What causes disease? - Clinical Tree

Causes of Disease

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Diseases are due to genetic, environmental or multifactorial causes
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Role of genetic and environmental factors can be distinguished by epidemiological observations, family studies or laboratory investigations
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Some diseases with a genetic basis may not appear until adult life
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Some diseases with environmental causes may have their effects during embryogenesis

Diseases may be:

entirely genetic — either inherited or prenatally acquired defects of genes
multifactorial — interaction of genetic and environmental factors
entirely environmental — no genetic component to risk of disease.

Features pointing to a significant genetic contribution to the cause of a disease include a high incidence in particular families or races, or an association with a known inherited feature (e.g. gender, blood groups, histocompatibility haplotypes). Environmental factors are suggested by disease associations with occupations or geography. Ultimately, however, only laboratory investigation can provide irrefutable identification of the cause of a disease. The extent to which a disease is due to genetic or environmental causes can often be deduced from some of its main features ( Table 3.1 ).

Table 3.1

Clues to a disease being caused by either genetic or environmental factors

Disease characteristic	Genetic cause	Environmental cause
Age of onset	Usually early (often in childhood)	Any age
Familial incidence	Common	Unusual (unless family exposed to same environmental agent)
Remission	No (except by gene therapy)	Often (when environmental cause can be eliminated)
Incidence	Relatively uncommon	Common
Clustering	In families	Temporal or spatial or both
Linkage to inherited factors	Common	Relatively rare

Predisposing factors and precursors of disease

Many diseases are the predictable consequence of exposure to the initiating cause; host (i.e. genetic) factors make relatively little contribution to the outcome. This is particularly true of physical injury: the results of mechanical trauma and radiation injury are largely dose related; the effect is directly proportional to the physical force.

Other diseases are the probable consequence of exposure to causative factors, but they are not absolutely inevitable. For example, infectious diseases result from exposure to potentially harmful environmental agents (e.g. bacteria, viruses), but the outcome is often influenced by various host factors such as age, nutritional status and genetic variables.

Some diseases predispose to others; for example, ulcerative colitis predisposes to carcinoma of the colon, and hepatic cirrhosis predisposes to hepatocellular carcinoma. Diseases predisposing to tumours are called preneoplastic conditions ; lesions from which tumours can develop are called preneoplastic lesions . Some diseases occur most commonly in those individuals with a congenital predisposition. For example, ankylosing spondylitis, a disabling inflammatory disease of the spinal joints of unknown aetiology, is much more common in people with the human leukocyte antigen (HLA)-B27 haplotype ( Ch. 25 ).

Some diseases predispose to others because they have a permissive effect , allowing environmental agents that are not normally pathogenic to cause disease. For example, opportunistic infections occur in those patients with impaired defence mechanisms, allowing infection by normally nonpathogenic organisms ( Ch. 8 ).

Prenatal factors

Prenatal factors, other than genetic abnormalities, contributing to disease risk are:

transplacental transmission of environmental agents
nutritional deprivation.

Diseases due to transplacental transfer of environmental agents from the mother to the fetus include fetal alcohol syndrome and congenital malformations due to maternal rubella infection (now much less common where rubella immunisation is routine).

The notion that disease risk in adult life could be due to fetal nutritional deprivation gained support from the work of David Barker (1938–2013). The Barker hypothesis is that an adult's risk of, for example, ischaemic heart disease and hypertension is programmed partly by nutritional deprivation in utero. Nutritional deprivation can have profound effects during critical periods of fetal morphogenesis.

Aetiology and age of disease onset

Do not assume that all diseases that manifest at birth have an inherited or genetic basis; as noted previously ( Ch. 2 ), diseases present at birth are classified into those with a genetic basis and those without a genetic basis. Conversely, although most adult diseases have an entirely environmental cause, genetic influences to disease susceptibility and vulnerability to environmental agents are being increasingly discovered.

The incidence of many diseases rises with age because of the following.

