“It must be in your genes”. This is a phrase that gets thrown around quite often, usually to explain some sort of behaviour or (often unwanted) physical trait. Our genes and the variation within them can, to a large extent, tell us a lot about ourselves, why we are the way we are and explain what makes us different from other humans and other organisms. Interestingly, we are about 99.5% genetically similar (when looking at the DNA sequence) to our fellow humans and about 98% similar to our furry chimpanzee friends. We do, however, differ in some parts of our genome and it is this unique “pattern” or variation that, along with some environmental and other factors, influences the way we look, the way we behave and the way we respond to certain things. For example, something as simple as whether or not one tastes the unpleasant bitter taste of Brussels sprouts is determined by the presence or absence of a certain genetic variant!
I have been interested in the field of genetics for a while now and am fascinated by the role that genetics plays in our lives. A more serious part of genetics and a main focus of research in the field is that of genetics related to disease. Our genetic makeup is believed to influence our susceptibility to developing certain diseases and the seriousness of a particular illness or associated symptom. My first exposure to this line of research was during my MSc degree where I was involved in a joint project between the Human Genetics department at Wits/NHLS and the pain lab of the BFRG. My research investigated the association of previously associated neuropathy and pain genes with susceptibility to developing HIV-associated sensory neuropathy (HIV-SN) and pain and variation in pain intensity. This was looked at in a black Southern African population. The population of choice was specifically significant as African populations have been largely understudied in the field of disease genetics compared to non-African populations. Based on the knowledge of genetic susceptibility to disease, it comes as no surprise that the risk of experiencing pain and neuropathy as well as the intensity of the pain experienced in HIV patients are considered to have a genetic component, but the big (and still not completely answered) question is exactly what genes and variants within the genes are involved? Having a supervisor from both the genetics and physiology departments offered the necessary expertise to understand the relationship between the genes and phenotypes under investigation and to try to come a bit closer to answering this question.
The project was an extension of work being done at the time by Toni Wadley for her PhD, with a deeper look into some of the regions of the genome that she had looked at, and was part of a larger study, headed by Prof Peter Kamerman, looking at various aspects of HIV-SN. The project used DNA samples from adult HIV positive patients, attending the Virology Clinic at the Charlotte Maxeke Johannesburg Academic Hospital, who had been on antiretroviral therapy for at least six months. This DNA was genotyped for a range of carefully selected single nucleotide polymorphisms (mutations/variants within genes) across the genes under investigation with the aim of being able to determine, as best we could, the role that the genes play in neuropathy and/or pain.
Apart from the specific statistical associations which resulted from analysing the genotype data against the phenotype data (HIV-SN status, pain status and pain intensity, etc; there is too much to mention here!), the research led to several observations/conclusions. The first thing to point out is that pain is very common in individuals with HIV-SN. Over 90% of individuals with the neuropathy experienced some sort of pain, mostly moderate to severe in nature. This made studying pain risk in these individuals rather difficult as the number of cases (those with pain) far out-weighed the number of controls (those without pain), therefore making the reliability of the pain risk results questionable. Secondly, it is clear that both HIV-SN and pain are complex traits. Unlike disorders such as Huntington’s disease or cystic fibrosis, which are monogenic, the results pointed towards several genes being associated with HIV-SN and pain risk and pain intensity. This brings about a particular challenge: how do we know what the exact causative genes/variants are? To answer this question, genetic association studies need to be coupled with functional studies to determine the actual functional role that the variants play, for example in altering the expression of the gene product, which could ultimately lead to differences in disease susceptibility and intensity. Lastly, there were inconsistencies between what was previously discovered in non-African populations and what we discovered in our African population, leading to us concluding that associations (in this study and in fact in most genetic association studies) are population-specific. This could be explained by the differences in diversity and structure of the genome among populations of different ethnicity, leading to different variants within different genes being associated with a particular trait.
A question you may have on your minds (possibly as non-geneticists) is “why is it so important to discover which genes are associated with a particular trait?”. Apart from the hunger for knowledge, one of the biggest factors to consider is that of treatment. Looking specifically at HIV-SN, treatment generally involves slowing the progression of the neuropathy or managing symptoms, rather than actually curing the neuropathy. What I haven’t yet mentioned is that the neuropathy and associated symptoms are often caused by the antiretrovirals that the individuals receive. Identifying individuals who are at a greater risk genetically for developing HIV-SN and pain associated with the neuropathy can result in these individuals being monitored more carefully and having the chance of being administered different antiretrovirals in the future.
The questions that I’m sure many geneticists ask themselves…Will the research ever end? Have we found all the answers yet? The answer, quite simply, is “no”. The genetic differences between populations and the complex and multifactorial nature of many traits/diseases make the research in this field anything but simple. With the advancing technologies and the increased ability to handle and analyse large sets of data, researchers seem to be getting a little closer, but, in many cases, the findings recorded so far are just the beginning with so much still to be uncovered…
1) Hendry L, Lombard Z, Wadley A, Kamerman P. KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study. J Acquir Immune Defic Syndr. 2013 May 1;63(1):27-30. doi: 10.1097/QAI.0b013e318285cf36. PubMed PMID: 23314412.
2) Wadley AL, Hendry LM, Kamerman PR, Chew CS, Price P, Cherry CL, Lombard Z. Role of TNF block genetic variants in HIV-associated sensory neuropathy in black Southern Africans. Eur J Hum Genet. 2015 Mar;23(3):363-8. doi: 10.1038/ejhg.2014.104. Epub 2014 Jun 4. PubMed PMID: 24896147; PubMed Central PMCID: PMC4326702.
3) Hendry LM, Wadley AL, Cherry CL, Price P, Lombard Z, Kamerman PR. TNF Block Gene Variants Associate With Pain Intensity in Black Southern Africans With HIV-associated Sensory Neuropathy. Clin J Pain. 2016 Jan;32(1):45-50. doi: 10.1097/AJP.0000000000000224. PubMed PMID: 25756557.