Studying populations

Population studies can help identify risk factors that increase the likelihood that an individual will develop a particular disease. Risk factors may be personal characteristics (such as age, sex or blood pressure), behavioural characteristics (such as smoking or participation in exercise activities) or external conditions (such as work environment or home address). To determine relative risk, individuals in the population under study are divided into two groups: those with the characteristic in question and those without. Comparing the incidence of disease between the two groups enables factors that may increase or decrease the risk of developing disease to be identified.

Such data collection is undertaken by a number of government organisations and networks. The Australian Department of Health and Ageing and the New Zealand Ministry of Health, which control the regulatory frameworks within which the healthcare systems operate in each country and coordinate the work of many other government organisations, have a strong focus on promoting healthy lifestyles, preventing disease and developing early intervention strategies.

In 2006–2007, the New Zealand Health Survey, ‘A portrait of health’,⁴ considered the distribution of a wide range of physical and mental health conditions, risk factors and the use of healthcare services according to parameters such as gender, age group, ethnic group and geographical region. In Australia, similar information is found in the Australian Institute of Health and Welfare’s publication, ‘Australia’s health 2008’.⁵

In some instances, hospitals collaborate to produce large data sets. For example, since 1999 the Australian and New Zealand Neonatal Network has been collecting data on all high-risk neonates admitted to level II and level II neonatal intensive care units throughout Australia and New Zealand.⁶ These data are used to identify trends in reasons for admissions, to monitor the performance of participating neonatal intensive care units units, and to contribute to the evaluation of new therapies and treatments.

However, the study of populations only partly explains the development of diseases and disorders. Just because an individual or a particular group in the population has risk factors does not mean that the disease will develop in these people. Rather, the presence of risk factors means that the individual is more likely to develop a disease or disorder compared with individuals without the risk factor. Often we hear stories about elderly people who smoked all their life and did not develop lung cancer or who followed poor dietary choices and did not develop diabetes, cancer or obesity. Yet some people who follow a healthy diet and exercise regularly get heart disease — is all that exercise a waste of time? Such stories abound and often there is confusion about their significance. The reality is that the influence of genes and how they interact with the lifestyle or environment predict the likelihood of disease development. While scientists do not have all the answers as to why the environment influences some genes and not others, there is an increasing body of knowledge that specifically links genetic and environmental aspects to particular diseases. We now look at how genetic and environmental influences on disease can be ascertained.

Studying families

Studying families provides an insight into what diseases are occurring in related sets of individuals. Often, this may indicate a genetic abnormality that is passed from generation to generation. However, it needs to be clarified that just because a condition occurs in a family, it does not necessarily follow that it has a genetic cause. For example, although obesity may occur in a particular family, it may be that the family members all have an unhealthy lifestyle, rather than having a genetic condition that leads to obesity. With that in mind, family studies give us an initial understanding of the types of conditions that are passed through genes.

Human family data are often represented by producing a pedigree, such as the pedigree for Parkinson’s disease shown in Figure 37-2. You will see that each generation occupies one row in the pedigree chart. Females are represented by circles and males by squares, and any individuals whose sex is unknown are represented by diamonds. Affected individuals are indicated by filling the shape with colour, and a diagonal line through a shape indicates that the individual has died.

FIGURE 37-2 Family pedigree for Parkinson’s disease, showing the pattern of inheritance in 3 generations.

Note that the mother passed the disease to one of her sons. Her affected son also produced an affected child. Her unaffected son produced 2 affected children. This is consistent with an autosomal recessive pattern of inheritance. The father in generation I is now deceased. Unaffected females = , unaffected males = . Affected females = •, affected males = . Where a male and female are joined by a horizontal line this indicates a partnership, and their offspring are shown in the vertical branching line. The offspring of a partnership in generation I are shown in generation II. Also, those individuals who have joined the family are shown in the second row, as the females who have partnered with the males.

While accurate pedigrees provide very useful information, it is often difficult to study patterns of disease within families. The collection of data from several generations is difficult, as family records are often incomplete and may be unreliable. Furthermore, many conditions may have been unrecognised or misdiagnosed in past generations, and paternity itself is sometimes doubtful.

Non-disjunction of autosomes

Zygotes with a single copy of a particular autosome (any chromosome, other than the sex chromosomes) are not seen: this indicates that at least 2 copies of each autosome are needed for cell survival. Trisomy of all autosomes has been detected in cells from fetuses that have spontaneously aborted. However, trisomy of the smallest chromosomes only is compatible with life. Individuals with trisomy 21 (Down syndrome) have an average life span of 55 years, but infants with trisomy 18 or 13 rarely survive infancy. Trisomy of larger chromosomes does not result in a live birth.⁷

Down syndrome is the most common cause of intellectual disability; it is also associated with characteristic facial features (see Figure 37-4) and heart malformations. The syndrome has an incidence of approximately 1 in 700 live births in Australia, but the true incidence is higher than this, as a significant proportion of Down syndrome pregnancies are terminated.^8,9 The frequency of trisomy 18 is approximately 1 in 3000 births and the frequency of trisomy 13 is approximately 1 in 5000 births.⁷ These two conditions result in severe heart, kidney and skeletal deformities, and affected infants rarely survive longer than 10 weeks. The frequency of all chromosomal abnormalities, Down syndrome in particular, increases with maternal age, as shown in Table 37-1.

FIGURE 37-4 Trisomy 21 (Down syndrome).

An infant exhibiting characteristic facial features, with karyotype showing 3 copies of chromosome 21.

