Genes, Environment-Lifestyle, and Common Diseases PDF

CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases Lynn B. Jorde http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Factors Influencing Incidence of Disease in Populations, 160 Natu...

CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases Lynn B. Jorde http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Factors Influencing Incidence of Disease in Populations, 160 Nature and Nurture: Disentangling the Effects of Genes and Concepts of Incidence and Prevalence, 160 Environment, 164 Analysis of Risk Factors, 161 Twin Studies, 164 Principles of Multifactorial Inheritance, 161 Adoption Studies, 165 Basic Model, 161 Genetics of Common Diseases, 166 Threshold Model, 161 Congenital Malformations, 166 Recurrence Risks and Transmission Patterns, 163 Multifactorial Disorders in the Adult Population, 167 Chapter 4 focuses on diseases that are caused by single genes or by in the population. The denominator is often expressed as person-years. abnormalities of single chromosomes. Much progress has been made The incidence rate can be contrasted with the prevalence rate, which in identifying specific mutations that cause these diseases, leading to is the proportion of the population affected by a disease at a specific better risk estimates and, in some cases, more effective treatment of point in time. Prevalence is thus determined by both the incidence rate the disease. However, these conditions form only a small portion of and the length of the survival period in affected individuals. For example, the total burden of human genetic disease. Most congenital malformations the prevalence rate of acquired immunodeficiency syndrome (AIDS) are not caused by single genes or chromosome defects. Many common is larger than the yearly incidence rate because most people with AIDS adult diseases, such as cancer, heart disease, and diabetes, have genetic survive for at least several years after diagnosis. components, but again they are usually not caused by single genes or Many diseases vary in prevalence from one population to another. by chromosomal abnormalities. These diseases, whose treatment col- Cystic fibrosis is relatively common among Europeans, occurring about lectively occupies the attention of most healthcare practitioners, are once in every 2500 births. In contrast, it is quite rare in Asians, occurring the result of a complex interplay of multiple genetic and environmental only once in every 90,000 births. Similarly, sickle cell disease affects factors. approximately 1 in 600 American blacks, but it is seen much less fre- quently in whites. Both of these diseases are single-gene disorders, and FACTORS INFLUENCING INCIDENCE OF they vary among populations because disease-causing mutations are DISEASE IN POPULATIONS more or less common in different populations. (This is in turn the result of differences in the evolutionary history of these populations.) Concepts of Incidence and Prevalence Nongenetic (environmental) factors have little influence on the current How common is a given disease, such as diabetes, in a population? prevalence of these diseases. Well-established measures are used to answer this question.1 The The picture often becomes more complex with the common diseases incidence rate is the number of new cases of a disease reported during of adulthood. For example, colon cancer was until recently relatively a specific period (typically 1 year) divided by the number of individuals rare in Japan, but it is the second most common cancer in the United 160  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 161 States. Stomach cancer, on the other hand, is common in Japan but The following discussion demonstrates how genetic and environmental relatively rare in the United States. These statistics, in themselves, cannot factors contribute to the risk of developing common diseases. distinguish environmental from genetic influences in the two populations. However, because large numbers of Japanese emigrated first to Hawaii PRINCIPLES OF MULTIFACTORIAL and then to the U.S. mainland, we can observe what happens to the INHERITANCE rates of stomach and colon cancer among the migrants. It is important that the Japanese émigrés maintained a genetic identity, marrying largely Basic Model among themselves. Among first-generation Japanese in Hawaii, the Traits in which variation is thought to be caused by the combined frequency of colon cancer rose several-fold—not yet as high as in the effects of multiple genes are polygenic (“many genes”). When envi- U.S. mainland but higher than that in Japan. Among second-generation ronmental factors are also believed to cause variation in the trait, Japanese on the U.S. mainland, colon cancer rates rose to 5%, equal to which is usually the case, the term multifactorial trait is used.2 Many the U.S. average. At the same time, stomach cancer has become relatively quantitative traits (those, such as blood pressure, that are measured rare among Japanese-Americans. on a continuous numeric scale) are multifactorial. Because they are These observations strongly indicate an important role for environ- caused by the additive effects of many genetic and environmental factors, mental factors in the etiology of cancers of the colon and stomach. In these traits tend to follow a normal, or bell-shaped, distribution in each case, diet is a likely culprit—a high-fat, low-iber diet in the United populations. States is thought to increase the risk of colon cancer, whereas techniques An example illustrates this concept. To begin with the simplest case, used to preserve and season the fish commonly eaten in Japan are suppose (unrealistically) that height is determined by a single gene with thought to increase the risk of stomach cancer. It is interesting that the two alleles, A and a. Allele A tends to make people tall, whereas allele incidence of colon cancer in Japan has increased dramatically during a tends to make them short. If there is no dominance at this locus, then the past several decades as the Japanese population has adopted a more the three possible genotypes (AA, Aa, aa) will produce three phenotypes: “Western” diet. These results do not, however, rule out the potential tall, intermediate, and short, respectively. Assume that the gene frequen- contribution of genetic factors in common cancers. Genes also play a cies of A and a are each 0.50. When looking at a population of individuals, role in the etiology of colon and other cancers. the height distribution depicted in Fig. 5.1, A, will be observed. Now suppose, a bit more realistically, that height is determined by Analysis of Risk Factors two loci instead of one. The second locus also has two alleles, B (tall) The comparison just discussed is one example of the analysis of risk and b (short), and they affect height in exactly the same way as alleles factors (in this case, diet) and their influence on the prevalence of A and a. There are now nine possible genotypes in our population: disease in populations. A common measure of the effect of a specific aabb, aaBb, aaBB, Aabb, AaBb, AaBB, AAbb, AABb, and AABB. An risk factor is the relative risk. This quantity is expressed as a ratio: individual may have zero, one, two, three, or four “tall” alleles, so now five distinct phenotypes are possible (see Fig. 5.1, B). Although the Increased rate of the disease among individuals height distribution in this fictional population is still not normal compared with an actual population, it approaches a normal distribution exposed to a risk factor more closely than in the single-gene case just described. als Incidence rate of the disease among individua From extension of this example, many genes and environmental not exposed to a risk factor factors influence height, each having a small effect. Then many phe- notypes are possible, each differing slightly from the others, and the A classic example of a relative risk analysis was carried out in a height distribution of the population approaches the bell-shaped curve sample of more than 40,000 British physicians to determine the relation- shown in Fig. 5.1, C. ship between cigarette smoking and lung cancer. This study compared It should be emphasized that the individual genes underlying a the incidence of death from lung cancer in physicians who smoked multifactorial trait such as height follow the mendelian principles of with those who did not. The incidence of death from lung cancer was segregation and independent assortment, just like any other gene. The 1.66 (per 1000 person-years) in heavy smokers (more than 25 cigarettes only difference is that many of them act together to influence the trait. daily), but