CHAPTER 15 Genetic Factors in Common Diseases
Medical genetics usually concentrates on the study of rare unifactorial chromosomal and single-gene disorders. Diseases such as diabetes, cancer, cardiovascular and coronary artery disease, mental health, and neurodegenerative disorders are responsible, however, for the majority of the morbidity and mortality in developed countries. These so-called common diseases are likely to be of even greater importance in the future, with the elderly accounting for an increasing proportion of the population.
The common diseases do not usually show a simple pattern of inheritance. Instead, the contributing genetic factors are often multiple, interacting with each other and environmental factors in a complex manner. In fact, it is uncommon for either genetic or environmental factors to be entirely responsible for a particular common disorder or disease in a single individual. In most instances, both genetic and environmental factors are contributory, although sometimes one can appear more important than the other (Figure 15.1).
Genetic Susceptibility to Common Disease
For many of the common diseases, a small but significant proportion of cases have single-gene causes, but the major proportion of the genetic basis of common diseases can be considered to be the result of an inherited predisposition or genetic susceptibility. Common diseases result from a complex interaction of the effects of multiple different genes, or what is known as polygenic inheritance, with environmental factors and influences due to what is known as multifactorial inheritance (see Chapter 9).
Types and Mechanisms of Genetic Susceptibility
Genetic susceptibility for a particular disease can occur through single-gene inheritance of an abnormal gene product involved in a particular metabolic pathway, such as occurs in early coronary artery disease arising from familial hypercholesterolemia (FH) (p. 175). In an individual with a mutation in the FH gene, the genetic susceptibility is the main determinant of the development of coronary artery disease, but this can be modified by environmental alteration like reduction in dietary cholesterol and avoidance of other risk factors such as obesity, lack of exercise, and smoking.
Inheritance of single-gene susceptibility does not, however, necessarily lead to development of a disease. For some diseases, exposure to specific environmental factors will be the main determinant in the development of the disease (e.g., smoking or occupational dust exposure in the development of pulmonary emphysema in persons with α1-antitrypsin deficiency [p. 320, Table 23.1]).
In other instances, the mechanism of the genetic susceptibility is less clear-cut. This can involve inheritance of a single gene polymorphism (p. 67) that leads to differences in susceptibility to a disease (e.g., acetaldehyde dehydrogenase activity and alcoholism). In addition, inherited single-gene polymorphisms appear to determine the response to as yet undefined environmental factors—for example, the antigens of the major histocompatibility (HLA) complex and specific disease associations (p. 200) such as type 1 diabetes, rheumatoid arthritis, and coeliac disease. Lastly, genetic susceptibility can determine differences in responses to medical treatment; isoniazid inactivation status in the treatment of tuberculosis (p. 186) is a good example.
Approaches to Demonstrating Genetic Susceptibility to Common Diseases
In attempting to understand the genetics of a particular condition, the investigator can approach the problem in a number of ways (Box 15.1). These can include comparing the prevalence and incidence in various different population groups, the effects of migration, studying the incidence of the disease among relatives in family studies, comparing the incidence in identical and nonidentical twins, determining the effect of environmental changes by adoption studies, and studying the association of the disease with DNA polymorphisms. In addition, study can be made of the pathological components or biochemical factors of the disease in relatives (e.g., serum lipids among the relatives of patients with coronary artery disease). Study of diseases in animals that are homologous to diseases that occur in humans can also be helpful (p. 73). Before considering the use of these different approaches in a number of the common diseases in humans, specific aspects of some of these approaches will be discussed in more detail.
Family Studies
Genetic susceptibility to a disease can be suggested by the finding of a higher frequency of the disease in relatives than in the general population. The proportion of affected relatives of a specific relationship—first degree, second degree, and so forth—can provide information for empirical recurrence risks in genetic counseling (p. 346), as well as evidence supporting a genetic contribution (see Chapter 9). Familial aggregation does not, however, prove a genetic susceptibility, since families share a common environment. The frequency of the disease in spouses who share the same environment but who will usually have a different genetic background can be used as a control, particularly for possible environmental factors in adult life.
Twin Studies
Both members of a pair of twins are said to be concordant when either both are affected or neither is affected. The term discordant is used when only one member of a pair of twins is affected. Both types of twins will have a tendency to share the same environment but, whereas identical twins basically have identical genotypes (p. 106), nonidentical twins are no more similar genetically than brothers and sisters. If a disease is entirely genetically determined, then apart from rare events such as chromosome nondisjunction or a new mutation occurring in one of a twin pair, both members of a pair of identical twins will be similarly affected, but nonidentical twins are more likely to differ. If a disease is entirely caused by environmental factors, then identical and nonidentical twins will have similar concordance rates.
Polymorphism Association Studies
The widespread existence of inherited biochemical, protein, enzyme, and DNA variants (p. 147) allows the possibility of determining whether particular variants occur more commonly in individuals affected with a particular disease than in the population in general, or what is known as association. Although demonstration of a polymorphic association can suggest that the inherited variation is involved in the aetiology of the disorder, such as the demonstration of HLA associations in the immune response in the causation of the autoimmune disorders (p. 200), it may only reflect that a gene nearby in linkage disequilibrium (p. 138) is involved in causation of the disorder.
The human genome contains approximately 10 million single nucleotide polymorphisms (SNPs). Developments in high-throughput microarray SNP genotyping, together with information about SNP haplotypes (from the HapMap project [p. 148]) and the availability of large collections of DNA samples from patients with common diseases, have collectively enabled genome-wide association (GWA) studies (p. 149) to reliably identify numerous loci harbouring such variants.