Source: Katz VL et al. Comprehensive gynecology. 5th edn. St Louis: Mosby; 2007.

Table 37-1 APPROXIMATE RISKS OF CHROMOSOMAL CHANGES ASSOCIATED WITH MATERNAL AGE

Source: Cuckle HS, Wald NJ, Thompson SG. Estimating a woman’s risk of having a pregnancy associated with Down syndrome using her age and serum alphafetoprotein level. Br J Obs Gyn 1987; 94:387–402; Hook EB. Rates of chromosomal abnormalities. Obs Gyn 1981; 58:282–285.

Non-disjunction of sex chromosomes

It is estimated that abnormal numbers of sex chromosomes occur in about 1 in 400 male births and 1 in 650 female births.⁷ These estimates may be unreliable, as many affected individuals have no obvious abnormalities and karyotyping is not routinely performed. If a Y chromosome is present, individuals are classed as males. In the absence of a Y chromosome, individuals are classed as females.

With Turner’s syndrome, affected individuals have a single X chromosome, making a total of 45 chromosomes (rather than the normal 46) per somatic cell. This condition appears in approximately 1 in 2000 births in Australia.⁷ Females are infertile, with a sexually immature appearance (see Figure 37-5), but normal intelligence. Although this condition is associated with a high spontaneous abortion (miscarriage) rate, it is benign after birth. Oestrogen replacement therapy may be useful to promote the development of secondary sexual characteristics.

FIGURE 37-5 A 15-year-old female with Turner’s syndrome, exhibiting classical features such as short stature and poor sexual development.

Karyotyping revealed that this individual is a mosaic, with both 45 (XO) and 46 (XX) karyotypes.

Source: Kliegman RM et al. Nelson textbook of pediatrics. 18th edn. Philadelphia: Saunders; 2007.

Autosomal dominant disorders

Dominant disorders arise due to the inheritance of a dominant allele (see Figure 37-6), resulting in the production of a ‘harmful’ protein. A single copy of the gene is sufficient, because any amount of the protein will cause disease. Individuals displaying the dominant phenotype may have 1 or 2 copies of the disease allele, but heterozygotes — with 1 dominant disease allele and 1 normal allele — are most common.

FIGURE 37-6 Pedigree illustrating autosomal dominant inheritance.

Note that the trait appears in every generation; every affected child has an affected parent.

Unaffected females = , unaffected males = . Affected females = •, affected males = .

Source: Courtesy of Edith Cheng, MD. Katz VL et al. Comprehensive gynecology. 5th edn. St Louis: Mosby; 2007.

Punnett squares can be used to investigate patterns of inheritance of dominant disorders. We will call the dominant disease allele D, and the recessive normal allele d, and consider the union of a normal unaffected parent and an affected parent. Most commonly, the unaffected parent will have 2 copies of the normal recessive allele (genotype dd) and the affected parent will have 1 copy of the dominant allele and 1 normal allele (genotype Dd).

The Punnett square shows that, on average, about half the children of affected parents will have the disorder. Because the disease allele is present on an autosome (non-sex chromosome), males and females are equally likely to be affected. And because every individual that possesses a copy of the allele will display the associated diseased phenotype, every affected child has an affected parent. These features are clearly seen in the autosomal dominant pedigree (see Figure 37-6).

The collagen disorders provide a good illustration of dominant disease. Collagen is the major structural protein of the body, present in the skin, tendons, ligaments, cartilage and bone. A complete collagen molecule is made up of 3 protein chains, each of which is encoded by a different gene. A defective collagen molecule is formed if any of the 3 collagen protein strands is defective, because the 3 strands are unable to assemble into a functional unit. The presence of a single mutant allele results in the production of defective protein chains that are randomly incorporated into the collagen molecules produced, so a high proportion of collagen molecules produced is defective. Therefore collagen disorders are dominant; every individual that carries a mutant allele will produce a mixture of normal and abnormal collagen molecules.

One of the most common collagen disorders is Marfan’s syndrome,¹² which affects the eyes, the skeletal system and the cardiovascular system, producing a wide range of clinical features. Affected individuals are typically tall and thin, with a very wide arm span and extremely flexible joints. Displacement of the lens of the eye is commonly observed; dilatation, then rupture, of the aorta is a common cause of sudden death. Although a tall slender physique is often well suited to sports such as basketball, Marfan’s sufferers are advised against vigorous exercise; some sport associations screen athletes for signs of Marfan’s syndrome. After the 2008 Beijing Olympics it was revealed that Michael Phelps, who won 8 gold medals in swimming for the United States, had been tested for Marfan’s syndrome but cleared. The variable phenotypes observed make definitive diagnosis of Marfan’s syndrome difficult; mild forms of the disease may not be recognised. Estimates range from 1 in 3000 to 1 in 5000 live births, but recent studies suggest that the incidence may be higher.¹³

Autosomal recessive disorders

In diseases that follow the recessive pattern of inheritance (see Figure 37-7), the dominant allele usually codes for a normal protein and the recessive allele codes for a dysfunctional form of the protein or prevents production of the normal protein. Individuals who have 2 copies of the recessive (defective) allele do not produce any normal protein, so have the disease. Those who have 1 normal allele and 1 defective allele produce half the amount of normal protein, which is often sufficient for normal function, so may ‘carry’ the defective gene without displaying any significant phenotypic changes. In families where the number of offspring is small, the disorder may be carried through several generations before an affected child is born.

FIGURE 37-7 Pedigree illustrating autosomal recessive inheritance of a rare disorder.