it was only 0.07 in the nonsmokers. The ratio of these two More than 200 genes have now been shown to be associated with variation incidence rates is 1.66/0.07, which yields a relative risk of 23.7 deaths. in human height. Thus, it is concluded that the risk of dying from lung cancer increased Blood pressure is another example of a multifactorial trait. A cor- by about 24-fold in heavy smokers compared with nonsmokers. Many relation exists between parents’ blood pressures (systolic and diastolic) other studies have obtained similar risk figures. and those of their children. The evidence is good that this correlation Although cigarette smoking clearly increases one’s risk of developing is partially caused by genes, but blood pressure is also influenced by lung cancer (as well as heart disease, as will be seen later), it is equally environmental factors, such as diet, exercise, and stress. Two goals of clear that most smokers do not develop lung cancer. Other lifestyle genetic research are the identification and measurement of the relative factors are likely to contribute to one’s risk of developing this disease roles of genes and environment in the causation of multifactorial (e.g., exposure to cancer-causing substances in the air, such as asbestos diseases. fibers). In addition, differences in genetic background may be involved. Smokers who have variants in genes that are involved in the metabolism Threshold Model of components of tobacco smoke (such as CYP1A1 and GSTM1) are A number of diseases do not follow the bell-shaped distribution. Instead, at significantly increased risk of developing lung cancer. they appear to be either present or absent in individuals, yet they do Many factors can influence the risk of acquiring a common disease not follow the inheritance patterns expected of single-gene diseases. A such as cancer, diabetes, or high blood pressure. These include age, commonly used explanation for such diseases is that there is an underlying gender, diet, amount of exercise, and family history of the disease. Usually, liability distribution for the disease in a population (Fig. 5.2). Those complex interactions occur among these genetic and nongenetic factors. individuals who are on the “low” end of the distribution have little The effects of each factor can be quantified in terms of relative risks. chance of developing the disease in question (i.e., they have few of the 162 UNIT II Genes, Gene-Environment Interaction, and Epigenetics Threshold Population frequency aa Aa AA Genotypes − + A Short Tall Low High Liability Population frequency aabb aaBb aaBB AaBB AABB Aabb AaBb AABb AAbb Genotypes B S Short Tall − + 30 Low High Number of individuals Liability 20 FIGURE 5.2 A Liability Distribution in a Population for a Multifactorial Disease. To be affected with the disease, an individual must exceed the threshold on the liability distribution. This figure shows two thresholds, a lower one for males 10 and a higher one for females (as in pyloric stenosis; see text). (From Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.) 0 0 5′0″ 5′6″ 6′0″ Height disease is expressed. Below the threshold, an individual appears normal; C above it, he or she is affected by the disease. FIGURE 5.1 Distribution of Height. A, Distribution of height in a population, A disease that is thought to correspond to this threshold model is assuming that height is controlled by a single locus with genotypes AA, Aa, and pyloric stenosis, a disorder that presents shortly after birth and is caused aa. B, Distribution of height, assuming that height is controlled by two loci. Five by a narrowing or obstruction of the pylorus, the area between the distinct genotypes are shown instead of three, and the distribution begins to look stomach and intestine. Chronic vomiting, constipation, weight loss, more like the normal distribution. C, Height is portrayed, realistically, as a trait and imbalance of electrolyte levels result from the condition, but it with a continuous statistical distribution. Because many genes contribute to height sometimes resolves spontaneously or can be corrected by surgery. The and tend to segregate independently of one another, the cumulative contribution prevalence of pyloric stenosis is about 3 per 1000 live births in whites. of different combinations of alleles to height forms a continuous distribution of It is much more common in males than females, affecting 1 of 200 possible heights, in which the extremes are much rarer than the intermediate males and 1 of 1000 females. It is thought that this difference in prevalence values. Variation also can be caused by environmental factors such as nutrition. reflects two thresholds in the liability distribution—a lower one in (A and B adapted from Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, males and a higher one in females (see Fig. 5.2). A lower male threshold Elsevier; C from Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.) implies that fewer disease-causing factors are required to generate the disorder in males. The liability threshold concept may explain the pattern of recurrence alleles or environmental factors that would cause the disease). Individuals risks for pyloric stenosis seen in Table 5.1. Note that males, having a who are closer to the “high” end of the distribution have more of the lower threshold, always have a higher risk than females. However, the disease-causing genes and environmental factors and are more likely sibling recurrence risk also depends on the sex of the proband (i.e., to develop the disease. For diseases that are either present or absent, it the first affected individual diagnosed in a family). It is higher when is thought that a threshold of liability must be crossed before the the proband is female than when the proband is male. This reflects the  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 163 TABLE 5.1 RECURRENCE RISKS (%) TABLE 5.2 RECURRENCE RISKS (%) FOR FOR PYLORIC STENOSIS, FIRST-, SECOND-, AND SUBDIVIDED BY GENDERS THIRD-DEGREE RELATIVES OF AFFECTED PROBANDS RISK AND RELATIVES FIRST SECOND THIRD GENERAL MALE PROBANDS FEMALE PROBANDS DEGREE DEGREE DEGREE DEGREE POPULATION RELATIVES LONDON BELFAST LONDON BELFAST Cleft lip/palate 4 0.7 0.3 0.1 Brothers 3.8 9.6 9.2 12.5 Clubfoot 2.5 0.5 0.2 0.1 Sisters 2.7 3.0 3.8 3.8 Congenital hip 5 0.6 0.4 0.2 dislocation NOTE: The risks differ somewhat between the two populations. Data from Carter CO: Br Med Bull 32(1):21–26, 1976. concept that females, having a higher liability threshold, must be exposed another because gene frequencies as well as environmental factors can to more disease-causing factors than males to develop the disease. Thus differ among populations (note the differences between the London a family with an affected female must have more genetic and environ- and Belfast populations in Table 5.1). mental risk factors, producing a higher recurrence risk for pyloric stenosis It is sometimes difficult to distinguish polygenic or multifactorial in future offspring. It would be expected that the highest risk category diseases from single-gene diseases that have reduced penetrance or would be male relatives of female probands; Table 5.1 shows that this variable expression. Large data sets and good epidemiologic data are is the case. necessary to make the distinction. Several criteria are commonly used A similar pattern has been observed in studies of autism spectrum to define multifactorial inheritance. disorder, a behavioral disorder in which the male to female ratio is First, the recurrence risk becomes higher if more than one family member approximately 4 : 1. As expected for a multifactorial disorder, the recur- is affected. For example, the sibling recurrence risk for a ventricular rence risk for siblings of male probands (10%) is lower than that of septal defect (VSD, a type of congenital heart defect) is 3% if one sibling siblings of female probands (12%).3 When the sex ratio for a disease has been affected by a VSD but increases to approximately 10% if two is reversed (i.e., more affected females than males), one would expect siblings have been diagnosed with VSDs.4 The same trend is seen for a higher recurrence risk when the proband is male. other multifactorial diseases like neural tube defects and autism. In A number of other congenital malformations are thought to cor- contrast, the recurrence risk for single-gene diseases remains the same respond to this model. They include isolated cleft lip and/or cleft palate regardless of the number of affected siblings. It should be emphasized (CL/P), neural tube defects (anencephaly, spina bifida), clubfoot (talipes), that this increase does not mean that the family’s