Animal Models
Recognition of the same disease/disorder that occurs in humans and in another species such as the mouse allows the possibility of experimental studies that are often not possible in humans. In many instances, however, the disorder in the animal model will have a single-gene basis that has been identified or bred for. Nevertheless, spontaneously occurring or transgenic animal models (p. 73), experimentally induced for mutations in single genes involved in the metabolic processes or disease pathways of common diseases, will provide vital insights into the genetic contribution to these disorders.
Disease Models for Multifactorial Inheritance
The search for susceptibility loci and polygenes, sometimes also referred to as quantitative trait loci, in human multifactorial disorders has met with increasing success in recent years. This is largely due to the success of GWA studies (p. 149). Examples of recent research in some common conditions will be considered to illustrate the progress to date and the extent of the challenges that lie ahead.
Diabetes Mellitus
There are two main forms of diabetes mellitus (DM) that are clinically distinct. Type 1 (T1DM) is the rarer juvenile-onset, insulin-dependent form (previous abbreviation IDDM) which affects 0.4% of the population and shows a high incidence of potentially serious renal, retinal, and vascular complications. T1DM has a peak age of onset in adolescence and can only be controlled by regular injection of insulin. Type 2 is the more common later-onset, non–insulin-dependent form that affects up to 10% of the population. It usually affects older persons and may respond to simple dietary restriction of carbohydrate intake, although many persons with T2DM require oral hypoglycemic medication, and some require insulin. An additional 1% to 2% of persons with diabetes have monogenic (single gene) forms of diabetes (Table 15.1).
Diabetes can also occur secondary to a variety of other rare genetic syndromes and nongenetic disorders. Examples include Prader-Willi syndrome (p. 122), Bardet-Biedl syndrome, Wolfram syndrome, and Friedreich ataxia (Table 2.5, p. 24). Diabetes mellitus is therefore aetiologically heterogeneous.
Monogenic Forms of Diabetes
Rare forms of diabetes that show high penetrance within families are usually due to mutations in single genes. More than 20 monogenic forms of diabetes have been identified (see Table 15.1).
Maturity-Onset Diabetes of the Young
Mutations in five additional genes which encode transcription factors required for development of the β cell have been reported. The hepatocyte nuclear factor 1α (HNF1A) and hepatocyte nuclear factor 4α (HNF4A) genes were identified through positional cloning efforts and are associated with a more severe, progressive form of diabetes usually diagnosed during adolescence or early adulthood. These patients are sensitive to treatment with sulphonylurea tablets; this is an example of pharmacogenetics (see Chapter 12). Good glycemic control is important, as patients have a long duration of diabetes and may suffer from diabetic complications. Mutations in the HNF1A gene are the most common cause of MODY in most populations (65% of UK MODY), and HNF4A mutations are less frequent.
Neonatal Diabetes
Neonatal diabetes can be transient or permanent. More than 70% of cases of transient neonatal diabetes result from the overexpression of paternally expressed genes on chromosome 6q24. The inheritance and extent of this abnormality of imprinting (p. 121) are variable. However, in a small percentage of cases, patients have imprinting abnormalities besides 6q24 at multiple loci in the genome; these are associated with mutations in the zinc-finger transcription factor gene, ZFP57. Patients with a 6q24 abnormality are usually diagnosed in the first week of life and treated with insulin. Apparent remission occurs by 3 months, but there is a tendency for children to develop diabetes in later life.
Permanent neonatal diabetes does not remit, and until recently, patients were treated with insulin for life. The most common causes (>50%) are mutations in the KCNJ11 or ABCC8 genes which encode the Kir6.2 and SUR1 subunits of the adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channel in the pancreatic β cell. Closure of these channels in response to ATP generated from glucose metabolism is the key signal for insulin release. The effect of activating mutations in these genes is to prevent channel closure by reducing the response to ATP, and hence insulin secretion. The most exciting aspect of this recent discovery is that most patients with this genetic aetiology can be treated with sulphonylurea drugs that bind to the channel and cause closure independently of ATP. Not only have patients been able to stop insulin injections and take sulphonylurea tablets instead, but they achieve better glycaemic control, which improves both their quality of life and later risk of diabetic complications.
Type 1 Diabetes
Initial research into the genetics of diabetes tended to focus on type 1 diabetes, where there is greater evidence for familial clustering (λs is 15 for T1DM versus 3.5 for T2DM [p. 146]). The concordance rates in monozygotic and dizygotic twins are around 50% and 12%, respectively. These observations point to a multifactorial aetiology with both environmental and genetic contributions. Known environmental factors include diet, viral exposure in early childhood, and certain drugs. The disease process involves irreversible destruction of insulin-producing islet β cells in the pancreas by the body’s own immune system, perhaps as a result of an interaction between infection and an abnormal genetically programmed immune response.
The first major breakthrough came with the recognition of strong associations with the HLA region on chromosome 6p21. The original associations were with the HLA B8 and B15 antigens that are in linkage disequilibrium with the DR3 and DR4 alleles (pp. 147, 200). It is with these that the T1DM association is strongest, with 95% of affected individuals having DR3 and/or DR4 compared with 50% of the general population. Following the development of PCR analysis for the HLA region, it was shown that the HLA contribution to T1DM susceptibility is determined by the 57th amino acid residue at the DQ locus, where aspartic acid conveys protection, in contrast to other alleles that increase susceptibility.