Note that the disorder is not present in every generation. Carriers possess the disease allele but do not display the trait (the carrier status of individuals in generation I is not known). In this example, marriage of first cousins in generation III, both of whom carry the disease allele, has produced affected children. The use of a double line between partners indicates a union between people who are genetically related.

Source: Katz VL et al. Comprehensive gynecology. 5th edn. St Louis: Mosby; 2007.

Again, Punnett squares can provide useful information about patterns of inheritance. We will call the normal dominant allele N, and the recessive disease allele n, and consider the union of an affected parent with 2 copies of the recessive disease allele (genotype nn) and an unaffected parent. The unaffected parent may have genotype NN or could carry a single copy of the disease allele (genotype Nn), so 2 alternative scenarios must be considered.

An individual affected with a recessive disorder must have the disease allele on both chromosomes, so must have received a copy of the disease allele from both parents. Therefore, affected parents will produce affected offspring only if their partner is a carrier of the disease allele. If the partner of an affected parent is not a carrier of the disease allele, none of the offspring will be affected, but all of the offspring will be carriers.

Pedigrees for diseases displaying autosomal recessive patterns of inheritance often contain affected children with unaffected parents; the disease appears to ‘skip’ generations. Punnett squares show that 2 unaffected parents can produce an unaffected child if both parents are carriers of the disease allele. Again, males and females are equally likely to be affected.

It has been estimated that each human carries about 30 ‘faulty’ alleles, which are effectively hidden by the presence of the corresponding normal allele. This is responsible for the increased rate (approximately double) of stillbirths, neonatal deaths and congenital malformations observed in offspring of first cousins.¹⁴ Marriage of relatives, such as cousins, is certainly ill-advised if the family is known to carry a serious recessive disorder.

Cystic fibrosis is the most common autosomal recessive paediatric disorder in Australia and New Zealand, occurring in approximately 1 in 2800 live births (cystic fibrosis is discussed in Chapter 25).¹⁵ However, the less well-known autosomal recessive condition hereditary haemochromatosis is much more common; approximately 1 in 300 Australians will be affected by this condition during their lifetime.⁷ In this disorder, iron absorbed from food slowly accumulates in organs and joints. Significant liver damage (cirrhosis and cancer) may cause premature death. Symptoms appear in the third or fourth decade for men and even later for women, as menstrual blood loss reduces the iron overload, delaying the onset of symptoms.

Sex-linked disorders

Sex-linked traits are determined by genes carried on the X and Y chromosomes. Because Y-linked disorders are extremely rare, sex-linked disorders are usually X-linked, so the terms sex-linkage and X-linkage are often used interchangeably. X-linked dominant disorders are not common, one example being hypophosphataemia. However, several diseases, including haemophilia, red–green colour blindness and Duchenne’s muscular dystrophy, are X-linked recessive traits.

Because most X-linked traits are recessive and females have 2 X chromosomes, many females carry the genes for X-linked traits without displaying the associated characteristics. The situation in males is very different: as males have 1 X chromosome (and 1 Y chromosome), they have only a single copy of all X-linked genes. Consequently, all males that carry the gene for an X-linked trait will display that trait. Transmission is typically from mothers to sons (see Figure 37-8).

FIGURE 37-8 Pedigree illustrating X-linked recessive inheritance.

Note that the trait may appear to skip a generation. Carrier females do not display the trait, but may pass either the normal X or the affected X chromosome to their offspring. Daughters receiving the affected X chromosome are carriers; sons receiving the affected X chromosome display the trait.

Source: Katz VL et al. Comprehensive gynecology. 5th edn. St Louis: Mosby; 2007.

X-linked recessive traits are common in males and rare in females. Punnett squares can be used to explore the most common situations: the union of an affected male with a non-carrier female and the union of a carrier female with an unaffected male. We will use X to represent the normal X chromosome and x to represent the X chromosome carrying the recessive disease allele.

The Punnett squares show that all daughters of affected males will be carriers. Carrier daughters will then pass the trait to (approximately) half of their sons, so that the trait will ‘skip’ generations. Affected males never pass the trait to their sons.

Fragile X syndrome

Fragile X syndrome, an X-linked disorder, is the most common cause of inherited intellectual disability, with a prevalence of approximately 1 in 3500 males.¹⁶ Affected individuals present with intellectual disability, delayed development of speech and motor skills, and behavioural problems including attention deficit disorder and autism. Fragile X syndrome is due to changes near the tip of the long arm of the X chromosome that give the chromosome a damaged or ‘fragile’ appearance, hence the name for this syndrome. This region of the X chromosome comprises a short sequence that is repeated many times. About 30 repeats are present in normal individuals, whereas individuals displaying the fragile X trait possess more than 200 repeats. Individuals whose X chromosomes contain 50–200 repeats are usually unaffected and are described as carriers.

Patterns of inheritance of the fragile X syndrome can be unclear, as the number of repeats increases when the X chromosome is passed from mothers to their children (male or female). In contrast, there is no change in the number of repeats when X chromosomes pass from fathers to daughters. As expected for an X-linked condition, the trait is more common in males, but females with 1 ‘fragile’ chromosome may also show symptoms (usually less severe than in males).

Neural tube defects

Increased intake of folic acid around the period of conception has been shown to significantly reduce the incidence of neural tube defects, including spina bifida; this is an example where the appropriate environment, namely adequate levels of folic acid, can influence the genetic appearance (see Figure 37-9). However, public education programs to encourage women of child-bearing age to voluntarily increase their folic acid intake have not had the desired outcomes.²⁰ Folic acid is particularly abundant in green leafy vegetables and our modern diets tend to have low quantities of these vegetables. Mandatory fortification of bread-making flour with folic acid commenced in Australia in September 2009 and will commence in New Zealand from 2012.