risk has actually and some forms of congenital heart disease. In this context, “isolated” changed. Rather, it means that there is more information about the means that this is the only observed disease feature (i.e., the feature is family’s true risk; because they have had two affected children, they not part of a larger constellation of findings, as in CL/P secondary to are probably located higher on the liability distribution than a family trisomy 13). In addition, many common adult diseases, such as hyperten- with only one affected child. In other words, they have more risk sion, coronary heart disease, stroke, diabetes mellitus (types 1 and 2), and factors (genetic or environmental) and are more likely to produce an some cancers, are caused by complex genetic and environmental factors affected child. and can thus be considered multifactorial diseases. Second, if the expression of the disease in the proband is more severe, the recurrence risk is higher. This is again consistent with the liability Recurrence Risks and Transmission Patterns model because a more severe expression indicates that the affected Whereas sibling recurrence risks can be given with confidence for individual is at the extreme tail end of the liability distribution (see single-gene diseases (e.g., 50% for typical autosomal dominant diseases, Fig. 5.2). His or her relatives are thus at a higher risk for inheriting 25% for autosomal recessive diseases), the situation is more complicated disease genes. For example, the occurrence of a bilateral (both sides) for multifactorial diseases. This is because the number of genes contribut- CL/P confers a higher recurrence risk on family members than does ing to the disease is usually not known, the precise allelic constitution the occurrence of a unilateral (one side) cleft. of the parents is not known, and the extent of environmental effects Third, the recurrence risk is higher if the proband is of the less commonly can vary substantially. For most multifactorial diseases, empirical risks affected sex (see the preceding discussion of pyloric stenosis). This is (i.e., risks based on direct observation of data) have been derived. To because an affected individual of the less susceptible sex is usually at a estimate empirical risks, a large series of families is examined in which more extreme position on the liability distribution. one child has developed the disease (the proband). Then the siblings Fourth, the recurrence risk for the disease usually decreases rapidly in of each proband are surveyed to calculate the percentage of siblings more remotely related relatives (Table 5.2). Whereas the recurrence risk who also have developed the disease. For example, in the United States for single-gene diseases decreases by 50% with each degree of relationship about 3% of siblings of individuals with neural tube defects also have (e.g., an autosomal dominant disease has a 50% recurrence risk for neural tube defects (Box 5.1). Thus the recurrence risk for parents who siblings, 25% for uncle-nephew relationships, 12.5% for irst cousins), have had one child with a neural tube defect is 3% in the United States. it decreases much more quickly for multifactorial diseases. This reflects For conditions such as CL/P that are not lethal or severely debilitating, the fact that many genes and environmental factors must combine to recurrence risks also can be estimated for the offspring of affected produce a trait. All the necessary risk factors are unlikely to be present parents. Because each multifactorial disease has different numbers and in less closely related family members. types of risk factors, empirical recurrence risks vary for each disease. Finally, if the prevalence of the disease in a population is f, the risk for In contrast to most single-gene diseases, recurrence risks for mul- offspring and siblings of probands is approximately f. This does not tifactorial diseases can change substantially from one population to hold true for single-gene traits because their recurrence risks are largely 164 UNIT II Genes, Gene-Environment Interaction, and Epigenetics BOX 5.1 NEURAL TUBE DEFECTS Neural tube defects (NTDs), which include anencephaly, spina bifida, and two, and three affected offspring, respectively. Recurrence risks tend to be slightly encephalocele (as well as several other less common forms), are one of the most lower in populations with lower NTD prevalence rates, as predicted by the important classes of birth defects, and they are seen in 0.5 to 2 of 1000 pregnancies. multifactorial model. Recurrence risk data support the idea that the major forms The prevalence of NTDs among different populations varies considerably, with of NTDs are caused by similar factors. An anencephalic conception increases an especially high rate among some northern Chinese populations (as high as 6 the recurrence risk for subsequent spina bifida conceptions, and vice versa. or more per 1000 births). The prevalence of NTDs has been decreasing in many NTDs can usually be diagnosed prenatally, sometimes by ultrasound and usually parts of the United States and Europe during the past three decades, partly by an elevation in α-fetoprotein (AFP) level in the maternal serum or amniotic because of dietary changes. fluid (see Chapter 20). A spina bifida lesion can be either open or closed (i.e., Normally the neural tube closes at about the fourth week of gestation. A defect covered with a layer of skin). Fetuses with open spina bifida are more likely to in closure, or a subsequent reopening of the neural tube, results in a neural tube be detected by AFP assays. defect. Spina bifida (Fig. 5.3, A) is the most commonly observed NTD and consists A major epidemiologic finding is that mothers who supplement their diet with of a protrusion of spinal tissue through the vertebral column (the tissue usually folic acid at the time of conception are less likely to produce children with NTDs. includes meninges, spinal cord, and nerve roots). About 75% of individuals with This result has been replicated in several different populations and thus appears spina bifida have secondary hydrocephalus, which sometimes in turn produces to be well confirmed. It has been estimated that as many as 50% to 70% of intellectual disability. Paralysis or muscle weakness, lack of sphincter control, NTDs can be avoided simply by dietary folic acid supplementation. (Traditional and clubfeet are often observed. A study conducted in British Columbia showed prenatal vitamin supplements have little effect because administration does not that survival rates for people with spina bifida have improved dramatically over usually begin until well after the time that the neural tube closes.) It is now the past several decades. Less than 30% of people born between 1952 and 1969 recommended that all women of reproductive age supplement their diet with survived to 10 years of age, whereas 65% of those born between 1970 and 1986 0.4 mg of folic acid each day; many foods in the United States are supplemented survived to this age. Anencephaly (see Fig. 5.3, B) is characterized by partial or with folic acid. Consequently, average folate levels in U.S. females have doubled, complete absence of the cranial vault and calvarium and partial or complete and the incidence of neural tube defects has declined by 30% to 50% in the absence of the cerebral hemispheres. At least two-thirds of newborns with past decade. anencephaly are stillborn; term deliveries do not survive more than a few hours Because mothers would be likely to ingest similar amounts of folic acid from or days. one pregnancy to the next, folic acid deficiency could well account for at least NTDs are thought to arise from a combination of genetic and environmental part of the elevated sibling recurrence risk for NTDs. This is an important example factors. In most populations surveyed thus far, empirical recurrence risks for of a nongenetic factor that contributes to familial clustering of a disease. It is siblings of affected people range from 2% to 5%. Consistent with a multifactorial likely that there is genetic variation in response to folic acid, which helps to model, the recurrence risk increases with additional affected siblings. Studies explain why most mothers with folic acid deficiency do not bear children with conducted in Great Britain showed that the sibling recurrence risk was approxi- NTDs and why some who ingest adequate amounts of folic acid nonetheless mately 5% when one sibling was affected and 10% when two were affected. bear children with NTDs. To address this issue, researchers are testing for A Hungarian study showed that the overall prevalence of NTDs was 1 in 300 associations