ISTS Asks: Genomics

6 min read

What is Genomics?

Just from looking at the word, you could hazard a guess that it involves genes. A gene is a sequence of DNA inherited from a parent that determines some physical characteristics of the offspring. Combinations of these are what makes us unique – e.g. having blue eyes, attached earlobes, or naturally blonde hair. Unfortunately, we inherit both the good and the bad, and it can go deeper than outer physical appearances.

Hereditary Diseases

Among the genes which we inherit from our family, some may be gene mutations that can put you at risk of having a genetic disorder. Some examples of genetic disorders are cancer and familial hypercholesterolemia. Advancements in genome sequencing technologies have allowed doctors to make better, more informed decisions about the treatment, management and prevention of genetic diseases. In Singapore, researchers are also piloting how genetic testing can be incorporated into our clinics and hospitals.

ISawtheScience got in touch with Dr. Chiang Jianbang and Dr. Sharon Pek Li Ting, both specialised in genetics and its advancements.

Questions for Dr Chiang Jianbang on cancer

Generally, why is it important to know one’s family history in understanding cancer risk?

A person with a strong family history of cancer may be at higher risk of cancer than the general population. Knowing one’s family history can encourage the family members affected with cancer to undergo genetic testing to determine if there is an underlying hereditary cancer syndrome in the family.

How is knowledge of family history and cancer risk derived? Is genetic screening part of the study process?

A person can ask his/her family members about their family’s history of cancer. A clear and detailed family history will help the genetics team determine what hereditary cancer syndrome the person is at risk for.

In your opinion, is this knowledge better to know, or would knowing this cause undue or unnecessary stress to people given the social stigma of cancer? For example, a couple looking to have children may become unnecessarily worried after genetic counselling that it affects their physical and mental health.

We did a local study on this and found that most Singaporeans are actually not distressed by the genetic test result. But rather, the information helped them understand why their family is at a higher risk for cancer.

What role does precision medicine or genomics play in this relationship between family history and cancer risk?

We like to draw an analogy that genomics is akin to a pair of headlights. It illuminates the path ahead so that cars can drive safely in the dark. In the same way, genomics helps a person understand what cancers he/she is at risk for, and undertake necessary surveillance to detect cancer early when it is most treatable.

Questions for Dr. Sharon Pek Li Ting on familial hypercholesterolemia

Could you explain in layman terms what familial hypercholesterolemia (FH) is?

Cholesterol is the fatty substance floating in our blood. Generally, we consider Low density lipoprotein cholesterol (LDL-C) as the “bad” cholesterol.  High levels of them can build up at the walls of blood vessels and raise the risk for heart attack.

Familial Hypercholesterolemia (FH) is having very high levels of LDL-C, which can be inherited in the family. Most of the time, this is due to inheriting one (heterozygous) or two (homozygous) copies of a dysfunctional gene, which prevents LDL-C from breaking down properly.

How serious is FH, and how is it detected?

When untreated, high cholesterol levels can lead to early heart attack. For people with heterozygous FH, this may occur before 60 years old, sometimes even as early as 40-years of age. This is compared to the general population where the median age of heart attack is 70 years old. For those with homozygous FH, this can occur even earlier, within the second decade of life.

We can detect FH by measuring a person’s blood LDL-C; This is usually more than 4.9mmol/l in people with FH. Coupled with a strong family history of very high cholesterol levels and/or early heart attack, this would suggest that one may have FH.

If genetic testing is available, DNA sequencing in a few genes (LDLR, APOB, PCSK9) will identify the specific type of gene that has caused high cholesterol levels. This also allows us to test the family members at the same gene location. Known as Cascade Testing, it is an efficient way to make an early diagnosis of FH and allows for early treatment of very high cholesterol levels to prevent an early heart attack.

What are some of the present cures or treatments for FH?

While exercise and lifestyle modifications such as following a diet with low saturated fat is important and essential, this alone will not lower cholesterol levels to a healthy range. Patients with FH should be treated with lipid-lowering medications such as statins and ezetimibe and has to be adhered for life. These medication(s) are safe and well-tolerated. Serious adverse reactions are extremely rare.

In recent years, many new and effective medications have been made available. These include injections like Proprotein covertase subtilisin/kexin type-9 (PCSK9)-based therapies and angiopoietin-Like Protein 3 (ANGPLT3)-inhibitors. Clinical trials, tablets and these injections have been shown to effectively lower blood cholesterol levels as well as reduce risk of heart attack and stroke. These are also shown to be effective in people with homozygous FH (inherited two copies of the dysfunctional gene, one from each parent).

LDL-apheresis is another type of treatment for FH. While it is able to reduce LDL-C to healthy levels, this requires the use specialised facilities and trained personnel, and needs to be repeated on a regular basis almost once every two weeks.

What is your opinion in the use of gene therapy/precision medicine in the treatment of FH?

Precision medicine:

The use of these novel therapeutics were discovered through precision medicine. Knowledge in mechanisms of action of molecules like PCSK9 and ANGPLT3 have allowed scientists and pharmaceutical companies to manufacture specific antibodies targeting these molecules, leading to a reduction of cholesterol levels. This reduction is possible even when patients with FH have genes that do not function properly. Such approach in precision medicine also allows us predict response to medication. 

Gene therapy:

Gene therapy is a subset of precision medicine. In FH, PCSK9 silencing is currently undergoing clinical trials and showing to be effective cholesterol-lowering. In other areas of gene therapy such as gene editing and use of retrovirus, benefits over current standard of care is not clear at the moment and mostly in the infancy of trials in homozygous FH. Side effects include immune responses and off-target unwanted effects are currently being monitored. Such techniques may also face ethical challenges.

RNA, DNA and antibody-based therapies for FH are each at different stages of development. Emerging therapeutics for FH are promising in lowering cholesterol levels and the risk of early heart attack.


Leave a Reply