 allele is not a strong predictor of whether AD will develop, despite the three-fold increased risk conferred for the disease. Thus, most individuals heterozygous for an ε4 allele identified through APOE testing as being at increased risk will not develop AD. Even with two ε4 alleles, which occurs in ~1.5% of the population and is associated with an eight-fold increased risk relative to genotypes without ε4 alleles, the chance is still less than one in four to develop AD. APOE testing for the ε4 allele is, therefore, not recommended in asymptomatic individuals but is used by some practitioners in the evaluation of individuals with symptoms and signs of dementia.

The utility of testing asymptomatic individuals at their APOE locus to assess risk for AD is also controversial. First, knowing that one is at increased risk for AD through APOE testing does not lead to any preventive or therapeutic options. Thus, under a strict definition of clinical utility – that is, the result is actionable and leads to changes in medical management – there would be little value in APOE testing for AD risk.

There may be, however, positive and negative out comes of testing that are psychological or economic in nature and more difficult to assess than the purely clinical factors. For example, testing positive for a susceptibility genotype could empower individuals with knowledge of their risks as they make important life decisions. On the other hand, it has been suggested that knowing of an increased risk through APOE testing might cause significant emotional and psychological distress. However, careful studies of the impact of receiving APOE genotype information have shown little harm in appropriately counseled individuals with a family history of AD who wished to know this information. Finally, individuals who test negative for the ε4 alleles could be falsely reassured that they are at no increased risk for the disorder, despite having a positive family history or other risk factors for dementia. Balancing all of these considerations, APOE testing is still not recommended in asymptomatic individuals, even in light of such a strong genotype- disease association, because of the low positive predictive value and lack of clinical utility, rather than because such information is harmful.

As in all of medicine, the benefits and costs for each component of individualized genetic medicine need to be clearly demonstrated and continually reassessed. The requirement for constant reevaluation is obvious: imagine how the recommendations for APOE testing, despite its low positive predictive value, might change if a low- risk and inexpensive medical intervention were discovered that could prevent or significantly delay the onset of dementia.

Heterozygote Screening

 In contrast to screening for genetic disease in newborns or for genetic susceptibility in individuals, screening for carriers of mendelian disorders has, as its main purpose, the identification of individuals who are themselves healthy but are at substantial risk (25% or higher) to have children with a severe autosomal recessive or X- linked illness. The principles of heterozygote screening are shown in the accompanying (see Box 3).

Box3. CRITERIA FOR HETEROZYGOTE SCREENING PROGRAMS

Until recently, heterozygote screening programs focused on particular population groups in which the frequency of variant alleles is high. In contrast to new born screening, heterozygote screening is voluntary and focuses on individuals who identify themselves as members of particular high- risk groups. Heterozygote screening has been used extensively for a battery of disorders for which carrier frequency is relatively high: Tay- Sachs disease (the prototype of carrier screening), Gaucher disease, and Canavan dis ease in the Ashkenazi Jewish population; sickle cell dis ease in the black population of North America; and β- thalassemia in high- incidence areas, especially in Cyprus and Sardinia, or in extended consanguineous families from Pakistan.

Carrier screening for cystic fibrosis has become standard of care for couples contemplating a pregnancy. more than 2000 different disease- causing variants have been described in the CFTR gene. Although the vast majority of disease- causing variants in CFTR can be readily detected with greater than 99% sensitivity when the entire gene is sequenced, such an approach for every couple seeking preconception carrier testing would be expensive if carried out on a population- wide basis, particularly in individuals with low prior probability of carrying a variant. Current recommendations are to report pathogenic and likely-pathogenic variants identified by sequencing or targeted testing. Targeted testing panels range from the most frequent 23 variants found in persons of European ancestry—as proposed by the American College of Medical Genetics and Genomics (ACMG), to consider ably more extensive panels with more than 60 distinct variants that include those identified in populations with lower frequencies of disease, such as of African or Asian ancestry. Because this approach is intended to find only the most frequent variants, their sensitivity is around (88 to 90%) in individuals of European descent and 64 to 72% among those of African descent.

The classification- based reporting technique involves giving individuals comprehensive cystic fibrosis testing that includes an evaluation of all the exonic coding regions and +/ −2 bp proximal splice junctions of the CFTR gene, as well as reporting on all pathogenic and likely-pathogenic variants for classic cystic fibrosis. Sanger sequencing has long been employed in medical laboratories for the study of CFTR because of its accuracy, precision, and simplicity of use. The analysis of CFTR using next-generation sequencing approaches is now successful, although there is still a danger of false negatives and positives. Furthermore, certain regions may need Sanger sequencing to detect variants. Multiplex ligation- dependent probe amplification (MLPA) continues to be an efficient method to detect large deletions and duplications in the CFTR gene, and commercial reagents exist.

Regardless of the test indication, all CFTR variants should be classified using ACMG sequence variant classification criteria. Information from CFTR variant data bases can be used to inform those variant classifications.

As the cost of variant detection using next-generation sequencing has fallen, it has become much less compel ling to restrict carrier screening to a small number of alleles common in certain ancestral groups in genes that are known to be associated with disease. It is possible now to expand carrier screening beyond disorders common to particular groups, such as cystic fibrosis, sickle cell trait, or thalassemia, to include carrier status for more than 400 autosomal recessive and X- linked dis orders. With sequencing instead of allele- specific detection methods, there is no longer any limit to which genes and which alleles in these genes can (theoretically) be detected. Rare variant alleles in genes associated with known disease will be found, thereby raising the sensitivity of carrier detection methods. Sequencing, however, can uncover variants—particularly missense changes, of uncertain significance in genes whose role in the disease may be known or unknown. Unless great care is taken in assessing the clinical validity of rare variants detected by sequencing, the frequency of false- positive carrier test results will increase.

The impact of carrier screening in lowering the incidence of a genetic disease can be dramatic. Carrier screening for Tay- Sachs disease in the Ashkenazi Jewish population began in some communities in 1969. Screening followed by prenatal diagnosis, when indicated, has already lowered the incidence of Tay- Sachs disease by 65 to 85% in this group. In contrast, attempts to screen for carriers of sickle cell disease in the US Black community have been less effective, with little impact on the incidence of the disease. The success of carrier screening programs for Tay- Sachs disease, as well as the relative failure for sickle cell anemia, underscores the importance of community consultation, community engagement, and the availability of genetic counseling and prenatal or preimplantation genetic diagnosis as critical requirements for an effective program.

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مواضيع ذات صلة

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer

Pharmacogenomics

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes

Genetic Basis of Cancer

Conditional Mutations Can Be Used to Study Essential Genes in Yeast

Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity

Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function