between NTDs and variants in several genes whose products (e.g., births and that the sibling recurrence risks were 3%, 12%, and 25% after one, methylene tetrahydrofolate reductase) are involved in folic acid metabolism. Data from Copp AJ, Stanier P, Greene NDE: Lancet Neurol 12:799–810, 2013; Daly LE et al: JAMA 274(21):1698–1702, 1995. independent of population prevalence. It is not an absolute rule for research strategies are reviewed that often are used to estimate the relative multifactorial traits either, but many such diseases tend to conform to influence of genes and environment: twin studies and adoption studies. this prediction. Examination of the risks given in Table 5.2 shows that the first three diseases follow the prediction fairly well. However, the Twin Studies observed sibling risk for the fourth disease, infantile autism, is substan- Twins occur with a frequency of about 1 in 100 births in white popula- tially higher than that predicted by f. tions. They are a bit more common in blacks and a bit less common among Asians. Monozygotic (MZ, identical) twins originate when the NATURE AND NURTURE: DISENTANGLING THE developing embryo divides to form two separate but identical embryos. Because they are genetically identical, MZ twins are an example of EFFECTS OF GENES AND ENVIRONMENT natural clones. Dizygotic (DZ, fraternal) twins are the result of a double Family members share genes and a common environment. Family ovulation followed by the fertilization of each egg by a different sperm. resemblance in traits such as blood pressure reflects both genes (nature) Thus dizygotic twins are genetically no more similar than siblings. and environment (nurture). For centuries people have debated the Because two different sperm cells are required to fertilize the two eggs, relative importance of these two types of factors. It is a mistake, of it is possible for each DZ twin to have a different father. Whereas MZ course, to view them as mutually exclusive. Few traits are influenced twinning rates are constant across populations, DZ twinning rates vary only by genes or only by environmental factors. Most are influenced somewhat. DZ twinning increases with maternal age until about 40 by both. It is useful to try to determine the relative influence of genetic years, after which it declines. and environmental factors (Fig. 5.4). This can lead to a better understand- Because MZ twins are genetically identical, any differences between ing of disease etiology. It can also help in planning public health strategies. them should be caused only by environmental effects.5 MZ twins should A disease in which the genetic influence is relatively small, such as lung thus resemble one another very closely for traits that are strongly cancer, may be prevented most effectively through emphasis on lifestyle influenced by genes. DZ twins provide a convenient comparison because changes (avoidance of tobacco). When a disease has a relatively larger their environmental differences should be similar to those of MZ twins, genetic component, as in breast cancer, examination of family history but their genetic differences are as great as those between siblings. Twin should be emphasized in addition to lifestyle modification. Here, two studies thus usually consist of comparisons between MZ and DZ twins.6  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 165 Environmental and Genetic factors lifestyle factors Influenza Diabetes Cystic fibrosis Measles Heart disease Hemophilia A FIGURE 5.4 Continuum of Genetic Diseases. Some diseases (e.g., cystic fibrosis) are strongly determined by genes, whereas others (e.g., infectious diseases) are strongly determined by environmental factors. (Adapted from Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.) the assumption that the environments of MZ and DZ twins are equally similar. As one would expect, MZ twins are often treated more similarly than DZ twins. A greater similarity in environment can make MZ twins more concordant for a trait, inflating the apparent influence of genes. In addition, MZ twins may be more likely to seek the same type of environment, further reinforcing environmental similarity. On the other hand, it has been suggested that MZ twins tend to develop personality differences in an attempt to assert their individuality. A Adoption Studies Studies of adopted children also are used to estimate the genetic contribution to a multifactorial trait. Children born to parents who have a disease but are then subsequently adopted by parents lacking the disease can be studied to find out whether these children develop the disease. In some cases such children develop the disease more often than a comparative control population (i.e., adopted children who were born to parents who do not have the disease). This provides some evidence that genes may be involved in the causation of the disease, because the adopted children do not share an environment with their affected natural parents. For example, about 8% to 10% of adopted children of a schizophrenic parent develop schizophrenia, whereas only B 1% of adopted children of unaffected parents develop schizophrenia. FIGURE 5.3 Spina Bifida and Anencephaly. A, Spina bifida in a newborn. As with twin studies, several precautions must be exercised in B, Anencephaly, showing the absence of the cranial vault. (From Jones KL: Smith’s interpreting the results of adoption studies. First, prenatal environmental recognizable patterns of human malformation, ed 6, Philadelphia, Saunders, 2006, influences could have long-lasting effects on an adopted child. Second, p. 705.) children are sometimes adopted after they are several years old, ensuring that some environmental influence would have been imparted by the natural parents. Finally, adoption agencies sometimes try to match the If both members of a twin pair share a trait (e.g., a cleft lip), they are adoptive parents with the natural parents in terms of background, said to be concordant. If they do not share the trait, they are discordant. socioeconomic status, and other factors. All of these factors could For a trait determined totally by genes, MZ twins should always be exaggerate the apparent influence of biologic inheritance. concordant, whereas DZ twins should be concordant less often, because These reservations, as well as those summarized for twin studies, they, like full siblings, share only 50% of their DNA. Concordance rates underscore the need for caution in basing conclusions on twin and may differ between opposite-sex DZ twin pairs and same-sex DZ pairs adoption studies. These approaches do not provide definitive measures for some traits, such as those that have different frequencies in males of the role of genes in multifactorial disease, nor can they identify and females. For such traits, only same-sex DZ twin pairs should be specific genes responsible for disease. Instead, they serve a useful purpose used when comparing MZ and DZ concordance rates, because MZ in providing a preliminary indication of the extent to which a multifacto- twins are necessarily of the same sex. rial disease may be caused by genetic factors. Sophisticated molecular Table 5.3 gives concordance rates for a number of traits. Note that techniques are being used to identify the specific genes that underlie the concordance rates for contagious diseases such as measles are quite predisposition to multifactorial diseases. similar in MZ and DZ twins. This is expected because a contagious This discussion should make clear that most common diseases are disease is unlikely to be influenced markedly by genes. On the other not the result of either genetics or environment. Instead, genetic and hand, the concordance rates are quite dissimilar for schizophrenia and nongenetic factors usually interact to influence one’s likelihood of bipolar affective disorder, suggesting a sizable genetic component for developing a common disease. In some cases a genetic predisposition these diseases. The MZ correlations for dermatoglyphics (fingerprints), may interact with an environmental factor to increase the risk of disease which are determined almost entirely by genes, are close to 1.0. acquisition to a much higher level than would either factor acting alone. At one time, twins were thought to provide a perfect “natural labo- A good example of a gene-environment interaction is given by α1- ratory” in which to determine the relative influences of genetics and antitrypsin deficiency, a genetic condition that causes pulmonary environment, but several difficulties arose. One of the most important is emphysema and is greatly exacerbated by cigarette smoking (Box 5.2). 