Why are some groups of people, in families, in localities, from specific geographical areas, or races, more susceptible to Covid-19?  This is a huge questions for health services to answer, as they see the disease concentrating in certain areas and amongst specific groups of people.   If we can understand why, then surely we may be able to develop strategies to prevent this happening.  

In June last year, in this blog, I wrote about how, as well as all older people, the virus has managed to target exactly the groups of people who already suffer from long term diseases such as obesity, diabetes, cardiovascular disease such as heart problems and strokes.  These people are killed disproportionately by the virus, as we now know, and in western societies the people who have a much higher incidence of these diseases are older people, and some who have  a BAME background.   It has become  abundantly clear that the reasons these people are getting the virus in the first place is because of inequality, low pay, poor eating habits because of poverty, working in unsafe environments, such as meat processing plants, garment factories, and more than anything else, working in front-facing jobs in health and social care.  So they are at risk regardless of their genetic background or susceptibility. 

But there is another, rather sensitive question.  Do some people have an inherently worse genetic risk than others, a risk that is encoded in their DNA?   There is considerable scientific interest in this, and it seems that there is considerable variation among people’s immunity to viruses like Sars-CoV-2, and some of it even dates back to our cousins, the Neanderthals, more than 40,000 years ago, and how their genes affect our immunity today. 

To go into more detail, we need to know how our immune system works to protect people from disease, before we can understand how our genes affects it.  I am not sure that many people actually know what the “immune system” is; where in the body it resides, and how it works. 

The system works through many different sorts of cells, located in various organs in the body, (liver, spleen, lymph nodes, etc)  all of which have their specific jobs to do and way of working. There are two sorts of immune system — the “innate” and the “adaptive”  The innate ones will tackle all infections in a general way, through blood cells like neutrophils and monocytes, and  require no specific training.  The adaptive ones consist of T-cells and B-cells, which need “training” through contact with antigens in the virus, or through vaccination, to do their jobs, and proteins in the blood called “complement”, which facilitate that.  Infants have only innate  response and have to learn how to cope with infections as they encounter them. 

 If you would like to know, this is a link:

https://primaryimmune.org/immune-system-and-primary-immunodeficiency

In general it has been known for a long time that old age, gender and nutrition affect the immune system.  Nowadays, the number of words written about how to boost your immune system is extreme.  Health and fitness are the most popular subjects for blogs, partly due to their capacity for making money, though some of them give sensible advice on lifestyle factors.  There are innumerable blogs on how zinc, or vitamins C and  D,  and many others, can improve the immune response, but the science behind them is complex and disputed.  Vitamin deficiencies are rare, and the number of people nowadays who suffer disease because of them is even rarer.  A healthy diet and lifestyle is enough for most people to stay healthy.  But it is good that people are concerned about their health and most “remedies” do no harm, and definitely make money for some people!

This blog does not make money.  I don’t have anything to sell.  But I am interested in how the immune system works and like to share my thoughts. 

It is a fact that some people’s immune systems do work better than other people’s, and this can be due to both social factors as above, and genetic factors.  Certainly with infections, there is a lot of evidence that the genetic code, the DNA, of people in areas of high levels of infections can alter over time, through natural selection, to obviate some of the worse effects of severe infections.  It happens in the animal kingdom, and it happened in our distant past.  It doesn’t always work very well, and sometimes acquiring a resistance to one disease, usually an overwhelming long term infection, predisposes you to another quite separate one.  

The ones I heard of when I was  a young medic, were the diseases of the  red blood cells, the haemoglobinopathies, that existed because one copy of the gene protected against malaria, which was (and still is) a real killer, especially of children.  The flip side of that was that two copies of that gene would cause a separate, extremely severe disease, sickle cell disease.  The gene survived because most people had only one copy of the gene and survived longer than those without it.  The few people with two copies were collateral damage as it were, in a genetic sense.  Sickle cell disease is a very unpleasant disease which can also kill, but fewer people, because far fewer people had two copies.  Other such pairings were diseases such as cholera and cystic fibrosis, tuberculosis and Tay-Sachs disease, and many others.  Sometimes we discover some lucky people who have developed a resistance to specific diseases that other people don’t have, and we are always looking out for such people so that we can possibly learn to tweak or target biochemical changes in order to  protect more people. Some mutations also can cause an increase in susceptibility to illness, immunodeficiency, and cause a lot of ill health.  In all these cases it is worth doing research to start looking for cures for difficult infections such as HIV rabies and Ebola, as well as Covid-19. 