Probability of contact with an environmental cause increases with duration of exposure risk.
The disease may depend on the cumulative effects of one or more environmental agents.
Impaired immunity with ageing increases susceptibility to some infections.
The latent interval between the exposure to cause and the appearance of symptoms may be decades long.

Multifactorial aetiology of disease

Many diseases with no previously known cause are being shown to be due to interacting environmental factors and genetic susceptibility ( Fig. 3.1 ). These discoveries are the rewards of detailed family studies and, in particular, application of the new techniques of molecular genetics. Diseases of adults in which there appears to be a significant genetic component include:

breast cancer
Alzheimer disease
diabetes mellitus
osteoporosis
coronary atherosclerosis.

One of the reasons why there may be only slow progress in characterising the genetic component of the diseases listed above and others is that two or more genes, as well as environmental factors, may be involved. Pursuing the genetic basis of these polygenic disorders requires complex analyses.

Fig. 3.1, Proportionate risk of disease due to genetic or environmental factors.

Evidence for genetic and environmental factors

Genetic contributions to disease incidence are exposed when any putative environmental factors are either widely prevalent (most individuals are exposed) or nonexistent (no known environmental agents). The epidemiologist Geoffrey Rose (1926–1993) exemplified this by suggesting that, if every individual smoked 40 cigarettes a day, we would never discover that smoking was responsible for the high incidence of lung cancer; however, any individual (especially familial) variation in susceptibility to lung cancer would have to be attributed to genetic differences. An environmental cause, such as smoking, is easier to identify when there are significant individual variations in exposure which can be correlated with disease incidence; indeed, this enabled Doll and Hill in the 1950s to demonstrate a strong aetiological link to lung cancer.

Family studies

Strong evidence for the genetic cause of a disease, with little or no environmental contribution, comes from observations of its higher than expected incidence in families, particularly if they are affected by a disease that is otherwise very rare in the general population. Such diseases are said to ‘run in families’.

Having identified the abnormality in a family, it is then important to provide genetic counselling so that parents can make informed decisions about future pregnancies. The precise mode of inheritance will determine the proportion of family members (i.e. children) likely to be affected. Because inherited genetic disorders are either sex-linked, or autosomally dominant or autosomally recessive, not all individuals in one family may be affected even if the disease has no environmental component.

Studies on twins

Observations on the incidence of disease in monozygotic (identical) twins are particularly useful in disentangling the relative influences of ‘nature and nurture’. Uncommon diseases occurring in both twins are more likely to have a genetic component to their aetiology, especially if the twins have been brought up and lived in different environments.

Studies on migrants

The unusually high incidence of a particular disease in a country or region could be due either to the higher prevalence of a genetic predisposition in the racial or ethnic group(s) in that country or to some environmental factor such as diet or climatic conditions. Compelling evidence of the relative contributions of genetic and environmental factors in the aetiology and pathogenesis of a disease can be obtained by observations on disease incidence in migrant populations ( Fig. 3.2 ). For example, if a racial group with a low incidence of a particular disease migrates to another country in which the disease is significantly more common, there are two possible outcomes leading to different conclusions.

If the incidence of the disease in the migrant racial group eventually rises, environmental factors (e.g. diet) are probably responsible for the high incidence in the indigenous population.
If the incidence of the disease in the migrant racial group remains low, the higher incidence in the indigenous population is probably due to genetic factors.

Most observations on disease incidence in migrant populations have been made on neoplastic disorders (cancer). This is because cancer is a major illness, likely to be reliably diagnosed by biopsy, and, in many countries, documented in cancer registries.

Fig. 3.2, Clues to genetic and environmental causes from disease incidence in migrants.

Association with gene polymorphisms

There are many normal genetic variations or polymorphisms. The effect of some of these polymorphisms is obvious: examples are skin, hair and eye colour, body habitus, etc. When possessed by large groups of people of common ancestry, a cluster of polymorphic variants constitutes racial characteristics. In other instances, the polymorphism has no visible effects: examples are blood groups and HLA types (see below).

Polymorphisms of greatest relevance to disease susceptibility are:

HLA types
blood groups
cytokine genes.