FIGURE 37-9 Risk of developing neural tube defects.

In this condition, the environmental factor of maternal folic acid intake can influence the genetic development of disease in the fetus.

Fetal alcohol syndrome

Alcohol is known to induce developmental abnormalities in the fetus; the outcomes vary according to the stage of pregnancy and the amount of alcohol consumed. Key features of fetal alcohol syndrome include mental retardation, microcephaly (reduced head size and poor brain development), characteristic facial features (see Figure 37-10) and behavioural problems. Babies of binge drinkers are most at risk of having this syndrome; alcohol consumption in the first 8 weeks of pregnancy has the most serious effect on brain and craniofacial development.²¹ Children who have been exposed to alcohol during pregnancy, but do not have diagnostic features of fetal alcohol syndrome, are more likely to display reduced IQ, learning difficulties and aggressive behaviour than children who were not exposed to alcohol during pregnancy.²² This disorder represents a powerful influence between the genetics of the fetus and the environment of intrauterine life, based on the mother’s lifestyle.

FIGURE 37-10 Characteristic facial features of a child affected by fetal alcohol syndrome.

Note the short, downslanting eye openings, sunken nasal bridge, short upturned nose, long smooth philtrum (midline groove from below the nose to the upper lip) and thin upper lip.

Source: Keane JF et al. Nadas’ pediatric cardiology. 2nd edn. Philadelphia: Saunders; 2006.

In addition, a fetus with a genetic variation on the ADH gene may be more susceptible to intrauterine exposure to alcohol. Therefore, both the fetal genes and the fetal environment within the uterus appear to be important in the potential development of fetal alcohol syndrome (see Figure 37-11). It also appears that there is an interaction between genes and the environment in this condition.²³

FIGURE 37-11 Risk of developing fetal alcohol syndrome.

A combination of both the genetic predisposition in the fetus and the maternal environment of exposure to alcohol can influence the development of fetal alcohol syndrome.

Fetal alcohol syndrome is often unrecognised or misdiagnosed; it is estimated that the prevalence in Australia is approximately 1 in 1000 live births.²⁴ Early diagnosis allows for appropriate intervention, which is essential to reduce the societal and economic impact of this disorder.

Phenylketonuria

In phenylketonuria (PKU), an accumulation of the amino acid phenylalanine within the brain can result in mental retardation. However, the extent of this retardation is determined by the amount of phenylalanine that is consumed and a diet low in this amino acid can minimise the effects of the disease.²³ Because of the importance of early diagnosis, this condition is assessed during the routine newborn screening program (discussed in Chapter 5). Therefore, even though this disease has a genetic basis, it is the environment that determines the severity.

Cardiovascular disease

Coronary heart disease

Coronary heart disease (blockage of the coronary arteries, causing angina and myocardial infarctions; see Chapter 23) is the leading individual cause of registered deaths in Australia and New Zealand — 16% of deaths in Australia in 2007;²⁷ 21% of deaths in New Zealand in 2006.²⁸ Approximately 1 in 20 New Zealand adults have been diagnosed with coronary heart disease: 4% experience angina and 3% have had a myocardial infarction requiring hospitalisation.

Coronary heart disease is a very complex condition. Whether disease develops, and the severity of the disease, is determined by the combined interaction of many genes and environmental factors. An individual’s genotype determines their general predisposition to coronary heart disease; and environmental factors such as activity levels, diet and smoking can determine whether disease develops. As seen in Figure 37-14, where an individual has more genetic risk factors and more environmental risk factors, they are most likely to develop coronary heart disease while young.²⁹ The interaction between these genes and environmental factors is being further investigated.

FIGURE 37-14 Model for gene–environment interaction.

This model proposes that each individual occupies a position on the genetic risk spectrum, depending upon how many risk-increasing gene variants have been inherited. Similarly, individuals are exposed to a range of environmental challenges depending on lifestyle choices. This theory proposes that risk of CHD occurs only when an individual at high genetic risk enters a high-risk environment, and that genetic risk factors and environmental risk factors alone will not trigger a CHD event. CHD = coronary heart disease.

Source: Based on Talmud PJ. Gene-environment interaction and its impact on coronary heart disease risk. Nutr Metab Cardiovasc Dis 2007; 17:148–152.

Studies of twins have clearly indicated that genes play a significant role in the development of coronary heart disease, but the number of genes potentially involved makes data interpretation difficult.³⁰ Interestingly, these studies suggest that the genetic component is stronger in females than in males (heritability = 0.6 and 0.26, respectively). Genes associated with increased risk of coronary heart disease include genes involved in the metabolism of lipids (especially cholesterol), the maintenance of veins and arteries, blood clotting and inflammation.

Obesity

Obesity has widespread impact in our community — in Australia and New Zealand, almost two-thirds of the population are above their ideal weight range and are defined as being either overweight or obese.^4,34 In Chapter 35 we discussed modifiable lifestyle factors for obesity. There is substantial evidence that indicates the importance of these risk factors in the development, treatment and prevention of obesity. The potential role of genetics in obesity is still being understood.

There are some rare monogenetic causes of obesity in humans, including abnormalities associated with leptin or the leptin receptor.³⁵ Such abnormalities are an example of genetic conditions that may alter energy balance through interactions between leptin and the hypothalamus or influence brain development relating to the hypothalamus.³⁶ Prader-Willis syndrome is another example of a monogenetic cause of obesity, with a chromosomal abnormality that relates to obesity, short stature and other effects including mental retardation.³⁷ However, these genetic abnormalities appear to be rare and are not related to obesity in most individuals.