166 UNIT II Genes, Gene-Environment Interaction, and Epigenetics TABLE 5.3 CONCORDANCE RATES BOX 5.2 α1-ANTITRYPSIN DEFICIENCY: IN MZ AND DZ TWINS THE INTERACTION OF GENES FOR SELECTED TRAITS AND ENVIRONMENT-LIFESTYLE AND DISEASES α1-Antitrypsin (AAT) deficiency is one of the most common autosomal recessive TRAIT OR CONCORDANCE RATE disorders among whites, affecting approximately 1 in 2500 members of this ethnic group. AAT, synthesized primarily in the liver, is a serine protease DISEASE MZ TWINS DZ TWINS HERITABILITY inhibitor. It does bind trypsin, as its name suggests. However, AAT binds much Affective disorder 0.79 0.24 >1* more strongly to neutrophil elastase, a protease that is produced by neutrophils (bipolar) (a type of leukocyte) in response to infections and irritants. It carries out its Affective disorder 0.54 0.19 0.7 binding and inhibitory role primarily in the lower respiratory tract, where it (unipolar) prevents elastase from digesting the alveolar septi of the lung. Individuals with less than 10% to 15% of the normal level of AAT activity Alcoholism >0.6 1 during their 30s, 40s, or 50s. In addition, at least 10% develop liver cirrhosis as a result of the accumulation of variant AAT molecules in the liver; AAT Blood pressure 0.58 0.27 0.62 deficiency accounts for nearly 20% of all nonalcoholic liver cirrhosis cases in (diastolic)† the United States. An important feature of this disease is that cigarette smokers Blood pressure 0.55 0.25 0.6 with AAT deficiency develop emphysema much earlier than do nonsmokers. (systolic)† This is because cigarette smoke irritates lung tissue, increasing secretion of neutrophil elastase. At the same time it inactivates AAT, so there is also less Body fat percentage† 0.73 0.22 >1 inhibition of elastase. One study showed that the median age of survival of Body mass index † 0.95 0.53 0.84 nonsmokers with AAT deficiency was 62 years, whereas it was only 40 years for smokers with this disease. Because the combination of cigarette smoking Cleft lip/palate 0.38 0.08 0.6 (an environmental factor) and the AAT mutation (a genetic factor) produces Clubfoot 0.32 0.03 0.58 more severe disease than either factor alone, it is an example of a gene- environment interaction. Dermatoglyphics 0.95 0.49 0.92 Typically, AAT deficiency is tested first by a straightforward assay for reduced (finger ridge count)† serum AAT concentration. Because a variety of conditions can reduce serum Diabetes mellitus 0.45–0.96 0.03–0.37 >1 AAT level, additional testing, through a type of protein electrophoresis or DNA testing, is carried out to confirm a diagnosis of AAT deficiency. Direct DNA Diabetes mellitus 0.55 – – testing became feasible with the identification of SERPINA1, the gene that (type 1) encodes AAT. More than 100 SERPINA1 mutations have been identified, but Diabetes mellitus 0.9 – – only 2 missense variants, labeled the S and Z alleles, are common and clinically (type 2) significant. Approximately 95% of cases of AAT deficiency are either ZZ homozygotes or SZ compound heterozygotes. The latter genotype generally Epilepsy (idiopathic) 0.69 0.14 >1 produces less severe disease symptoms. Two large studies have indicated Height † 0.94 0.44 1 that the risk of developing emphysema among ZZ homozygotes is 70% for nonsmokers and 90% for smokers. Intelligence quotient 0.76 0.51 0.5 (IQ)† Data from Abboud RT et al: Appl Clin Genet 4:55–65, 2011; Stockley RA, Turner AM: Trends Mol Med 20:105–115, 2014. Measles 0.95 0.87 0.16 Multiple sclerosis 0.28 0.03 0.5 GENETICS OF COMMON DISEASES Myocardial infarction 0.39 0.26 0.26 (males) Some common multifactorial disorders, the congenital malformations, are by definition present at birth. Others, including heart disease, cancer, Myocardial infarction 0.44 0.14 0.6 diabetes, and most psychiatric disorders, are seen primarily in adolescents (females) and adults. Because these disorders are complex, unraveling their genetics Schizophrenia 0.47 0.12 0.7 is a daunting task. Nonetheless, significant progress is being made. Spina bifida 0.72 0.33 0.78 Congenital Malformations NOTE: Heritability, which is defined as the proportion of the variation in Congenital diseases are present at birth. Approximately 2% of newborns a trait that is due to genetic factors, can be measured as 2(CMZ − CDZ), present with a congenital malformation; most of these are multifactorial where CMZ and CDZ are the concordance rates for MZ twins and DZ in etiology. Table 5.4 lists some more common congenital malforma- twins, respectively. These figures were compiled from a large variety tions. Sibling recurrence risks for most of these disorders range from of sources and represent primarily European and U.S. populations. 1% to 5%. *Several heritability estimates exceed 1. Because it is impossible for Some congenital malformations, such as CL/P and pyloric stenosis, >100% of the variance of a trait to be genetically determined, these are relatively easy to repair and thus are not considered to be serious values indicate that other factors, such as shared environmental problems. Others, such as neural tube defects, usually have more severe factors, must be operating. † consequences. Although some cases of congenital malformations occur Because these are quantitative traits, correlation coefficients are given rather than concordance rates. in the absence of any other problems, it is quite common for them to DZ, Dizygotic; MZ, monozygotic. be associated with other disorders. For example, hydrocephaly and  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 167 TABLE 5.4 PREVALENCE RATES OF TABLE 5.5 PREVALENCE OF COMMON COMMON CONGENITAL ADULT DISEASES IN THE MALFORMATIONS UNITED STATES IN WHITES NUMBER AFFECTED PREVALENCE PER 1000 BIRTHS DISEASE (APPROXIMATE) DISORDER (APPROXIMATE) Alcoholism 14 million Cleft lip/palate 1 Alzheimer disease 4 million Clubfoot 1 Arthritis 43 million Congenital heart defects 4–8 Asthma 17 million Hydrocephaly 0.5–2.5 Cancer 8 million Isolated cleft palate 0.4 Cardiovascular disease (all forms) Neural tube defects 1–3 Coronary artery disease 13 million Congestive heart failure 5 million Pyloric stenosis 3 Congenital defects 1 million Hypertension 50 million Stroke 5 million clubfoot are often seen secondary to spina bifida, CL/P is often seen in Depression and bipolar disorder 17 million babies with trisomy 13, and congenital heart defects are seen in children with many other disorders, including Down syndrome. Diabetes (type 1) 1 million Environmental factors also cause some congenital malformations. Diabetes (type 2) 15 million An example is thalidomide, a sedative used during pregnancy in the early 1960s. When ingested during early pregnancy this drug often Epilepsy 2.5 million caused phocomelia (severely shortened limbs) in babies. Maternal Multiple sclerosis 350,000 exposure to retinoic acid, which is used to treat acne, can cause congenital defects of the heart, ear, and central nervous system. Maternal rubella Obesity* 60 million infection can cause congenital heart defects. Parkinson disease 500,000 Multifactorial Disorders in the Adult Population Psoriasis 3–5 million Until quite recently, very little was known about speciic genes responsible Schizophrenia 2 million for common adult diseases. With the more powerful laboratory and analytic techniques now available, this situation is changing. This section *Body mass index >30. reviews recent progress in understanding the genetics of the major Data from National Center for Chronic Disease Prevention and Health common adult diseases. Table 5.5 gives approximate prevalence figures Promotion; American Heart Association (2002 Heart and Stroke for these disorders in the United States. Statistical Update); National Institute on Alcohol Abuse and Alcoholism; Office of the U.S. Surgeon General; American Academy of Allergy, Asthma and Immunology; Cown WM, Kandel ER: JAMA Coronary Heart Disease 285:594–600, 2001; Flegal et al: JAMA 288:1723–1727, 2002. It is well known that coronary heart disease (CHD) is the leading killer of Americans, accounting for approximately 25% of all deaths in the United States. It is caused by atherosclerosis (narrowing as a result of the formation of lipid-laden lesions) of the coronary arteries. This What part do genes play in the familial clustering of heart disease? narrowing impedes blood flow to the heart and can eventually result Because of the key role of lipids in atherosclerosis, many studies are in a myocardial infarction (destruction of heart tissue caused by an focusing on the genetic determination of various lipoproteins.8 An inadequate supply of oxygen). When atherosclerosis occurs in arteries important advance in this area has been the identification of several supplying blood to the