Human leukocyte antigen types

Clinical and experimental observations on the fate of organ transplants led to the discovery of genes known as the major histocompatibility complex (MHC). In humans, the MHC genes reside on chromosome 6 and are designated HLA genes . HLA genes are expressed on cell surfaces as substances referred to as ‘antigens’, not because they normally behave as antigens in the individual who bears them, but because of their involvement in graft rejection ( Ch. 8 ). The body does not normally react to these substances: it is immunologically tolerant of them — they are recognised as ‘self’ antigens.

HLA types are grouped into MHC classes.

MHC class I are on the surface of all nucleated cells. In all diploid cells, there are pairs of allelic genes at each of three loci: these genes are known as HLA-A , HLA-B and HLA-C . MHC class I enables cytotoxic T lymphocytes to recognise and eliminate virus-infected cells.
MHC class II are expressed on the surface of cells that interact with T lymphocytes by physical contact, such as antigen-presenting cells (e.g. Langerhans cells). The six main MHC class genes are HLA-DPA1 , -DPB1 , -DQA1 , -DQB1 , -DRA and -DRB1 . The normal role of MHC class II is initiation of immune responses.

Diseases may be associated with HLA types because:

some infective microorganisms bear antigens similar to those of the patient's HLA substances and thereby escape immune recognition and elimination
the immune response to an antigen on an infective microorganism cross-reacts with one of the patient's HLA substances, thus causing tissue damage
the gene predisposing to a disease is closely linked (genetic linkage; p. 33 ) to a particular HLA gene.

Diseases associated with HLA types are listed in Table 3.2 . They are all chronic inflammatory or immunological disorders. In some instances, the association is so strong that HLA testing is important diagnostically, for example the association of HLA-B27 with ankylosing spondylitis ( Ch. 25 ).

Table 3.2

Examples of disease associated with HLA types

Disease	HLA type(s)	Comments
Allergic disorders (e.g. eczema, asthma)	A23	Requires environmental allergen
Ankylosing spondylitis	B27	Associated in c. 90% of cases
Coeliac disease	DR3, B8	Gluten sensitivity
Graves disease (primary thyrotoxicosis)	DR3, B8	Due to thyroid-stimulating immunoglobulin
Hashimoto thyroiditis	DR5	Aberrant HLA class II expression on thyroid epithelium
Insulin-dependent (juvenile onset) diabetes mellitus	DR3, DR4, B8	Immune injury to beta-cells in pancreatic islets
Rheumatoid disease	DR4	Autoimmune disease

HLA , Human leukocyte antigen.

Autoimmune diseases (diseases in which the body's immunity destroys its own cells) are most frequently associated with specific HLA types. The combination of HLA-DR3 and HLA-B8 is particularly strong in this regard, but it must be emphasised that it is present in only a minority of patients with autoimmune disease. Autoimmune diseases also illustrate a separate feature of the association between HLA types and disease. Normally, MHC class II types are not expressed on epithelial cells. However, in organs affected by autoimmune disease, the target cells for immune destruction are often found to express MHC class II types. This expression enables their immune recognition and facilitates their destruction.

Blood groups

Blood group expression is directly involved in the pathogenesis of a disease only rarely; the best example is haemolytic disease of the newborn due to rhesus antibodies ( Ch. 23 ). A few diseases show a weaker and indirect association with blood groups. This association may be due to genetic linkage; the blood group determinant gene may lie close to the gene directly involved in the pathogenesis of the disease.

Examples of blood group-associated diseases include:

duodenal ulceration and group O
gastric carcinoma and group A.

Cytokine genes

The incidence or severity of chronic inflammatory diseases may be linked to polymorphisms within or adjacent to cytokine genes. Cytokines are important mediators and regulators of inflammatory and immunological reactions. Logically, therefore enhanced or abnormal expression of cytokine genes may influence disease risk and severity.