There is evidence that genetic factors involved in obesity are polygenetic — that is, several genetic factors may be involved.^38,39 Genetic factors that appear to be important include the β₃-adrenergic receptor gene,³⁵ as this receptor is found on adipose cells. Overall, it is possible that there are some major obesity genes, with other minor obesity genes having a lesser contribution to individual obesity.

Interestingly, in a study of minority groups from a rural area in China (Xinjiang), mainly herdsmen and peasants, almost 50% of the population were above their ideal weight.⁴⁰ It may be said that these people have a strong genetic link to obesity, as their environmental influences would be substantially different from the urbanised experience in cities in developed countries. However, although these peasants are isolated from large cities, their diets are rich in alcohol, salty food and meat. Therefore, these data may contribute to our understanding of the role of these risk factors in obesity.

As with other chronic diseases, there is evidence that both genetics and environmental factors are important in obesity (see Box 37-1). Obesity genes may be involved in gene–gene interactions, such as the β₃-adrenergic receptor genes, which can disrupt mitochondrial energy usage. Furthermore, there are gene–environment interactions, such as the β₃-adrenergic receptor genes influencing physical activity.³⁵ Thus a genetic abnormality may lead to altered adipose cell physiology, thereby contributing to obesity. A gene–environment interaction has been suggested relating a genetic component (PPAR; peroxisome-proliferated activator receptor) to the proportion of polyunsaturated fat to saturated fat.³⁷ Gene–environment interactions in obesity are in the early stages of being understood and future research may clarify this relationship.

Metabolic syndrome

Metabolic syndrome is related to obesity, diabetes mellitus, cardiovascular disease and renal disorders. There is evidence that gene–environment interactions may be significant in its development. One factor that is important in the development of this syndrome is alcohol intake. It has been proposed that gene–environment interactions may underlie alcohol intake, alcohol metabolism and hence development of this syndrome.⁴¹ As shown in Figure 37-15, there may be an interaction between genetics and the environment through a number of avenues that lead to this disorder. This highlights the complexity of the relationships among genetic and environmental factors.

FIGURE 37-15 Complex levels of gene–alcohol–environment interactions in the metabolic syndrome.

Source: Based on Corella D. Gene-alcohol interactions in the metabolic syndrome. Nutr Metab Cardiovasc Dis 2007; 17:140–147.

Diabetes mellitus

Diabetes mellitus is characterised by hyperglycaemia and accompanying glycosuria (see Chapter 35 to review this disease). Type 1 diabetes is an autoimmune disease in which the insulin-producing beta cells of the pancreas are destroyed; it accounts for approximately 10% of diabetes cases in Australia.⁴² At least 7 different genetic locations, distributed across 6 chromosomes, have been found to have a role in determining an individual’s susceptibility to developing type 1 diabetes.⁴³ These loci include the insulin gene itself and genes that control its expression; the HLA genes (see Chapter 15), which have a well-defined role in the development of autoimmune disease; and other genes linked to autoimmune disease states. About half of the genetic susceptibility to type 1 diabetes is associated with the inheritance of particular HLA alleles. The remaining 6 genes determine the balance of an individual’s susceptibility to type 1 diabetes, but no single one of these 6 genes makes a significant contribution to disease risk.⁴⁴

While the genotype determines an individual’s predisposition to developing type 1 diabetes, disease onset is triggered by environmental factors, which are not yet clear. Viral infections, in particular congenital rubella infection, have been implicated in the development of type 1 diabetes. Exposure to protein allergens, such as cow’s milk proteins, may also trigger disease onset. It has been noted that disease is more common in cold climates. Overall, it appears that there is a genetic likelihood of developing type 1 diabetes, with an environmental influence (as yet poorly understood) that triggers the commencement of this disease.

Type 2 diabetes is much more common and is often associated with obesity. Approximately 4.5% of adults in Australia⁴² and New Zealand have been diagnosed with type 2 diabetes, rising to 14% of people aged over 65.⁴ These individuals produce insulin, but the amount is reduced and/or its activity is compromised, so removal of glucose from the bloodstream is inefficient. To date, 18 susceptibility genes scattered throughout the genome have been shown to be associated with type 2 diabetes.⁴⁵ One important gene is the PPAR-gamma gene (peroxisome-proliferated activator receptor gamma gene), which is involved in the processing of dietary fats. While the biological role of many of these genes is not yet clear, analysis indicates that most affect insulin secretion, rather than insulin action.

Environmental triggers include obesity, a sedentary lifestyle, high blood pressure and high blood cholesterol. The interaction between genes and lifestyle, although not fully understood, appears to be significant in development of type 2 diabetes.⁴⁶ For example, there is evidence that a genetic abnormality in the PPAR-gamma gene can interact with different dietary fats to influence insulin resistance, BMI and type 2 diabetes.^{47–49 4 6}

Unlike for type 1 diabetes, there is strong evidence indicating the significance of environmental or lifestyle factors in the development and progression of type 2 diabetes. On the other hand, the genetic influence on the development of type 1 diabetes appears to be clear, whereas the role of genetics is less certain in the development of type 2 diabetes.