brain, a stroke can result. Many risk factors for genes that encode the processing of low-density lipoproteins and that, heart disease have been identified, including obesity, cigarette smoking, when mutated, can cause familial hypercholesterolemia (Box 5.3). Many hypertension, elevated cholesterol level, and positive family history other genes involved in lipid variation, coagulation, and hypertension (usually defined as having one or more affected first-degree relatives). have been identified, including several genes encoding apolipoproteins Many studies have examined the role of family history in CHD, and (the protein components of lipoproteins) (Table 5.6).9 Functional analysis they show that an individual with a positive family history is two to of these genes is leading to an increased understanding, and eventually seven times more likely to have heart disease than is an individual with more effective treatment, of CHD. no family history (this would be the relative risk of heart disease as a Environmental factors, many of which are easily modified, are also result of a positive family history). Generally, these studies also show important causes of CHD. Abundant epidemiologic evidence shows that the risk increases if (1) there are more affected relatives; (2) the that cigarette smoking and obesity increase the risk of CHD, whereas affected relative or relatives are female (the less commonly affected sex) exercise and a diet low in saturated fats decrease the risk. Indeed, the rather than male; and (3) the age of onset in the affected relative is approximate 50% decline in CHD prevalence in the United States during early (before 55 years). For example, one study showed that men between the past 40 years is usually attributed to a decrease in the proportion the ages of 20 and 39 years had a relative risk of 3 for CHD if they had of adults who smoke cigarettes, a decreased consumption of saturated one affected first-degree relative. The relative risk increased to 13 if two fats, and an increased emphasis on exercise and a generally healthier first-degree relatives were affected with CHD before 55 years of age.7 lifestyle. 168 UNIT II Genes, Gene-Environment Interaction, and Epigenetics BOX 5.3 FAMILIAL HYPERCHOLESTEROLEMIA surface but incapable of normal binding to LDL. Class 4 mutations, which are Food comparatively rare, produce receptors that are normal except that they do not Intestines Liver migrate specifically to coated pits and thus cannot carry LDL into the cell. The Blood final group of mutations, class 5, produces an LDL receptor that cannot dissociate vessel from the LDL particle after entry into the cell. The receptor cannot return to the cell surface and is degraded. Each class of mutations reduces the number of VLDL effective LDL receptors, resulting in decreased LDL uptake and hence elevated LDL receptor levels of circulating cholesterol. The number of effective receptors is reduced LDL by about half in FH heterozygotes, and homozygotes have virtually no functional Peripheral fat LDL receptors. Alimentary fat absorption Understanding the defects that lead to FH has helped to develop effective LDL Organs therapies for the disorder. Dietary reduction of cholesterol (primarily through the reduced intake of saturated fats) has only modest effects on cholesterol levels in FH heterozygotes. Because cholesterol is reabsorbed into the gut and then Excess deposits in blood recycled through the liver (where most cholesterol synthesis takes place), serum vessels and tissues cholesterol levels can be reduced by the administration of bile acid–absorbing ATHEROSCLEROSIS resins, such as cholestyramine. The absorbed cholesterol is then excreted. It is interesting that reduced recirculation from the gut causes the liver cells to form additional LDL receptors, lowering circulating cholesterol levels. However, the Autosomal dominant familial hypercholesterolemia (FH) is an important cause decrease in the concentration of intracellular cholesterol also stimulates cholesterol of heart disease, accounting for approximately 5% of myocardial infarctions in synthesis by liver cells, so the overall reduction in plasma LDL level is only about individuals less than 60 years of age. FH is one of the most common autosomal 15% to 20%. This treatment is much more effective when combined with agents dominant disorders: in most populations surveyed to date, about 1 in 500 people that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme is a heterozygote. Plasma cholesterol levels are approximately twice as high as A (HMG-CoA) reductase (the “statin” class of drugs). Decreased synthesis leads normal (i.e., about 300 to 400 mg/dL), resulting in substantially accelerated to further production of LDL receptors. When these therapies are used in combina- atherosclerosis and distinctive cholesterol deposits in skin and tendons (xanthomas tion, serum cholesterol levels in FH heterozygotes can be reduced to approximately [Fig. 5.5]). Data compiled from five studies showed that approximately 75% of normal levels. men with FH developed coronary disease, and 50% had a fatal myocardial infarction The picture is less encouraging for FH homozygotes. The therapies just discussed by 60 years. The corresponding percentages for women were lower (45% and can enhance cholesterol elimination and reduce its synthesis, but they are largely 15%) because women generally develop heart disease at a later age than men. ineffective because homozygotes have few or no LDL receptors. Liver transplants, Consistent with Hardy-Weinberg predictions, about 1 in 1 million births is which provide hepatocytes that have normal LDL receptors, have been successful homozygous for the FH gene. Homozygotes are much more severely affected, in some cases, but this option is often limited by a lack of donors. Plasma with cholesterol levels ranging from 600 to 1200 mg/dL. Most experience exchange, carried out every 1 to 2 weeks, in combination with drug therapy, can myocardial infarctions before 20 years of age, and a myocardial infarction at 18 reduce cholesterol levels by about 50%. However, this therapy is difficult to months of age has been reported. If untreated, most FH homozygotes die before continue for long periods. Somatic cell gene therapy, in which hepatocytes carrying 30 years of age. normal LDL receptor genes are introduced into the portal circulation, is now All cells require cholesterol as a component of their plasma membrane. They being tested. It may eventually prove to be an effective treatment for FH can either synthesize their own cholesterol or, preferably, obtain it from the homozygotes. extracellular environment, where it is carried primarily by low-density lipoprotein FH also can be caused by inherited mutations in the gene that encodes apo- (LDL). In a process known as endocytosis, LDL-bound cholesterol is taken into lipoprotein B. In addition, a small number of FH cases are caused by mutations the cell via LDL receptors on the cell’s surface (Fig. 5.6). FH is most commonly in the gene that encodes PCSK9 (proprotein convertase subtilisin/kexin type 9), caused by a reduction in the number of functional LDL receptors on cell surfaces. an enzyme that plays a key role in degrading LDL receptors. Gain-of-function Lacking the normal number of LDL receptors, cellular cholesterol uptake is reduced mutations in the PCSK9 gene reduce the number of LDL receptors, causing FH. and circulating cholesterol levels increase. Loss-of-function mutations in this gene can increase the number of LDL receptors, Much of what we know about endocytosis has been learned through the study resulting in exceptionally low circulating LDL levels. These findings have led to of LDL receptors. The process of endocytosis and the processing of LDL in the the development of drugs that inhibit PCSK9 activity, thus lowering LDL cholesterol cell are described in detail in Fig. 5.6 (endocytosis is discussed in Chapter 1). levels. These drugs, which have been approved for clinical use, can reduce LDL These processes result in a fine-tuned regulation of cholesterol levels within cholesterol levels by approximately 50% in the general population of persons cells, and they influence the level of circulating cholesterol as well. with hypercholesterolemia and produce significant effects even in those who The identification of the LDL receptor gene in 1984 was critical in understanding are using statin drugs. exactly how LDL receptor defects cause FH. More than 1000 different mutations, The FH story illustrates how medical research has made important contributions including missense and nonsense substitutions as well as insertions and deletions, both to our understanding