The genetics of AF

We aren’t going to go into the actual genes that are associated with AF but instead focus on the implications of what genetics has taught us about AF and what it can do for us going forwards.

Most cases of atrial fibrillation are not caused by inherited mutations in single genes. Some people with AF have a strong inherited component; called ‘familial AF’, but often these patients have several family members developing AF at a young age (under 50's). In a larger number of people with AF, their genetic profile may increase their risk for developing AF rather than any single gene causing their AF.

Genes have been helpful in promoting our understanding of how AF may develop. One of the more commonly associated genes with AF is PITX-2. When patients have mutations in this gene that stop it from working properly, their risk of AF increases. This gene expresses itself normally in the left atrium and the pulmonary veins (the area in the heart where AF commonly originates). The function of PITX-2 seems to be suppressing the genes in these areas that are trying to generate a new heart rhythm. So identifying genes associated with AF may help us understand the areas of the heart that drive AF and potentially understand why it happens.

But our genes are with us since birth? So why does AF tend to occur later in life? Why don’t these abnormalities show themselves from childhood? One hypothesis is that we all have our genetic risk- our threshold point at which we will develop AF and it’s the accumulation of inflammation and oxidative stress- damage done to the body by high blood pressure, obesity, and exercise, that causes the risk to translate into an event. Some of us may have a lower threshold than others because of our genetic profile. As genetic testing and our understanding of genetics become clearer- one possibility may be to use it to identify patients at high risk of AF and monitor them more closely for AF whilst promoting healthy lifestyle behaviours to them as well.

Another reason to continue our genetic investigation of AF is that these culprit genes may be future targets for genetic therapies for AF. Now we are still far off this in AF but a team in Oxford is investigating this possibility as a treatment for a different heart condition that has a very strong genetic component- hypertrophic cardiomyopathy (the most common genetic heart condition that causes. The British Heart Foundation awarded £30 million to explore the use of CRISPR technology to try and target the abnormal gene in this condition. This is already a tough challenge, and it’ll be tougher in AF where different people have different gene targets (and some will have none!). But it’s worth exploring because the benefit of treatment that reverses AF at the genetic level is a worthy goal!