The interesting areas for me are those concerning targeted treatment of certain cancers, which is underpinned by carefully controlled clinical trials, and has had a lot of success in improving survival rates in ovarian cancers and many other diseases.  Your DNA can be explored and doctors can work out which treatment is likely to work best for you. 

And of course finally to Covid-19.  What do we know about the genetic reasons for susceptibility to Covid-19?  It is obvious there are some; we have all heard of families which have been struck down with Covid, with brothers dying side by side, and several members of the same family in intensive care as the virus rips through communities.  Many of these families have been from BAME communities.  But it is complicated. Recently, scientists have discovered genes that can affect Covid-19, which came originally from Neanderthals – those hominids closely related to us who died out 40,000 years ago.  We now know that their genes did not die out completely because some of them  interacted with modern humans, had sex with them, and had children.  Their descendants lived all over Europe and Asia and so the people there now have an average of 2% of their genes which originally came from Neanderthals, and overall, over half the Neanderthal  genome still survives.  This immediately introduces a disparity in modern human DNA, as Neanderthal ancestors left Africa long before modern humans came into existence and they were isolated outside Africa for thousands of years.  They never made it back to Africa, and so any genes that changed through mutations to help them survive the challenges of a cold northern environment are not going to appear in modern Africans, apart from the ones who have an admixture of non-African genes. 

We know that changes to the Neanderthal genome that survive have disproportionally affected the immune system, and  this may be related to the fact that the Neanderthals came from a small population, often interbreeding with close relatives. This is known to cause  susceptibility to infection in infants, and genes to protect themselves against these infections had an advantage.  It is extremely likely that they passed some of these on to modern humans.  One of these may be a Neanderthal haplotype (sequence of genes), found on chromosome 12.  Its effect is protective, as having a single copy is associated with a 22% lower chance of critical illness in covid-19. Between 25% and 35% of the population of Eurasia carry at least one copy. In Vietnam and eastern China more than half the population are carriers.  It is not found in sub-Saharan Africa. However, Americans of mostly African descent can carry the genes if they have some Eurasian ancestry as well.  It seems to reduce the spread of viruses such as Sars-CoV-2 by causing infected cells to self-destruct more easily, and has been around for a while as it also provides some protection against viruses such as West Nile virus.

But there is also a genetic variation which can cause more severe disease. This sequence is found on chromosome 3, and also came from Neanderthals originally.  A person with it has double the chance of needing intensive care.  If such a person has 2 copies – one on each chromosome –  the risk of severe disease is even greater.  The gene-sequence is most common among people of South Asian descent, with 63% of the population of Bangladesh carrying at least one copy; and among Europeans, where the prevalence is around 16%.  As expected, it is virtually absent from Africa.  More strikingly, it is also very rare in large swathes of eastern Asia.  It appears to make the disease worse  by increasing the production of cytokines, the defensive system that  can go into overdrive and cause severe disease.  An overly aggressive immune response is one mechanism by which covid-19 kills.  This may not be the whole story though, as in Bangladesh despite the prevalence of the harmful haplotype, the official covid-19 death rate in Bangladesh is just 5.1 per 100,000, lower than in many countries without the gene sequence.  And in sub-Saharan Africa, despite not getting the protective genes from Neanderthals, the population has not suffered to the same extent as Europeans and south Asians, and this shows that environmental factors must still be very important indeed.

Pulling everything together, therefore we can explain why some Bangladeshi and other South Asian men  and women in Britain have been so badly affected.  They are not only more likely to work in public-facing jobs, to be obese, suffer from diabetes and hypertension, but they may also be more likely to carry this deleterious gene sequence.  They may live in poorer neighbourhoods, but I remember being shocked at the beginning of the pandemic when several accounts in the medical press told of Asian doctors in their late 60’s and early 70’s, who had worked all their lives for the NHS, and given great service, but then died quickly with Covid after returning to the front line. They were motivated by a desire to help, but they and their families cannot have imagined  that they would have been at such great risk, as they were well off and lived healthy lives.  If only we could have known then what we know now.