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Genetic Epidemiology: an Expanding Scientific Discipline1 Genetic epidemiology: an expanding scientific discipline1 Diego F. Wyszynski 2 ABSTRACT Genetic epidemiology is a relatively new discipline that studies the interaction between genetic and environmental factors in the etiology of human diseases. Taking advantage of genetic markers provided by molecular biological research, complex computerized algorithms, and large databases, the field of genetic epidemiology has undergone significant development over the past 10 years. Using concrete examples from recent scientific literature, this article describes the objectives and methodology of genetic epidemiology. The notion that environmental fac- (4) were forerunners in associating the cases of congenital hypothyroidism tors interact with the genome in the term genetic epidemiology with the and phenylketonuria. Finally, tertiary production of diseases emerged discipline that strives to control and prevention consists of minimizing the around the middle of the 19th century, prevent illness by identifying the role effects of a disease by reducing the when certain individuals were ob- of genetic factors, in interaction with complications and damage it causes. served to be more resistant than others environmental factors, in the etiology An example of tertiary prevention of a to communicable diseases. Almost 100 of human disease (5). genetic disease is the use of prophy- years passed, however, before epi- Prevention can take place at the pri- laxis with antibiotics and immuniza- demiologists interested in genetics and mary, secondary, and tertiary levels. tion for individuals with sickle cell geneticists interested in epidemiology Primary prevention refers to reducing trait to prevent certain bacterial infec- were able to develop the first analytic the incidence of a disease in a popula- tions that could endanger the life of methods to identify environmental tion (6). The best known example of the patient. and genetic factors involved in the primary prevention is immunization Genetic mutations are the basis of pathologic process (1). to prevent certain infectious diseases. variation in the population (8). Like Although expressions such as “epi- In the scope of genetic epidemiology, other clinically expressed or mani- demiologic genetics” (2) and “clinical avoiding an environmental risk factor fested traits (phenotypes), diseases population-based genetics” (3) had al- (maternal smoking, for example) that involve genetic factors in three ready been coined, Morton and Chung interacts with genetic susceptibility ways, which are not always mutually (genotype A2 of the TGF␣ TaqI marker exclusive: in the fetus), thereby leading to a cer- tain pathologic process (cleft palate), is 1. The mutation may be directly 1 This article has been published in Spanish in this an example of primary prevention (7). harmful to the individual. This cat- journal (Vol. 3, No. 1, 1998, pp. 26–34) under the Secondary prevention refers to pre- egory includes the many disorders title “La epidemiología genética: disciplina cientí- fica en expansión.” vention of the clinical manifestations transmitted in an autosomal domi- 2 The Johns Hopkins University, School of Hygiene of a disease through early detection nant manner through a single gene, and Public Health, Baltimore, Maryland, USA. Mailing address: Department of Epidemiology, and effective intervention in the pre- such as achondroplasia and Marfan School of Hygiene and Public Health, The Johns clinical stage (6). Well-known exam- syndrome. Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA. Tel: (410) 955-7961; Fax: (410) 955- ples of secondary prevention include 2. The mutation may be harmful, but 0863. E-mail: [email protected] early detection and intervention in it may remain dormant for genera- Rev Panam Salud Publica/Pan Am J Public Health 3(3), 1998 179 tions. For instance, certain meta- history of diseases, both in popula- knowledge of characteristics of the bolic disorders of the newborn, tions and families. Analytic studies disorder and their ability to recall such as cystic fibrosis, appear only answer the “why?” and “how?” ques- them may also be greater if they have when an individual inherits two tions of genetic epidemiology. an affected relative. Table 1 demon- copies (alleles) of the mutated gene, strates a simple method of calculating that is, one from each parent. relative risk (RR) through the use of a 3. The mutation may be harmful only Family recurrence studies 2 ϫ 2 table, illustrated in the study of when it interacts with other genetic Mettlin et al. (10), who investigated or environmental factors (1). For A fundamental aspect of genetic epi- familial history of breast cancer in 779 example, individuals who have demiology is the study of aggregation patients and 1 558 controls admitted to both mutated alleles for phenylke- (or recurrence) of certain diseases in the Roswell Park Memorial Institute in tonuria or congenital hypothyroid- given families. King et al. (9) proposed Buffalo, New