Tumour necrosis factor ( TNF ) gene polymorphism is associated with Graves disease of the thyroid ( Ch. 17 ) and systemic lupus erythematosus ( Ch. 25 ). The TNF gene resides on chromosome 6 between the HLA classes I and II loci; this genetic proximity may explain an indirect association between TNF gene polymorphism and disease. There are also associations between interleukin-1 (IL-1) gene cluster (chromosome 2) polymorphisms and chronic inflammatory diseases. The associations seem to be stronger with disease severity than with susceptibility.

Gender and disease

Gender, like any other genetic feature of an individual, may be directly or indirectly associated with disease. An example of a direct association is haemophilia. Haemophilia is an X-linked recessive disorder of blood coagulation inherited by male children from their mother. Haemophilia is rare in females because they have two X chromosomes, only one of which is likely to bear the defective gene. Males inherit their single X chromosome from their mother; if the mother is a haemophilia carrier, half of her male children are likely to inherit the disease.

Some diseases show a predilection for one of the sexes. For example, autoimmune diseases (e.g. rheumatoid disease, systemic lupus erythematosus) are more common in females than in males. Atheroma and its consequences (e.g. ischaemic heart disease) tend to affect males earlier than females, but after the menopause the female incidence approaches that in males. Females are more prone to osteoporosis, a common cause of bone weakening, particularly after the menopause.

In some instances, the sex differences in disease incidence are due to social or behavioural factors. The higher incidence of carcinoma of the lung in males is due to the fact that they smoke more cigarettes than do women.

Racial differences

Racial differences in disease incidence may be genetically determined or attributable to behavioural or environmental factors. Racial differences may also reflect adaptational responses to the environmental factors. A good example is provided by malignant melanoma ( Ch. 24 ). Ultraviolet light causes malignant melanoma of the skin; the highest incidence is in Caucasians living in parts of the world with high ambient levels of sunlight, such as Australia. The tumour is, however, less common in Africa, despite its high sunlight levels, because the indigenous population has abundant protective melanin in the skin.

Some abnormal genes are more prevalent in certain races. For example, the cystic fibrosis gene is carried by 1 in 20 Caucasians, whereas this gene is rare in Africans and Asians. Conversely, the gene causing sickle cell anaemia is more common in those of Sub-Saharan African descent than in any other race. These associations may be explained by a heterozygote advantage conferring protection against an environmental pathogen ( Table 3.3 ).

Table 3.3

Associations between disease and race

Disease	Racial association	Explanation
Cystic fibrosis	Caucasians	Hypothesised that defective gene increases resistance to intestinal infection by Salmonella bacteria
Sickle cell anaemia *( HbS* gene)**	Sub-Saharan African descent	Sickle cells resist malarial parasitisation HbS gene more common in those of Sub-Saharan African descent in areas of endemic malaria
Haemochromatosis	Caucasians	Mutant HFE protein may have conferred protection against European plagues caused by Yersinia bacteria

Other diseases in different races may be due to socioeconomic factors. Perinatal mortality rates are often used as an indicator of the socioeconomic welfare of a population. Perinatal mortality rate is much higher in some racial groups, but this is due almost entirely to their social circumstances and is, therefore capable of improvement.

Parasitic infestations are more common in tropical climates, not because the races predominantly dwelling there are more susceptible, but often because the parasites cannot complete their life cycles without other hosts that live only in the prevailing environmental conditions.

Genetic Abnormalities in Disease

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Genetic abnormalities may be inherited, acquired during conception or embryogenesis, or acquired during postnatal life
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Genetic abnormalities inherited or prenatally acquired are often associated with congenital metabolic abnormalities or structural defects
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Polygenic disorders result from interaction of two or more abnormal genes
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Neoplasms (tumours) are the most important consequences of postnatally acquired genetic abnormalities

Advances in genetics and molecular biology have revolutionised our understanding of the aetiology and pathogenesis of many diseases and, with the advent of gene therapy, may lead to their amelioration in affected individuals ( Table 3.4 ).

