Familial Hypercholesterolaemia - genes, environment, evolution

Genetics, Environment and Evolution

Part 1 - Example of Familial Hypercholesterolaemia (FH)

 View of Delft, Johannes Vermeer 1660-61

We have seen familial hypercholesterolaemia (FH) in a large family in the Netherlands. 

The members of the large family affected had a major health advantage relative to the general population of the country during the 19th century. This advantage was lost in the 20th century and the family members had a very high mortality rate during the epidemic of coronary heart disease (CHD). 

The 20th century epidemic of CHD in the UK, displaying CHD deaths only.

I have suggested that the early advantage of FH was due to the high level of expression of cholesterol in the defensive inflammatory process, and this assisted in controlling and clearing infections within the body. In the 19th century infections were clearly the major causes of death, especially in the earlier years of life. Apart from the advantage in the family described, it is known that a high level of cholesterol in the blood is associated with reduced risk of pneumonia, post-operative infections, and the development of AIDS. LDL-cholesterol (the "bad" cholesterol)is known to inhibit toxins produced by Staphylococci. It is not "bad" but it an important part of body defences against infections. High cholesterol is of no disadvantage above the age of 50 years:  "After age 50 years there is no increased overall mortality with either high or low serum cholesterol levels.”) and in women of all ages, and it is of  a positive advantage above the age of 70 years.

But when it comes to the inflammatory process in CHD (perhaps or probably in response to infection) the high expression of cholesterol causes excessive swelling. Swelling is part of the inflammatory process, described in the 1st century AD as the four cardinal signs of rubor, tumor, calor, dolor - redness, swelling, heat, pain. Under certain circumstances swelling can cause major problems that might in themselves be life-threatening. Examples are stridor in throat infections in children, intestinal obstruction in Crohn’s disease, and of course myocardial infarction when there is inflammation in the coronary arteries of the heart.

When there was no CHD , the members of the family with a high cholesterol had an advantage but during the epidemic of CHD they had a major disadvantage. Half the age-standardised mortality rate became twice the age-standardised mortality rate.

How did it come about that members of this family in the Netherlands had a high level of cholesterol synthesis and blood level? The metabolic “abnormality” is genetic and therefore its development and obvious widespread distribution within the large family was the result of a mutation at an indefinite time in the past.

The mutation

Mutations, changes in genetic sequence, are common and they are usually of no significance. Several mutations can result in FH but the technical term for the mutation occurring with family from the Netherlands is the V408M mutation. 

If it going to be of clinical significance, a mutation can be expected to be a disadvantage and result in disease. We know of many genetic diseases, rare as they might be. But there is no reason in theory why a mutation cannot lead to an advantage, and clearly this has been the way in which evolution has progressed during the millennia. 

However evolution is a very slow process, so slow that in Homo sapiens we cannot observe it in action. A bacterium such as E Coli  can have up to 70 generations per day, and so evolution might be observed over a short time-scale (for example the emergence of antibiotic resistance) but in Homo sapiens 70 generations will take about 2,000 years. Observing evolution does not appear to be possible. 

But in the family with the FH mutation the Netherlands we do have a glimpse of evolution in action. The family has been investigated with good and reliable records of ages at death during a period of about 150 years. This has allowed age-related mortality rates to be determined, and then compared to the population of the country, allowing the expression of the standardised mortality rate (SMR). 

Observations

The relative mortality rate (SMR) of the family with FH in the Netherlands
 during the epidemic of CHD. This shows all-cause mortality.

The family members had a low SMR in the mid-19th century, as low as 50% for women. A 50% reduction in age-related death rate must be regarded as a remarkable evolutionary advantage. This is borne out by the large size of the family. This was in an era when children and young people had a significant risk of death from infectious disease, and it was in the resistance to this that the evolutionary advantage appeared to lie.

A large family with a considerable health advantage (the health advantage would have led to the late size of the family) would spread the genes through normal marriage and breeding outside the family. The genetic advantage would spread gradually into the general population. But something went wrong. With the onset of the unexpected epidemic of CHD in the early 20th century, what was an advantage became a serious disadvantage. Early deaths, high SMR, could have slowed down the spread of the mutation, but deaths would have occurred almost entirely after the age of reproduction. 

However now that the epidemic of CHD deaths has almost come to an end, the relative disadvantage of FH is diminishing and might by now have reverted to an advantage. Unfortunately we do not know current details as the research study has not been continued. The mutation is likely to be spreading once again, and with this the health advantage. 

We can therefore appreciate the evolutionary advantage of a high level of expression of LDL-cholesterol in the defensive inflammatory process. It gives the advantages of:

in the family studied, up to 50% reduction in age-standardised all-cause mortality rate;

• improved survival rate above the age of 60 years;
• reduced risk of post-operative infection complications;
• reduced risk of pneumonia;
• reduced risk of AIDS.

Although the risk of death from CHD is higher, now that the epidemic of CHD is virtually at an end, the advantages of a high cholesterol expression will become clear.

This gives a huge research opportunity to observe evolution in action, and hopefully advantage of this will be taken in the future, especially in the present era of cheap and extensive genetic investigation of large numbers of people. There is no reason why the study should not be revived.

Further information will follow shortly in the future Blog Posts:

Part 2 - Mechanisms of Genetics

Part 3 - Examples of Sickle Cell Disease and Thalassaemia

Johannes Vermeer - Girl with the pearl earring 1665-67