of basic cell biology and to our advances in clinical have been identified in the LDL receptor gene. These can be grouped into five therapy. The process of receptor-mediated endocytosis, elucidated largely by broad classes according to their effects on the activity of the receptor. Class 1 research on the LDL receptor defects, is of fundamental significance for cellular mutations result in no detectable protein product. Thus, heterozygotes would processes throughout the body. Equally important is that this research, by clarifying produce only half the normal number of LDL receptors. Class 2 mutations in the how cholesterol synthesis and uptake can be modified, has led to significant LDL receptor gene result in production of the LDL receptor, but it is altered such improvements in therapy for this important cause of heart disease. The discovery that it cannot leave the endoplasmic reticulum. It is eventually degraded. Class of rare mutations in PCSK9 has led to PCSK9 inhibitor drugs that may benefit 3 mutations produce an LDL receptor that is capable of migrating to the cell millions of persons with high cholesterol levels. VLDL, very-low-density lipoprotein. Data from Brautbar A et al: Curr Atheroscler Rep 17:491, 2015; Roberts R: Trends Cardiovasc Med 64(23):2525–2540, 2014; Varret MM et al: Clin Genet 73(1):1–13, 2008.  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 169 also must be important causes of blood pressure variation. The most Hypertension important environmental risk factors for hypertension are increased Systemic hypertension, which has a worldwide prevalence of approxi- sodium intake, decreased physical activity, psychosocial stress, and obesity mately 25% to 30%, is a key risk factor for heart disease, stroke, and (but, as discussed later, the latter factor is itself influenced by both genes kidney disease. Studies of blood pressure correlations within families and environment). indicate that about 20% to 40% of the variation in both systolic and Blood pressure regulation is a highly complex process that is diastolic blood pressure is caused by genetic factors. The fact that this influenced by many physiologic systems, including various aspects of igure is substantially less than 100% indicates that environmental factors kidney function, cellular ion transport, and heart function.10 Because of this complexity, much research is now focused on specific components that may influence blood pressure variation, such as the renin-angiotensin system (involved in sodium reabsorption and vasoconstriction), vasodila- tors such as nitric oxide and the kallikrein-kinin system, and ion-transport systems such as adducin and sodium-lithium countertransport (Fig. 5.7). These individual factors are more likely to be under the control of smaller numbers of genes than is blood pressure itself, simplifying the task of identifying these genes and their role in blood pressure regulation. For example, linkage and association studies have implicated several genes involved in the renin-angiotensin system (e.g., the genes that encode angiotensinogen, angiotensin-converting enzyme, angiotensin receptors) in the causation of hypertension. Cancer Cancer is the second leading cause of death in the United States. It is well established that many major types of cancer (e.g., breast, colon, prostate, ovarian) cluster strongly in families. This is caused by both inherited genes and shared environmental factors. Although numerous cancer-causing genes are being isolated,11 environmental factors also FIGURE 5.5 Xanthoma. Fatty deposits, referred to as xanthomas as seen here play an important role in causing cancer. In particular, tobacco use is on the knuckles, are often noted in individuals with familial hypercholesterolemia. estimated to account for one-third of all cancer cases in the United (From Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.) States, making it the most important known cause of cancer.12 Typically, TABLE 5.6 LIPOPROTEIN GENES KNOWN TO CONTRIBUTE TO CORONARY ARTERY DISEASE RISK GENE CHROMOSOME LOCATION FUNCTION OF PROTEIN PRODUCT Apolipoprotein A-I 11q HDL component; LCAT cofactor Apolipoprotein A-IV 11q Component of chylomicrons and HDL; may influence HDL metabolism Apolipoprotein C-III 11q Allelic variation associated with hypertriglyceridemia Apolipoprotein B 2p Ligand for LDL receptor; involved in formation of VLDL, LDL, IDL, and chylomicrons Apolipoprotein D 2p HDL component Apolipoprotein C-I 19q LCAT activation Apolipoprotein C-II 19q Lipoprotein lipase activation Apolipoprotein E 19q Ligand for LDL receptor Apolipoprotein A-II 1p HDL component LDL receptor 19p Uptake of circulating LDL particles Lipoprotein(a) 6q Cholesterol transport Lipoprotein lipase 8p Hydrolysis of lipoprotein lipids Hepatic triglyceride lipase 15q Hydrolysis of lipoprotein lipids LCAT 16q Cholesterol esterification Cholesterol ester transfer protein 16q Facilitates transfer of cholesterol esters and phospholipids between lipoproteins HDL, High-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin cholesterol acyltransferase; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Adapted in part from King RA, Rotter JI, editors: The genetic basis of common diseases, ed 2, New York, 2002, Oxford University Press. 170 UNIT II Genes, Gene-Environment Interaction, and Epigenetics Cell LDL receptor 3 Plasma membrane 1 2 Coated pit Nucleus Newly synthesized LDL mRN particle Tr LDL receptor an sc Ribosomes A rip DN 4 tio A n Endosome Endoplasmic Inhibits reticulum 10 Cholesterol storage 5 6 Excess Activates 9 cholesterol 7 Lysosome Bile acids, etc. ACAT Cholesterol Inhibits 8 HMG-CoA reductase FIGURE 5.6 Process of Receptor-Mediated Endocytosis. Numbers in parentheses correspond to numbers shown in the figure. 1, The low-density lipoprotein (LDL) receptors, which are glycoproteins, are synthesized in the endoplasmic reticulum of the cell. 2, From here, they pass through the Golgi apparatus to the cell surface, where part of the receptor protrudes outside the cell. 3, The circulating LDL particle is bound by the LDL receptor and localized in cell surface depressions called coated pits (so named because they are coated with a protein called clathrin). 4, The coated pit invaginates, bringing the LDL particle inside the cell. 5, Once inside the cell, the LDL particle is separated from the receptor, taken into a lysosome, and broken down into its constituents by lysosomal enzymes. 6, The LDL receptor is recirculated to the cell surface to bind another LDL particle (each LDL receptor goes through this cycle approximately once every 10 minutes even if it is not occupied by an LDL particle). 7, Free cholesterol is released from the lysosome for incorporation into cell membranes or metabolism into bile acids or steroids. Excess cholesterol can be stored in the cell as a cholesterol ester or removed from the cell by associating with high-density lipoprotein (HDL). 8, As cholesterol levels in the cell rise, cellular cholesterol synthesis is reduced by inhibition of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. 9, Rising cholesterol levels also increase the activity of acyl coenzyme A (acyl CoA):cholesterol acyltransferase (ACAT), an enzyme that modifies cholesterol for storage as cholesterol esters. 10, In addition, the number of LDL receptors is decreased by lowering the transcription rate of the LDL receptor gene itself. This decreases cholesterol uptake. (From Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.) these environmental factors cause cancer by creating somatic mutations 85 years or older. Formerly the leading cause of cancer death among (see Chapter 4) in specific cell types. Thus, cancer can be caused both women, it has been surpassed by lung cancer. Breast cancer aggregates by inherited genetic variants and by noninherited somatic mutations strongly in families; for example, if a woman has one affected first-degree acquired during an individual’s lifetime. relative, her risk of developing breast cancer doubles. This risk increases Breast Cancer. Breast cancer is the most common cancer among further if the age of onset in the affected relative is early and if the women, affecting approximately 12% of American women who live to cancer is bilateral (tumors in both breasts).  