It is difficult to determine the heritability of diabetes. Studies involving identical twins have shown that if one twin has diabetes, the likelihood that the second twin will develop diabetes is approximately 50% for type 1 diabetes and 60–80% for type 2.⁵⁰ This might suggest that type 2 diabetes has a stronger genetic component than type 1. However, it is difficult to separate the genetic effects from those of the environment, as identical twins usually have very similar lifestyles, and lifestyles that can increase the risk of type 2 diabetes are likely to be shared by twins.

Therefore, twin studies alone cannot distinguish between genetic and environmental causes, particularly if the twins adopt a similar lifestyle. So, although a disease may be seen among different family members, it does not necessarily mean that it is a genetic condition, as their lifestyle and environment may be similar as well as their genes.

Some patients with diabetes develop chronic kidney disease and end-stage kidney disease. In these patients, there appears to be an interaction between genetics and environmental factors.⁵¹ It has been suggested that the toxic internal environment of these patients with kidney disease (due to uraemia) may actually make them more susceptible to any genetic predisposition⁵² — this would demonstrate a strong interaction between genes and the environment.

Cancers

When all cancers from different organ systems are added together, cancer may be considered the leading cause of death in Australia and New Zealand, causing 18% of deaths in Australia in 2007²⁷ and 29% of deaths in New Zealand in 2006.⁴ (Note though that because the cancers in different organs are different, they are not usually summed in health statistics.) Cancers typically arise due to genetic changes that occur within specific cells and tissues during an individual’s lifetime. Both genetic and environmental factors contribute to the development of cancers.

For some cancers, environmental factors play a major role. For example, chemicals present in cigarette smoke alter DNA bases, altering the genes and leading to lung cancer. UV exposure causes genetic mutations, leading to melanoma (which is also why exposure to X-rays is carefully limited). Skin cancers are much more prevalent in people with fair skin,⁵³ and represent a type of condition in which the environmental risk (sunlight exposure) interacts differently depending on whether the person is genetically fair-skinned or darker-skinned. In this case, the gene–environment interaction is relatively simple to understand, even without having detailed knowledge of the genes involved.

However, twin and family studies indicate that a predisposition towards particular types of cancer is inherited,⁵⁴ although for most cancers the specific genes involved are not yet known.⁵⁵ There is evidence that environmental factors are responsible for at least 65% of cancer cases.⁵⁶

Breast cancer is the most common cancer among women in Australia and New Zealand (refer to Figure 36-29) and accounts for 10% of all new cancers diagnosed worldwide each year.⁵⁷ A range of environmental and behavioural factors are associated with the development of breast cancer, including diet, alcohol intake, use of oral contraceptives and short periods/absence of breastfeeding. Many of these contribute to the major risk factor for breast cancer: exposure to oestrogen. Consistent with the prevailing patterns of diet, childbearing and breastfeeding, breast cancer incidence rates in Australia and New Zealand are among the highest in the world.

Mutations in two genes, BRCA1 and BRCA2, have been shown to strongly increase an individual’s predisposition towards breast and ovarian cancers.⁵⁸ Compared with a woman without these mutations, a woman with the BRCA1 or BRCA2 mutation is 5 times more likely to develop breast cancer and 10 times more likely to develop ovarian cancer. Approximately 6% of males carrying the BRCA2 mutation also develop breast cancer. Individuals carrying the BRCA mutations are encouraged to undergo regular screening; some affected individuals elect to have breast tissue removed before breast cancer develops.

Both genetic and environmental influences also appear to be important in colorectal cancer. The most common genetic alteration in this disease is mutation of the p53 tumour-suppressor gene, which protects against cancers. In one study, patients with colorectal cancer who had this genetic abnormality also had a higher intake of red meat and alcohol.⁵⁹ However, the interaction between the abnormal gene and dietary intake remains unclear.

One theme that may be relevant in the progression of cancers involves disturbance to the regular circadian rhythm (the sleep–wake cycle; refer to Chapter 6). Clock genes, which are important in regulating this cycle, are actually tumour-suppressor genes and it may be that people whose circadian rhythm is disrupted are more prone to cancer development. In addition, some chemotherapy drugs used to treat colon cancer actually may be more effective at different times during the circadian rhythm,⁶⁰ which suggests a powerful environmental influence for this cancer. Studies are needed to determine whether regulating the circadian clocks of these patients can improve their quality of life⁶⁰ — this would be a promising example of an interaction between genes and the environment.

Although pancreatic cancer has a relatively low incidence rate in Australia and New Zealand, it has a high mortality rate (see Chapter 36). It has been estimated that genetic factors account for 5–10% of cases of pancreatic cancer.⁶¹ Several genes have been identified, including the familial pancreatic cancer gene PALB2, the cystic fibrosis CFTR gene, the hereditary pancreatitis genes PRSS1 and SPINK1 and the hereditary breast cancer gene BRCA2. Lifestyle and environmental contributing factors include tobacco smoking, obesity, diabetes mellitus and chronic pancreatitis.⁶¹ In order to assess the risk of an individual developing pancreatic cancer, it may be useful to consider a combination of DNA analysis, family pedigree and lifestyle factors.^61,62

Ultimately, there appears to be roles for both genetic and environmental factors in the development of cancers (see Figure 37-16).⁶³ The complex interaction between them can influence the progression of cells from being normal, to being susceptible to becoming cancerous, to finally becoming cancerous.

FIGURE 37-16 Both genetic and environmental factors can have a significant role in the development of cancer.

The interaction between genetics and the environment, as well as the variation or effects that may be unique to each individual, can influence the development of cancer.

Source: Based on Shields PG, Harris CC. Cancer risk and low-penetrance susceptibility genes in gene–environment interactions. J Clin Oncol 2000; 18:2309–2315.

