Diseases that run in families are diagnosed via genomic testing. Screening and management measures can then be introduced to protect these individuals from the development or progression of disease, as far as possible.
The diagnosis of a hereditary disease in one family member also opens up the possibility of ‘cascade testing’, meaning other family members can be tested, too. The ripple effect of a genetic diagnosis can therefore be very significant.
An individual’s genetics can increase their risk of developing a specific disease, even when they do not have an inherited condition/susceptibility.
Genome-wide association studies have revealed a range of genetic risk factors that can influence susceptibility to a given disease, for example diabetes, coeliac disease or inflammatory bowel disease (IBD).
We are only at the beginning of understanding these genetic risk factors, but in some instances we can use this information in a clinical setting. A good example is the HLA typing of those with suspected coeliac disease, which can in many cases rule out coeliac disease and enable the patient to continue to eat gluten.
Targeted treatment and management
When a precise genetic diagnosis is made, treatment and management can often be altered accordingly.
Chemotherapy with 5-fluorouracil is usually offered to people with colorectal cancer who require systemic treatment, but it may be less effective in people with Lynch syndrome. Avoiding this chemotherapy may therefore avoid unnecessary toxicity. Conversely, newer immunotherapy agents such as checkpoint inhibitors are only effective in those with Lynch syndrome or those with Lynch-like tumours.
The approach to surgical management of colorectal cancer may also be adapted, with extensive resection often favoured in people with Lynch syndrome, who are at higher risk of recurrence than others.
As an example in another field, when patients are referred with suspected hepatitis C, the genotyping of the hepatitis C virus (HCV) is a vital tool in the selection of antiviral therapy. Because there are seven distinct genotypes and more than 67 subtypes of HCV, genotype information is helpful in defining the epidemiology of hepatitis C and recommending appropriate treatment with direct-acting antiviral (DAA) and/or interferon therapy.
Preventing adverse drug reactions
An individual’s genetics play a part in how they respond to certain drugs (this is known as pharmacogenomics).
Our understand in this area is growing, but one good example in current use is the selection of azathioprine for people with IBD. Because of variation in the TPMT gene, people can have very different reactions to this drug – some serious and hazardous. Genetic testing is used to determine whether the use of thiopurines should be avoided, and what dose may be most effective for a particular individual.
Drug development/novel therapies
Genome-wide association studies (GWAS) have enabled the identification of genetic risk factors for common conditions that affect the GI tract. Thanks to genomic research, increased understanding of the mechanistic role of these genetic risk factors is opening up the possibility of new targeted therapies.
As an example, an important recent discovery has been made in the gene that makes the interleukin 23 receptor, and this is leading to the development of novel therapies. The IL23R gene is involved in the differentiation of the Th-17 lymphocytes, resulting in dysregulated cytokine production, which is implicated in the pathogenesis of Crohn’s disease. Ustekinumab, through inhibition of IL-12 and IL-23, inhibits key molecules in cellular immunity, and is effective in the induction and maintenance of remission of Crohn’s disease.
Polygenic risk scores
Genomic studies have also enabled us to understand more about genetic risk factors that increase or decrease all of our risk of developing certain common conditions, whether diabetes, coeliac disease or IBD. When these individual factors are combined they create a disease risk profile, ranging from low to high risk, unique to an individual. This is known as a polygenic risk score. We are only at the beginning of understanding this, but are starting to use it in clinical practice and it is an area that is sure to develop.
Research using genomic data is enabling deeper understanding of the whole picture of disease. For example, GWAS have resulted in a greater appreciation of the role of the microbiome and host immune system in IBD. Common risk-associated alleles have been associated with features of gut immunity, including autophagy and gut mucosal barrier function, highlighting the complex interaction between the host immune system and the gut microbiome in the pathogenesis of IBD.