Saturday, 30 January 2016

The 20th century CHD epidemic - report from the USA

Tucson, Arizona

Several of my Posts refer to the epidemic of coronary heart disease (CHD) that occurred in the 20th century, and which is now almost over. I reported this in the medical literature (Quarterly Journal of Medicine) in 2012.

People may question my assertion that there has been an epidemic of CHD, but as I have mentioned previously the evidence is well documented. The national documentation requires a level of organisation which is not always present but it is present in the highly sophisticated civil service of the UK and the documents are readily available. The national registration of deaths has been present since the late 19th century, and the great advantage of the NHS is that vast quantities of data have been created and saved.

I have just come across a publication from a medical team from the University of Arizona School of Medicine, concerning “The 20th century epidemic of CHD”. It was published in 2014 in the American Journal of Medicine. The study is based on exclusive USA data and no reference is made to my earlier work, which used mainly UK data.

It mentions that “heart disease” was only the fourth common cause of death in the USA in the early years of the 20th century, but by the middle of the century it had become the most common cause. It did not identify rheumatic and syphilitic heart disease which were present in the early years, but they were declining as causes of death. The deaths from these causes would have reduced to zero by 1970. Something new was appearing to increase substantially the total number of deaths from heart disease.

Working in Chicago, Dr James Bryan Herrick (1861-1954) was in 1912 the first to diagnose myocardial infarction (MI), the most serious and important manifestation of CHD. This is a sudden episode of severe chest pain with collapse and high risk of early death, loosely called a “heart attack”. The clinical diagnosis was straight-forward but it required pathological corroboration from autopsy evidence to understand the condition. A few years later Herrick was one of the first to use the electrocardiogram (ECG) as an aid to diagnosis of MI. Herrick was also the first to identify Sickle Cell Disease, initially called Herrick’s Disease.

But the diagnosis did not just depend on clinical features and ECG. The condition had a high mortality rate. Pathology was of supreme importance and the autopsy was a vital way to learn.  At the time imaging procedures were effectively unknown, X-ray machines identifying only major damage to bones. 

The correlation between clinical features and findings at autopsy (clinico-pathological correlation) was a major part of medicine until very recently. Whereas in the earlier years of the 20th century the ward round would end in the autopsy room, in later years it would end in the X-ray imaging department. Continuous learning is integral to clinical medicine and looking inside the body is part of this.

And so the pathology of MI, and CHD in general, became well established during early part of the 20th century. The emergence of CHD, the new epidemic, was clear and beyond dispute. There were those who wondered how they could have missed the diagnosis in the years before the First World War, but although they did not fully understand this, the disease was simply not present at that time.

Figure 1. Decline of deaths from CHD in the USA

The emergence of a new disease was certainly a mystery, but during the first half of the 20th century there were more important events in the USA and Europe, such as two world wars and a catastrophic economic depression between them. As Dalen and colleagues point out, it was the subsequent sudden decline in deaths from CHD in the late 1960s, clear from good quality national data, that caused surprise.

Figure 2 The rise and fall of deaths from heart disease in the USA

The data is not entirely clear. Figure 1 shows deaths from CHD per 100,000. I assume that the data are age adjusted but this is not stated. Similar for Figure 2, but this shows all heart deaths and not just CHD. There is no data given for specific CHD deaths before the 1965 peak but the increase in total heart deaths was clearly due to the emergence of the new CHD.

The peak of CHD deaths is identified as 466 per 100,000 per year, slightly lower than 522 in the UK. The peak in the west of Scotland was an astounding 960 deaths per 100,000 men per year. The decline of heart disease deaths in the USA appears to be only to 130 per 100,000 per years, but this is total deaths. Although the overall decline is the result of many fewer CHD deaths, in the UK the CHD deaths had declined to only 40 per 100,000 per year (age adjusted) in 2007.

Dalen and colleagues also report autopsy findings in US soldiers killed in wars. In the young men who died in the Korean war (1951–1953),  pathological evidence of CHD was found in 77%. This had fallen to 45% in those who died in the Vietnam war (1968–1978), and to 8.5% in those who died in the Iraq and Afghanistan wars (2000–2011). There is clearly a major decrease of the pathological basis of CHD, corresponding to the decrease of deaths in the general population.

Figure 3: CHD findings at autopsy in young US soldiers killed in wars

The clinical consequences of CHD were diminishing at the same time, as judged by the decline of admissions to hospital on account of sudden onset of MI.