Mental illness

Although some studies point to significant interactions between genes and the environment in mental illness, other studies have not shown an interaction.²³ This is one important field where additional research is necessary to provide further information on the development of these conditions.

There is evidence that major depression is heritable, and that the heritability of schizophrenia and bipolar disorder is actually higher (that is, they are both more likely to be passed through the family).⁶⁴ Interestingly, the relevant environmental factors — such as parenting style and socioeconomic factors — are not so important to the population, but are important to the individual’s risk of developing depression. It has been concluded that depression is a result of both genetic and environmental influences.⁶⁴ Similarly, while genetics seem to contribute to 30–40% of the likelihood of suicidal behaviour, there appear to be complex interactions between genes and environmental risk factors in these individuals.⁶⁵

There is even evidence that genetics may influence the ability to control cravings relating to addictive behaviours such as cigarette smoking and drinking alcohol, as those with a particular genotype (DRD4 long gene for the dopamine receptor) exhibit stronger cravings.⁶⁶ This type of research may be useful in the future in determining the interaction between genes and the environment. Ultimately, it is the interaction between genes and the environment that will lead to improved knowledge about diseases.

Interestingly, genes can actually influence an individual’s behaviour or lifestyle. One example is the gene involved in the metabolism of alcohol, ALDH2 (alcohol dehydrogenase).²³ This gene may be involved in addictive behaviour. Individuals with abnormalities associated with the ALDH2 gene cannot metabolise alcohol efficiently and hence they experience an unpleasant facial flushing, nausea and headache associated with alcohol consumption. Individuals who are homozygous for abnormalities in this gene (and hence have low levels of alcohol dehydrogenase to metabolise alcohol) usually have a relatively low intake of alcohol. In turn, their lower consumption of alcohol can actually lower the development of other alcohol-related disorders, particularly cancers.^23,67 Hence, the genes influence the environment, which in turn influence the development of other diseases.

Some mental health conditions, such as posttraumatic stress disorder, mood disorders and anxiety disorders, are strongly linked to the stress response. There is evidence that the individual variability in the stress response, mediated through the hypothalamic-pituitary-adrenal axis (see Chapter 34), may actually be influenced by both genes and the environment. For example, two genes that are involved are CRHR1 and FKBP5, while environmental factors may include both positive and negative life experiences.⁶⁸ Socioeconomic status can also contribute to the developing stress response, due to experiences with nutrition, poverty, housing and healthcare factors.⁶⁹ Furthermore, the interactions between these genes and the environment early in life may influence the stress response in later life.^68,69

The future of disease prevention and treatment

If genes associated with multifactorial disorders can be clearly identified, population screening could be used to identify individuals with ‘high-risk’ genotypes. Those who are predisposed to develop a particular disease could then be advised to take appropriate action to control relevant environmental factors or to take other preventive measures.

The Human Genome Project has identified the human genome sequence, the complete genetic information on humans. The project was a collaborative effort involving scientific teams from every continent and was completed in April 2003. Mapping the human genome has provided detailed chromosome maps that are assisting researchers in their quest to identify disease genes. (Remember that a gene is a sequence of DNA, so mapping even one gene involves determining substantial amounts of DNA; see Chapter 5.) The sequence of the human genome shows that 99% of the DNA base sequence is identical for all individuals; it is the remaining 1% that makes us interesting! Clearly, these components of DNA cannot easily be mapped for every individual.

Although the human genome sequence is known, the position of many genes is still uncertain. Present estimates are that the human genome contains about 30,000 genes, but the function of half of these genes remains unknown. The average gene size is 3000 bases, but some genes are much larger. For example, the dystrophin gene, associated with Duchenne’s and other muscular dystrophies, covers approximately 2.4 million bases on the X chromosome. The enormous size of this gene means that it is highly prone to mutations, many of which involve deletions of gene segments.

Considerable research effort has been focused on determining the position of genes on chromosomes and identifying disease markers. At present, more than a million single nucleotide polymorphisms (sites where single base variations are observed) have been identified. These sites are associated with variability between individuals and with genetic diseases. Family studies may identify single nucleotide polymorphisms linked to particular diseases and hence help to pinpoint relevant genes. Once disease genes are located and their sequence is known, targeted therapies may be developed:

The potential benefits of mapping the full human genome include the improved ability to diagnose, treat and even prevent diseases in the future. Treatment of chronic disease that may be modified according to genes would allow treatment to be individualised — targeted to the patient, depending on their genes. As an example, someone with the slow variant of the gene UGT1A6 metabolises aspirin more slowly and so this drug appears to have a greater benefit in the prevention of colorectal polyps.⁵³ Aspirin use and dosage could be modified depending on the individual’s variant of the UGT1A6 gene, thereby targeting treatment to match genetics. Population-level screening programs could be introduced to allow early identification and management of genetic conditions.

To conclude, by understanding the function of genes and how genetics are inherited using methods such as family studies and population studies we can define the importance of genetics in disease (see Figure 37-19). In addition, environmental factors are increasingly becoming better understood in their role in disease development. Overall, there is a role for both genetic and environmental factors in the development of disease, although the interaction between them is complex and not completely understood for many conditions. Even if all genes for a particular disease were defined, the ability to use genetic treatments as suggested by the Human Genome Project is still some distance away in the future.

FIGURE 37-19 The relationship between studying families and populations, genetics and environmental factors in the development of disease.

