Genomics and Medicine, with Aroon Hingorani

In recognition of February’s status as National Heart Month, Professor Aroon Hingorani recently took to the stage for a Lunch Hour Lecture about the opportunities and challenges associated with using genomics to improve personal and public health.

Genomics is the study of genomes – all of the DNA contained in the cell of an organism.

The ability to read, or ‘sequence’, DNA has been improving exponentially over the last few decades and we can sequence far more DNA than ever before, in less time and at a lower cost.

One of the most significant recent developments in this field was the completion of the Human Genome Project in 2003. This ambitious undertaking provided scientists everywhere with a blueprint of what our genomes look like.

By comparing DNA test results to this template researchers can identify the differences that might cause disease.

However, things are rarely that simple in medicine.

Some genetic diseases are caused by mutations in, or around, a single gene. This monogenic mutation is all that’s required to cause the pathology. These conditions behave according to fairly simple Mendelian laws and can be traced back to the mutant gene by linkage analysis.

You might think that if a single gene is responsible it would make these conditions easier to test for. Sadly, things get even more complicated.

A single gene can mutate in many places and the same disease could be caused by mutations in completely different genes, in completely different locations. As Professor Hingorani explained, it’s just not possible to come up with an off-the-shelf explanation to cover all situations.

Most diseases are even more complicated and involve a number of different genes (‘polygenic‘). In these cases scientists need to look for individual differences in the DNA – called single-nucleotide polymorphisms (or SNPs) – which can occur at almost any location throughout the genome.

No single SNP causes disease. Instead, certain SNPs, or combinations of SNPs (in addition to environmental factors), can lead to an increased chance of developing a disease.

As there are many possible SNPs, each of which might only correlate with a very subtle effect, it’s hard to know where to look for the SNPs that might be important.

In order to get around this people do genome-wide association studies (GWAS), looking at thousands of SNPs across many individuals to find a pattern and identify the SNPs that associate with disease.

Perhaps the most talked about potential use for genomics is in personalised medicine, where information about an individual’s genetic variants could be used to personalise their treatment. However, according to Prof. Hingorani, this field has lagged behind that of genomics and needs a lot more work before it becomes commonplace  in the clinic.

It seems that the next big application of genomics in medicine could be in drug development, particularly in the fight against cardiovascular disease.

Bringing a drug to market is a famously expensive and risky business. It takes a lot of time, money and effort. However, most drugs fail for one reason or another, and failing later in the process means more money and time wasted.

Often it’s hard to even tell whether the drug isn’t working, or if the the cellular process targeted by the drug was just a bad choice in the first place.

Take the example of statins, a widely used family of drugs which lower cholesterol.

We know that people with high cholesterol are at high risk of cardiovascular disease. Giving these people statins lowers their cholesterol, which in turn lowers their risk of heart disease.

Statins target an enzyme involved in making cholesterol. It turns out there’s a SNP-variant of the gene encoding that enzyme which is even better at lowering cholesterol than the drugs. Even if statins hadn’t been invented, we could have figured out that this enzyme could be worth targeting with drugs, based purely on the SNP data.

Obviously, resources are finite, so we really want to only invest them in the drugs that might work. Enter Mendelian randomisation, which mixes genomics and genetics with epidemiological techniques to find just this kind of treatment.

Prof. Hingorani has applied this approach to investigate the role of the interleukin-6 (IL-6) receptor in coronary heart disease (CHD).

All genomics fields are relatively new, and Mendelian randomisation trials are still in their infancy. However, they give researchers an incredibly powerful new tool which could change the face of drug development and the way we fight disease.