Table 3.4

Landmarks in genetics and molecular biology

Date	Discovery
1940s	Genes encoded by combinations of only four nucleotides in nuclear DNA
1950s	Complementary double-stranded helical structure of DNA 46 chromosomes in humans DNA polymerase enzyme
1960s	Plasmids — providing a mechanism for transfer of genes to bacteria Lyon hypothesis Restriction endonucleases
1970s	Recombinant DNA technology Chromosome banding Hybridisation techniques Southern blotting
1980s	Gene polymorphisms Polymerase chain reaction Transgenic mice
1990s	Gene therapy
Early 21st century	Human genome project completed RNA-mediated interference (RNAi)

Defective genes in the germline (affecting all cells) and present at birth, because of either inherited or acquired abnormalities, cause a wide variety of conditions, such as:

metabolic defects (e.g. cystic fibrosis, phenylketonuria)
structural abnormalities (e.g. Down syndrome)
predisposition to tumours (e.g. familial adenomatous polyposis, retinoblastoma, multiple endocrine neoplasia syndromes).

Most well-characterised inherited abnormalities are attributable to a single defective gene (i.e. they are monogenic ). However, some inherited abnormalities or disease predispositions are determined by multiple genes at different loci; such conditions are said to be polygenic .

Genetic damage after birth, for example, due to ionising radiation, is not present in the germline so will initially only be present in one cell. This genetic damage will only have an effect if that cell divides and grows to form a sizeable population within the body. It will not cause obvious metabolic defects affecting the entire individual, because the defect is concealed by the invariably larger number of cells with normal metabolism, nor structural abnormalities, because morphogenesis and development of organs has been completed. The main consequence of genetic damage after birth is, therefore tumour formation ( Ch. 10 ). There is, however, increasing evidence to suggest that cumulative damage to mitochondrial genes contributes to ageing ( Ch. 11 ).

Gene structure and function

Nuclear DNA

Each of the 23 paired human chromosomes contains, on average, approximately 10 ⁷ base (nucleotide) pairs arranged on the double helix of DNA; genes are encoded in a relatively small proportion of this DNA. To accommodate this length of DNA within the relatively small nucleus, the DNA is tightly folded. The first level of compaction involves wrapping the double helix around a series of histone proteins; the bead-like structures thus formed are nucleosomes . At the second level of compaction, the DNA strands are coiled to form a chromatin fibre and then tightly looped. During metaphase, when the duplicated chromosomes separate before forming the nuclei of two daughter cells, the DNA is even more tightly compacted.

During DNA synthesis (S phase) the bases are copied by complementary nucleotide pairing. Any copying errors are at risk of being inherited by the daughter cells and may result in disease. Copying during DNA synthesis starts in a coordinated way at approximately 1000 places along an average chromosome.

Nuclear genes

Genes are encoded by combinations of four nucleotides (adenine, cytosine, guanine, thymine) within DNA. Nuclear DNA is double stranded with complementary specific bonding between nucleotides on the sense and antisense strands — adenine to thymine, guanine to cytosine — the antisense strand thereby serving as a template for synthesis of the sense strand. Most of the DNA in eukaryotic (nucleated, e.g. mammalian) cells is within nuclei; a relatively smaller amount resides in mitochondria.

The nuclear DNA in human cells is distributed between 23 pairs of chromosomes: 22 are called autosomes; 1 pair is sex chromosomes (XX in females, XY in males). Only approximately 10% of nuclear DNA encodes functional genes; the remainder comprises a large quantity of anonymous variable and repetitive sequences distributed between genes and between segments of genes. These noncoding sequences include satellite DNA which is highly repetitive, located at specific sites along the chromosomes and probably important for maintaining chromosome structure. A crucial site of repetitive noncoding DNA is the telomere at the ends of each chromosome. Its integrity is essential for chromosomal replication. In cells lacking telomerase (i.e. most somatic cells) the telomeres shorten with each mitotic division, until eventually the cells are incapable of further replication.

The segments of genes encoding for the final product are known as exons ; the segments of anonymous DNA between exons are called introns ( Fig. 3.3 ). The exons comprise sequences of codons, triplets of nucleotides each encoding for an amino acid via messenger RNA (mRNA). In addition, there are start and stop codons defining the limits of each gene. Some genes are regulated by upstream promoters. During mRNA synthesis from the DNA template, the introns are spliced out and the exons may be rearranged.

