Inherited causes of disease in populations

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Genes can have implications for disease across the life course, with genetic disorders developing at any age and interacting with an individual's environment.

Birth
At birth, while individually rare, collectively genetic disorders are relatively common, with a combined prevalence of around 1-2% in the UK. Some 4,000 inherited diseases are known to be associated with mutations in single genes, with recognisable patterns of inheritance. These are classified according to the chromosome on which they are found: autosomal, X-linked or Y-linked and are covered in more detail in the following section: Basic genomic concepts.

Some genetic diseases at birth can be chromosomal with variation in the number inherited. An example of this is Down syndrome, in which there is an extra copy of chromosome 21. Occasionally changes in the number of sex chromosomes can be inherited. In most cases, this has no noticeable impact, but females with only one X chromosome have Turner syndrome while males with an extra X chromosome have Klinefelter syndrome. Alternatively, there can be structural abnormalities. An example is Cri-du-Chat syndrome resulting from a deletion on the short arm of chromosome 5 and Jacobsen syndrome, also called the terminal 11q deletion disorder. Some of these chromosomal changes are heritable.

Familial risk
Single gene mutations are not all congenital (present in the phenotype at birth). Subsets of common disease that develop later in life can be prevalent in several members of the same family and the disease shows a recognisable Mendelian inheritance pattern associated with a single gene. This suggests the existence of a single mutation that confers a high risk of disease developing in that family. Single gene subsets of common disease typically account for a maximum of ~5% of the total burden of disease. An example is familial hypercholesterolemia, a dominantly inherited condition characterised by a build-up of cholesterol and a high risk of premature cardiovascular disease. Another example is inheriting a mutated BRCA1/BRCA2 gene and the subsequent increased risk of developing breast cancer.

Susceptibility to common diseases that typically occur in middle and later life can also be associated with genetics other than with a single mutation. Certain genetic variants may increase the risk but do not absolutely predict occurrence, such as coronary heart disease (e.g. VAMP8 variant), diabetes (e.g. PCSK9 variant) and cancer (e.g. rs4143094 variant for bowel cancer). Cancer results from genetic alterations, occurring when DNA instructions are damaged so that the cell escapes normal regulation when replicating. Most genetic alterations that lead to cancerous behaviour arise in the individual and do not affect the germline (the genomic material that is heritable).

The predisposition to developing disease can be affected by both inherited and environmental/lifestyle factors. These diseases are termed multifactorial and account for the majority of genetic disorders, outnumbering the number of single gene disorders. There may be multiple genes involved which may interact with each other, with environmental factors and with lifestyle factors. The association, therefore, is often not clear and difficult to disentangle.

Epigenetics
Epigenetics is the study of changes in phenotype resulting from no modification in genotype. Changes in gene expression can result from DNA methylation, modification of histones and RNA-mediated modifications. This can result from environmental exposures such as chemicals, tobacco smoke, nutrition and stress. If this occurs in early life, this can have an impact on gene expression across the generation. For example, parental smoking during preconception and pregnancy has been associated with an increased risk of hepatoblastoma and childhood leukaemia in offspring.

This is a rapidly expanding field, with the understanding that both the environment and individual lifestyle can directly interact with the genome to influence epigenetic change. This, therefore, has significant implications for public health’s role in disease prevention and clinical implications. Identification of epigenetic changes could provide an indication of an increased risk of disease in later life if they result from potentially harmful exposures in populations. Epigenetic changes could also be potentially modifiable through lifestyle and diet changes.

Cancer was the first human disease to be linked to epigenetics and these epigenetic changes are among the best characterised. Epigenetic changes resulting in abnormal expression of cancer-associated genes can be used as biomarkers in the molecular diagnosis of early cancer. The impact has also been seen with immune disorders - abnormal DNA methylation affecting gene expression has been observed in patients with systemic lupus erythematosus. Furthermore, epigenetics can also be involved in certain birth defects that can be affected by nutritional factors, such as deficiency of folic acid in the diet. Maternal undernutrition has been shown to increase the risk for adult-onset of cardiovascular and metabolic disorders in offspring, while maternal obesity has also been linked to obesity and cardiovascular disorders in offspring.

There are however challenges in the study of and application of epigenetics, both with adapting technology to epidemiology studies to identify mechanisms associated with exposure and disease and recognising that epigenetic changes associated with environmental exposures or disease outcomes have typically been small in magnitude.

Role of genes in health and disease
The discipline of public health genetics is centred on the involvement of genes as determinants of health and their interactions with other genetic, environmental or social factors. As mentioned above, the majority of diseases are multifactorial and involve genetics and the environment. If an interaction with the environment is required for disease to develop, this provides an important opportunity to modify the risk of disease by altering the environment. An understanding of the genetic characteristics of disease may also help to understand the relative effectiveness of different pharmaceutical treatments in different people, a field termed pharmacogenetics. Another example of the role of genes in health is gene therapy. This is the use of viruses and plasmids (DNA naturally existing in bacteria distinct from chromosomal DNA) to insert genetic material in cells of people with a disease such as cystic fibrosis. The purpose is to compensate for abnormal genes or to make a beneficial protein.