York. The RR of suffer- ism manifest these diseases only three questions to help identify the ing from breast cancer associated with when they are exposed to elevated scope of studies of family recurrence: a positive family history was 1.62 (95% concentrations of phenylalanine or CI: 1.28 to 2.06) (see Table 1). When the reduced concentrations of thyroid 1. Are there diseases that affect vari- analysis was broken down by age of hormone, respectively. ous members of the same family? the cases and the controls (<55 or ≥55 2. Is this familial aggregation associ- years of age), the RRs were 1.34 (95% The goals of genetic epidemiology ated with common environmental CI: 0.94 to 1.92) and 1.88 (95% CI: 1.37 contrast with those of “traditional” exposure, hereditary susceptibil- to 2.58), respectively (Table 2). This dif- epidemiology and population genet- ity, or cultural inheritance of risk ference reveals a limitation in family- ics. “Traditional” epidemiology stud- factors? based case-control studies, especially ies the relationship between the envi- 3. If there is genetic susceptibility, when the illnesses that are studied ronment and the incidence of a given how is it inherited? appear at a later stage in life, because disease, although it recognizes the sig- family members of young patients nificance of the host and his or her The existence of familial aggrega- tend to be younger than those of the genetic makeup. Population genetics, tion can be determined by observing controls. on the other hand, seeks to predict the the prevalence of a given disease in Other methods, such as cohort anal- influences of population structure and family members of the index case (the ysis, regressions, and generalizable selection and mutation on bodily phe- index case is the affected individual estimation equations, allow calcula- notypes and diseases. Finally, genetic who introduces the family into the tions to be broadened to include more epidemiology studies the way envi- study) and of controls (individuals complex situations. It is important to ronmental risk factors interact with the who are not affected). Such an aggre- point out that a high family aggrega- genetic makeup of a given population. gation exists when relatives of affected tion does not prove the existence of individuals run a higher risk of suffer- a genetic mechanism producing the ing from the disease than relatives of disease, just as a low recurrence does METHODS OF GENETIC individuals who are not affected. This not exclude the possibility that such a EPIDEMIOLOGY method is efficient and inexpensive, mechanism exists. but one of its limitations is that infor- Although the comparison of family Genetic epidemiology uses two mation about characteristics of family members of patients and of controls types of research strategies: descrip- members and controls may give rise to may be considered to be an “epidemi- tive and analytic. The descriptive strat- bias. For example, if the researcher is ologic” technique, it is also possible to egy, at the population as well as at aware that the disease is present in identify a familial aggregation by the family level, is based on the study the participant’s family, he or she may means of “statistical genetics.” In this of time, location, and the individual. overdiagnose it. Family members’ case, the degree of aggregation of a Some questions that exemplify this strategy are as follows: What is the prevalence at birth of achondroplasia among the population, and what is the TABLE 1. Relative risk of suffering from breast cancer associated with a positive and a mutation rate for this disease? What negative family history, based on a group of 779 breast cancer patients and 1 558 controls are the frequencies of blood groups and of histocompatibility antigens in Cases Controls Total cases Total controls different population groups? Do geo- Other relative affecteda Yes a b 144 191 graphic differences exist in the preva- No c d 635 1 367 lence of a given genetic factor? In con- Relative risk (95% CI) ad/bc 1.62 (1.28 to 2.06) 1.00 trast, analytic studies seek to identify Source: Reference 10. the role of genetic factors in the natural a Other relative affected refers to any first-degree relative (mother, daughter, sister) with breast cancer. 180 Wyszynski • Genetic epidemiology: an expanding scientific discipline TABLE 2. Relative risk of suffering from breast cancer associated with a positive and a can be applied to phenotypes that are negative family history, based on a group of 779 patients and 1 558 controls, by age expressed as continuous variables, such as blood lipid or blood glucose Age concentrations, blood pressure, and <55 years old ≥55 years old hormone levels. Analyses of the vari- Cases Controls Cases Controls ance components, or alternatively path Other relative affecteda Yes 58 90 86 101 analysis, are also useful methods for No 300 626 335 741 studying these phenotypes. Relative risk (95% CI) 1.34 (0.94 to 1.92) 1.0 1.88 (1.37 to 2.58) 1.0 Once there is evidence of familial Source: Reference 10.
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