CHAPTER 5 Genes, Environment-Lifestyle, and Common Diseases 171 Renin Released from kidneys into serum Several known stimuli: ↓ Blood pressure ↓ Serum sodium ↑ β-Adrenergic tone Prostaglandin release Angiotensinogen Angiotensin I (made primarily Angiotensin- in the liver) converting ACE inhibitors enzyme (ACE) Angiotensin II (binding) AT1 receptor AT1 antagonists Stimulates release of aldosterone (sodium retention) and vasoconstriction ↑ Blood pressure Feedback to kidneys ↓ Renin secretion FIGURE 5.7 Renin-Angiotensin-Aldosterone System. (Modified from King RA, Rotter JI, Motulsky AG, editors: The genetic basis of common diseases, New York, 1992, Oxford University Press.) An autosomal dominant form of breast cancer accounts for approxi- cancer. Like breast cancer, it clusters in families (in fact, familial clustering mately 5% to 10% of breast cancer cases in the United States. Genes of this form of cancer was reported in the medical literature as early responsible for this form of breast cancer have been identified on as 1881). The risk of colorectal cancer in people with one affected chromosomes 17 (BRCA1) and 13 (BRCA2), and these genes can be first-degree relative is two to three times higher than that in the general tested for inherited cancer-causing mutations.13 Women who inherit a population. mutation in BRCA1 or BRCA2 experience a 50% to 80% lifetime risk This familial aggregation is caused in part by subsets of colorectal of developing breast cancer.14 BRCA1 mutations also increase the risk cancer cases that are inherited as single-gene traits. For example, familial of ovarian cancer among women (20% to 50% lifetime risk), and they adenomatous polyposis occurs in approximately 1 in 8000 whites. The confer a modestly increased risk of prostate and colon cancers. BRCA2 gene responsible for this disorder, APC, encodes a tumor suppressor.16 mutations also confer an increased risk of ovarian cancer (10% to 20% Importantly, somatic mutations of APC are found in at least 85% of lifetime prevalence). Approximately 6% of males who inherit a BRCA2 all colon tumors. Thus although inherited APC mutations cause rare mutation will develop breast cancer, representing a 100-fold increase familial adenomatous polyposis, somatic mutations are involved in the over the risk in the general male population. Evaluation of the BRCA1 great majority of all common colorectal cancers. and BRCA2 gene products, which are both involved in deoxyribonucleic Hereditary nonpolyposis colorectal cancer, which may account for as acid (DNA) repair, is yielding valuable evidence on the etiology of many as 5% of colorectal cancer cases, is caused by mutations in any breast cancer in general. of six genes.17 Research has shown that all of these genes are involved Although BRCA1 and BRCA2 mutations are the most common in the vital process of DNA repair. When this function is compromised, known causes of inherited breast cancer, this disease also can be caused cancer-causing mutations can persist in cells, leading eventually to by inherited mutations in several other genes (e.g., CHK2, ATM, PALB2, growth of a tumor. and TP53). Germline mutations in a tumor-suppressor gene called PTEN Other colorectal cancer cases are likely to be caused by a complex are responsible for Cowden disease, which is characterized by multiple interaction of multiple genes. In addition, environmental factors, such benign tumors and an increased susceptibility to breast cancer. Despite as a high-fat, low-fiber diet, are thought to increase the risk of colorectal the significance of these genes, it should be emphasized that more than cancer. 90% of breast cancer cases are not inherited as mendelian diseases. Prostate Cancer. Prostate cancer is the second most commonly Colorectal Cancer. Colorectal cancer is second only to lung cancer diagnosed cancer in men (after skin cancer), with approximately 220,000 in the number of cancer deaths occurring annually in the United States, new cases annually in the United States. Prostate cancer is second only with approximately 134,000 new cases (and 49,000 deaths) estimated to lung cancer as a cause of cancer death in men, causing more than in 2016.15 Approximately 1 in 21 Americans will develop colorectal 27,000 deaths each year. Having an affected first-degree relative increases 172 UNIT II Genes, Gene-Environment Interaction, and Epigenetics the risk of developing prostate cancer by a factor of two to three, and in the general population, this risk difference is inconsistent with the the heritability of prostate cancer is estimated to be approximately 40%. sex-specific threshold model for multifactorial traits). Twin studies The relatively late age of onset of most prostate cancer cases (median show that the empirical risks for identical twins of people with type 1 age 72 years) makes genetic analysis especially difficult. However, loss diabetes range from 30% to 50%. In contrast, the concordance rates of heterozygosity (see Chapter 12) has been observed in a number of for dizygotic twins are 5% to 10%. The fact that type 1 diabetes is not genomic regions in prostate tumor cells, possibly indicating the presence 100% concordant among identical twins indicates that genetic factors of genetic alterations in these regions. In addition, genome-wide associa- are not solely responsible for the disorder. There is good evidence that tion studies have identified several dozen polymorphisms associated specific viral infections contribute to the causation of type 1 diabetes in with prostate cancer risk. Several of these are located in chromosome at least some individuals, possibly by activating an autoimmune response. 8q24, which contains polymorphisms associated with several other The association of specific MHC class II alleles (see Chapter 22) cancers as well (colon, pancreas, and esophagus). Although the 8q24 and type 1 diabetes has been studied extensively, and it is estimated region contains no protein-coding genes, it contains enhancer elements that these alleles account for about 40% of the familial clustering of that affect expression of the MYC oncogene, located about 250 kilobytes type 1 diabetes. Approximately 95% of whites with type 1 diabetes have (kb) from 8q24. the human leukocyte antigen (HLA) (part of the MHC), DR3, and/or Nongenetic risk factors for prostate cancer may include a high-fat DR4 alleles, whereas only about 50% of the general white population diet. Because prostate cancer usually progresses slowly and because it has either of these alleles. If an affected proband and a sibling are can be detected by digital examination and by the prostate-specific heterozygous for the DR3 and DR4 alleles, the sibling’s risk of developing antigen (PSA) test, fatal metastasis can usually be prevented. type 1 diabetes is nearly 20% (i.e., about 40 times higher than the risk Cancer Gene Identification. Recently developed techniques, in the general population). In addition, the presence of aspartic acid including large-scale DNA sequencing, have identified hundreds of genes at position 57 of the HLA DQ chain is strongly associated with resistance that are mutated in various cancers. Some of these genes contribute to type 1 diabetes. In fact, those who do not have this amino acid at directly to a growth advantage in tumors and are considered primary position 57 (and instead are homozygous for a different amino acid) causes of cancer. Approximately 150 such driver genes have been are 100 times more likely to develop type 1 diabetes. The aspartic acid described.11 A much larger number of genes undergo somatic mutations substitution alters the shape of the HLA class II molecule and thus its during tumorigenesis, but these genes do not directly confer a growth ability to bind and present peptides to T cells. Altered T-cell recognition advantage to cells; these are termed passenger genes. The gene responsible may help protect individuals with the aspartic acid substitution from for retinoblastoma (see Chapter 4), which normally acts as a “brake” an autoimmune episode. on cell division, is an example of a well-known driver gene. The APC The insulin gene, which is located on the short arm of chromo- gene, discussed previously, is another example. some 11, is another logical candidate for type 1 diabetes susceptibility. Although many types of cancer, such as retinoblastoma or familial Polymorphisms within and near this gene have been tested for association adenomatous polyposis, are relatively rare, study of the causative genes with type 1 diabetes. It is estimated that inherited genetic variation has provided many important insights into the nature of carcinogenesis in the insulin region accounts for approximately 10% of the familial in general. This can lead to more effective treatment and prevention clustering of type 1 diabetes. of all cancers. Many additional genes have been shown to be associated with Diabetes Mellitus. Like the other disorders discussed in this susceptibility to type 1 diabetes. The most significant of these are cytotoxic chapter, the etiology of diabetes mellitus is complex and not fully ly