We’re going to have a bit of change of tack with topics and rather than talk about how polymorphisms can affect otherwise healthy people; I’ll instead talk about how polymorphisms can impact on people with already existing diseases. This also gives me a chance to talk about the research that initially got me interested in genetics and more recently how our individual genetic code can be used to personalise both medicine and nutrition.
In the third year of my undergraduate degree (Junior year for US readers) I was lucky enough to be accepted into the Cystic Fibrosis Gene Therapy group at Imperial College in London to undertake year-long research project into developing novel therapies for cystic fibrosis or CF. It was working there, feeling like I was making a difference (however small), that really inspired me to continue into a research career, with a particular focus on CF and other genetic diseases.
What is cystic fibrosis?
CF is a disease many of you will have heard about, and indeed many of you may even know someone with CF. When most of us think of CF we think of people with a severe respiratory disease but the truth is actually a lot more complex.
Cystic fibrosis the pancreas and nutrition
CF was first described in the 1930s and at this point babies born with CF typically only surviving a few months, dying due to a failure to thrive or with a later onset of respiratory disease (R). It was rapidly identified that people with CF were not secreting enzymes from their pancreas, and this was limiting their ability to digest food and therefore grow and thrive. Pancreatic enzyme replacement therapy soon followed and this resulted in an immediate improvement in life expectancy. To this day people with CF still have to take a significant number of tablets and supplements to replace their lost pancreatic activity.
However, once the issue of impaired digestion had been improved a new aspect of CF became apparent, which CF researchers are still attempting to remedy today (R). If you know anyone with CF you’ll know that their airways produce a thick sticky mucus which is difficult to clear and lead to them developing chronic infections and inflammation. This eventually leads to chronic lung damage, which is unfortunately the major cause of death in people with CF.
Huge strides have been made
Whilst it can all sound very negative, huge strides have been made in CF research which have massively improved both the quality of life for people with CF and their life expectancy which now stands in the 40’s in the US and UK. This excellent graph from the UK Cystic Fibrosis Trust demonstrates this point nicely, and you can see there are many emerging therapies and areas of research.
The genetics of CF
Whilst the disease itself was described in the 1930s (R), and researchers quickly realized that it was a recessive genetic disorder, it wasn’t until the 1980s that the exact gene associated with CF was identified (R). In a seminal paper researchers demonstrated that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene underlay the development of CF as a disease, and we can now state that CF is the most common life limiting autosomal recessive disorder affecting Western populations today. To quickly drill down into that sentence autosomal means that the gene is not located on a sex (X or Y) chromosome, meaning we should all have two working copies of the gene. Recessive means that for CF to be present as a disease both copies must carry mutations.
SNPs and CF
Whilst CF as a disease is driven by mutations in a single gene, CFTR, a really exciting area of research is attempting to identify reasons why two people with the same mutation in the same gene can have such different health outcomes. A large study in 2012 identified several SNPs that were associated with differing health outcomes in people with CF in genes such as SNAP23, KRT19 and PPP2R1A (R). However these genes, and in fact the majority of research, is focused on improvements on lung function and activity, with nutritional issues being placed somewhat on the back-burner.
CF and Choline
However, some new nutritional research is appearing. First reported in 2006 a depletion of choline and betaine, along with an increase in the harmful compound homocysteine (which is often associated with mutations in the MTHFR gene) (R). As discussed previously homocysteine accumulation is associated with a variety of disorders including cancers, heart disease, stroke and raised blood pressure (R,R,R). In otherwise healthy individuals these can impart a huge health burden, but in people with CF this is exacerbated even further.
Building on this investigation two trials investigating the effect of choline supplementation on people with CF were performed. The first using a choline rich lipid manufactured to be easily absorbed, showed a significant benefit to plasma choline and betaine levels but did not impact homocysteine levels, and importantly improved weight, BMI and lung function, key markers of general CF health (R).
Coincidentally a similar study was published in the same year (R). As with the above study no improvement in homocysteine levels was observed, but the authors did observe alterations in other amino acid concentrations. However, in this instance the authors did hypothesise that alterations in homocysteine concentrations may be related to excessive vitamin B6 and B12 intake associated with CF nutritional supplements, and suggest that this may be an area for clinical consideration.
The take home message from these studies remains unclear, as a benefit to choline supplementation was described, but not directly through homocysteine.
However, what was not investigated in these studies was the presence of SNPs in other genes which can alter homocysteine levels such as MTHFR, CBS, BHMT, PEMT or MTRR. It is possible to hypothesize that homocysteine levels may be further increased in people with CF if they carry one of the common SNPs in the aforementioned genes.