Figure 4: Admissions to hospital in the USA on account of MI

It is interesting to note that the decline was slightly earlier in the younger age-group (<65). This suggests a cohort effect – exposure to the cause was lower or modulated in those born later.

It is also interesting to note that CHD became a milder disease during the years after about 1970, and this is born out by doctors such as myself who were in clinical practice at that time.

Figure 5: Inpatient death rate following admission for MI, USA

The milder nature of CHD can be seen in the rapid reduction in hospital mortality rate. It is remarkable now to imagine a 37% mortality rate for those admitted on account of MI in the years slightly before and after 1970. This high mortality rate was also recorded in the UK literature at the time, and I remember it well.

And so putting together Figures 3, 4 and 5, we can see that there has been a major reduction of CHD, judging from autopsy and clinical data, a major decline in the incidence of MI, and also a major  decline in the case-fatality rate of those admitted to hospital on account of MI. The result is a major reduction of overall death rate from CHD. These were also the findings of the long-term MONICA project, set up in 1973 to try to find an answer to the mysterious decline in deaths from CHD.

It is very important that in their paper Dalen and colleagues recognise that there was a true epidemic of CHD - that there was a sudden onset, a peak and then a rapid decline. It would be a great contribution to knowledge and research if the epidemic were to be acknowledged generally. There are however many “epidemic deniers”, who assume that CHD has always been present.  This means that they need not consider its emergence, but this is clearly very important if we want to understand its decline. Those who deny the epidemic of CHD are obviously completely ignorant of the very clear data.

There have been reports of arterial disease being found in Egyptian mummies. Although this has given apparent justification to the epidemic deniers, it is not the same thing as CHD and it must not imply that CHD has been continuous during the past 4000 years.. There is no reason to assume that there has been only one epidemic of CHD in recent years and particularly in the distant past.

Figure 6: The 20th century epidemic of CHD in the UK

The observation of an epidemic is clear. The next stage is speculative, to consider possible causes, to produce hypotheses that can be tested by continuing research.

This will best be developed in another post.


Thursday, 21 January 2016

The decline of deaths from Coronary Heart Disease worldwide

The decline of the epidemic of CHD

Many of my Blog Posts refer to the 20th century epidemic of coronary heart disease, CHD. Many people must wonder if I have got it all wrong. Was there really an epidemic? Why do we not read of this "epidemic" elsewhere?  I also fail to understand this - surely other doctors and other observers must have read the original articles in the extensive medical literature. But sadly, perhaps not.

A new and recent publication in the International Journal of Epidemiology (reference at the end) was brought to my attention this week by my friend Dr Luca Mascitelli. The study looks at the decline of CHD deaths since 1980 in the countries of UK, Australia, Sweden, USA, Canada, Spain, France, Japan. 

Precise records of death require sophisticated medical services and also national public health and reporting systems. These are not always present and so it is necessary to obtain data from those countries where they do exist. The countries included in this study provide a large data set, as accurate as it is possible to be. 

It is clear from this study that there has been a major decline of age-related CHD deaths internationally, by up to 80% between 1980 and 2007. The title of the study suggests a follow-on from the Seven Countries Study, that we have seen. Now that epidemiology is much more sophisticated the new study is of much better quality and its findings are much more reliable.

The higher the incidence of age-related CHD deaths in 1980, the greater is the subsequent proportionate fall. This is an international phenomenon. There are of course countries, not in this study, in which CHD deaths do not appear to have presented an important public health problem. This could be a reporting problem but if present, then CHD would have been overshadowed by many other diseases.

The decline of age-related CHD deaths is substantial and universal, in men and in women, as shown in Figures 1 and 2.

Figure 1 CHD change in men, 1980-2007

Figure 2 CHD change in women, 1980-2007
We can also see the absolute decline, expressed as age-adjusted death rate per 100,000. In Figure 3 we see the death rates in men. Each county is represented by a series of vertical columns, each representing a period of time. All show a progressive reduction of death rate.

Figure 3: reductions in CHD death rates for men, 1980-2007

In 1980 the highest death rate from CHD was in the UK, with USA, Sweden, Australia and Canada close behind. Spain and France had lower rates of CHD deaths, and this well-known. In all countries in the study there was a major decline.

Japan is the outlier as usual with a very low number of CHD deaths. This is probably due to a high fish diet and location of most of the population at a low latitude fairly close to the equator, giving good exposure to the sun which also provides good vitamin D levels. The decline of CHD deaths was also seen in Japan, as part of the international trend.