For now, individuals who wish to reduce their likelihood of succumbing to disease may wish to construct a pedigree showing the diseases of family members, which may indicate genetic susceptibilities, as well as known genetic factors such as the skin colour of parents and grandparents. Environmental factors could also be added, such as those who smoke, have high lipid diets, whose lifestyle is relatively sedentary or spend time in the sun. Most chronic diseases are preventable, in that appropriate lifestyle choices can substantially decrease the risk of disease development (see Box 37-2). Individuals may modify the known (and possible) lifestyle or environmental risk factors, as well as considering preventive medications (such as aspirin) to lower the risks and thereby maintain homeostasis for a longer period of time and potentially delay the onset of disease.

CHAPTER SUMMARY

Studying health and disease

Diseases result from complex interactions between an individual’s genotype and the environment.

Population studies can identify risk factors for disease.

Pedigrees are used to investigate patterns of inheritance of disease within families.

Genetic conditions

Abnormalities during meiosis lead to gametes with altered numbers of chromosomes.

Non-disjunction produces gametes (or cells) with extra or missing chromosomes.

Non-disjunction of autosomes has severe consequences; the presence of an extra copy of the smallest autosome (chromosome 21) is the only non-disjunction event compatible with long-term survival.

Non-disjunction of the sex chromosomes produces variable outcomes; fertility and development of secondary sexual characteristics are most likely to be affected.

Inherited diseases

Many single gene disorders follow dominant/recessive patterns of inheritance.

In dominant disorders, a single copy of the disease allele is sufficient to cause disease. In family pedigrees, the disorder appears in every generation; affected individuals have an affected parent.

For recessive disorders, 2 copies of the disease allele are required to cause disease; individuals carrying 1 copy of the disease allele often display no symptoms. In family pedigrees, the disorder ‘skips’ generations; affected individuals often have unaffected parents.

The X chromosome carries several recessive disease alleles. Females, with two X chromosomes, may carry X-linked recessive traits; males, with a single X chromosome, display X-linked recessive traits. In family pedigrees, the disorder ‘skips’ generations and appears almost exclusively in males; affected females are very rare.

Genetic screening

Genetic screening can be used to detect disease alleles, therefore identifying carriers of disease alleles and/or potentially affected embryos.

To ensure that genetic disease markers provide useful information within a particular family, both affected and unaffected family members must be tested.

Congenital abnormalities

Congenital diseases are present from birth; they may be caused by genetic and/or environmental factors.

Exposure to teratogens increases the risk of congenital abnormalities.

Neural tube defects arise from insufficient levels of folic acid during embryonic and fetal life.

Fetal alcohol syndrome occurs in individuals who have a genetic susceptibility, plus exposure to alcohol during fetal life.

Multifactorial inheritance

Polygenic traits are controlled by several genes, so do not follow simple dominant/recessive patterns of inheritance.

Multifactorial traits are influenced by several genes and by environmental factors; twin studies are useful in determining the relative contributions of genes and environment.

Genotype determines an individual’s predisposition to disease; environmental factors may trigger the onset of disease.

Research aimed at identifying genes associated with multifactorial disease can help to identify individuals at risk of disease, to target implementation of preventive strategies and to develop new therapies.

Conditions arising from genetic and environmental factors

The development of most chronic diseases may be influenced by both genetic factors and environmental factors. Determining which genes are involved and which environmental factors are relevant are topics of ongoing research. The interactions between genetics and environmental factors may also be revealed with future research.

There is strong evidence for the role of both genetics and environmental factors in coronary heart disease; genetic influences may be more important in females than in males.

Familial hypercholesterolaemia may arise from a dominant genetic abnormality; considerable modification of the environment, including pharmacological treatment, is necessary.

Only 30% of hypertension may be hereditary; the remaining 70% is likely to be caused by the environment.

Approximately 40–70% of cases of obesity may result from heredity, with the rest the result of environmental factors. Rare genetic causes of obesity include those associated with leptin.

Several genetic causes have been determined for type 1 diabetes. Environmental factors, currently poorly understood, may trigger these genetic abnormalities and lead to the development of type 1 diabetes.

Genetic factors may be important in the development of type 2 diabetes; however, it is well known that environmental factors are implicated in its development.

Cancers occur due to abnormalities in the genes, but these abnormalities may arise due to a combination of genetic and environmental factors. Some cancers (such as some types of breast cancer and colorectal cancer) are related to well-defined genes. For most people, environmental factors are critical in the development of cancer.

Mental illness is linked to genetic and environmental factors. Some genes may influence the environment (such as intake of alcohol) important in the development of mental illness.

The relative importance of genetic and environmental contributions to disease

An individual with a genetic susceptibility and who experiences unfavourable environmental factors is likely to develop a disease early in life; however, if the same individual experiences mainly protective environmental factors, the disease may not develop until later in life.

An individual without a genetic susceptibility but who experiences unfavourable environmental factors may develop a disease earlier in life; however, if the same individual experiences mostly protective environmental factors, the disease is less likely to occur until much later in life.

The interaction between genes and the environment is yet to be determined in relation to the development of disease.

The prevention of disease

Complex relationships appear to be involved in not only the development of disease, but also protection from disease.

Identification of individuals with genetic susceptibility may lead to personalised prevention and treatment options.

The Human Genome Project is an important step in understanding the human genome and may assist in targeting future prevention and treatment strategies.

Additional research into the genetic and environmental factors involved in disease progression is ongoing. Understanding the complex interrelationships between these factors also forms the basis of continuing research.

Information about an individual’s susceptibility to particular diseases may be learned from a detailed family pedigree. Currently, the most appropriate manner for lowering the individual’s risk of disease is to address the modifiable lifestyle factors.