Fig. 3.3, Simplified structure of a gene and its messenger RNA product.

Gene linkage and recombination

Linkage and recombination are important processes enabling tracing of genes associated with disease. During meiosis, there is exchange of chromosomal material between maternally and paternally derived chromosomes. Adjacent genes on the same chromosome are unlikely to be separated by this process and are said to show a high degree of linkage . When exchange of chromosomal material does occur, the result is called recombination . The distance between genes can be expressed in centimorgans (after a geneticist called T H Morgan); one centimorgan is the distance between two gene loci showing recombination in 1 in 100 gametes.

These processes of linkage and recombination are not only responsible for the balance between familial characteristics and individual diversity but are also important phenomena enabling defective genes to be identified, even when their precise function or sequence is unknown, by tracking the inheritance of neighbouring DNA in affected individuals and families.

Gene transcription and translation

The normal flow of biochemically encoded information is that a mRNA transcript is made corresponding to the nucleotide sequence of the gene encoded in the DNA. The RNA transcript comprises nucleotide sequences encoding only the exons of the gene. The RNA is then translated into a sequence of amino acids specified by the code and the protein is assembled.

Under some circumstances, however, the flow of genetic information is reversed. In the presence of reverse transcriptase , an enzyme present in some RNA viruses, a DNA copy can be made from the RNA ( Fig. 3.4 ).

Fig. 3.4, Reverse transcription of DNA from RNA.

Recently, RNA-mediated interference (RNAi) has been discovered as a potentially important mechanism of inhibiting the expression of specific genes. The small inhibiting fragments of RNA (microRNA, or small interfering RNA) are the direct product of genes, so part of the normal regulatory processes of gene expression. However, they are also very useful for silencing specific gene expression in cell experiments and may eventually have novel therapeutic uses.

Homeobox genes

Homeobox ( HOX ) genes regulate patterns of anatomic development. They contain a highly conserved 183 base-pair sequence and are clustered on chromosomes as a homeotic sequence. These genes encode homeodomain protein products that are transcription factors sharing a characteristic protein fold structure that binds DNA. Their expression during embryogenesis follows the order in which they are arranged, thereby sequentially directing body axis formation.

HOX genes can be subject to endocrine regulation, for example, in the endometrium through the menstrual cycle and pregnancy. They can also be modulated by vitamin A, thus accounting for the malformations induced by excess or deficiency.

Mitochondrial genes

Most inherited disorders are carried on abnormal genes within nuclear DNA. There are, however, a small but significant number of genetic abnormalities inherited through mitochondrial DNA. Mitochondrial DNA differs from nuclear DNA in several important respects; it is characterised by:

circular double-stranded conformation
high rate of spontaneous mutation
few introns
maternal inheritance.

The structure of mitochondrial DNA resembles that of bacterial DNA. Consequently, it is postulated that eukaryotic cells acquired mitochondria as a result of an evolutionary advantageous symbiotic relationship with bacteria.

Because the head of the fertilising spermatozoon consists almost entirely of its nucleus, the mitochondria of an individual are derived from the cytoplasm of the mother's ovum. Thus mitochondrial disorders are transmitted by females, but may be expressed in males and females.

The genes in mitochondrial DNA encode mainly for enzymes involved in oxidative phosphorylation. Therefore defects of these enzymes resulting from abnormal mitochondrial genes tend to be associated with clinicopathological effects in tissues with high energy requirements, notably neurones and muscle cells. Examples of disorders due to inheritance of defective mitochondrial genes include familial mitochondrial encephalopathy and Kearns–Sayre syndrome .

Mitochondria and ageing

Because mitochondria play a key role in intracellular oxygen metabolism, it is hypothesised that defects of mitochondrial genes and the enzymes encoded by them could lead to the accumulation of free oxygen radical-mediated injury. Such injury could include damage to nuclear DNA, thus explaining not only the phenomenon of ageing ( Ch. 11 ) but also the higher incidence of neoplasia in the elderly ( Ch. 10 ).

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