Figure 4 shows the same trends in women. Please note that the numbers on the vertical axis are different. Compared with Figure 3 we can see that the death rate in women has been only about one third that in men. This is also well-known.

Figure 4: reductions in CHD death rates for women, 1980-2007

The decline in CHD deaths has been well and repeatedly documented. Our risk of dying from CHD is  now low, and this is why there are so many people living so long. The new epidemic is that of very old age, the elderly now being those who 40 years ago by good fortune did not not die a premature death from CHD, a fate that at that time was experienced by many. 

I stress that the mortality data are age-adjusted. There is no useful purpose in comparing the mortality rate of 50 year-olds at one time or place with 75 year-olds at another. People still die of CHD today, but they are mainly the very old, age greater than 75. We can see this clearly in Figure 5.

Figure 5: Deaths from CHD in the UK in 2010

It is interesting to note that above the age of 75 the current risk of dying from CHD is equal between men and women. Figure 5 shows the number of actual deaths in 2010 and not death rates. The equal numbers might reflect the fact that there are more women than men in this age-group.

It is clear that people below the age of 75 years, those born in the second half of the 20th century, are at much less risk, and that risk has probably diminished progressively during this time.The high risk of CHD appears to be among those born before, during or shortly after World War 2, a "cohort effect". It is as though there was during that time an environmental agent that has either disappeared or to which we have developed immunity.

The data in the study that we having been viewing started at 1980, but the death rate had been declining in the UK and the USA since 1970. The decline of stroke deaths started slightly earlier in about 1960 (Figure 6).

Figure 6: decline of cardiovascular mortality in the USA, expressed as percentage change each year

In the UK, the age-adjusted mortality rate in men in 1980, as shown in the present study (Figure 3), was 460 per 100,000, whereas in 1970 it was 520, representing 11.5% decline in ten years. 

Two important papers were presented in the UK documenting the decline of CHD between 1990 and 2002, in both men and women, and extrapolating (perhaps without justification) to the end of the epidemic by about 2020. The first was a report by the UK Government Department of Health. It was very much a "snap-shot" looking at just a twelve-year period.

Figure 7: Decline of CHD deaths in the UK, 1990-2002

The second was a paper written by Dr John Appleby, chief economist of the UK King's Fund for the study of health. He reported the decline of CHD death rates  between 1979 and 2007, comparing the UK with France. The latter started at a much lower level and so as the graph lines came together the proportionate fall in France was much less.

Figure 8: Decline of CHD deaths in the UK and France, 199-2007

But there is another aspect to the recent paper in the International Journal of Epidemiology, as appears in the title:

The low number of CHD deaths in Japan, compared to Europe, North America and Australia, was perhaps first brought to attention in the Seven Countries Study. The explanation generally given is that it is the result of a low animal fat and a high fish diet of the Japanese. The average blood cholesterol levels in Japan were also noted to be low, and these findings became an important foundation of the diet-cholesterol-heart hypothesis, which we now know to be seriously flawed and not viable.

In the present study, it was found that whereas in Japan the CHD death rate went down in men by 27% between 1980 and 2007, the average blood cholesterol level rose. This was not expected as the levels had gone down slightly in other countries. We can see the change in Figures 9 and 10. The graphs shows the average total cholesterol levels in the blood for the four age-groups shown for the years 1990 and 2008. 

Figure 9: Average blood cholesterol level by age, Japan, Men

Figure 10: Average blood cholesterol level by age, Japan, Women

This finding could have led to the conclusion that the findings in Japan, and also the worldwide reduction of CHD deaths, were incompatible with the diet-heart-cholesterol hypothesis, which would therefore be invalidated. However I suspect that this was not mentioned in the paper as such a controversial view could not be published.

The reason for the declines are usually stated to be the result of medical, pharmaceutical and public health interventions. There is no question that there has been a substantial reduction in cigarette smoking, and this was recorded in the paper. The reductions ranged between 7.1% in French men and 25.5% in Japanese and Canadian men, whereas in women there was a maximum reduction of 21.3% in Canadian women but an increase of 1.8% in French women. We can see than changes by comparing the rates in 1980 and 2012 in Figure 11.

Figure 11: cigarette smoking in 1980 in 2012, men and women

It is interesting to note the high prevalence of cigarette smoking in Japanese men. Despite this there is a very low incidence of deaths from CHD. We have already seen this in Greece, suggesting a major paradox, and now we see the Japanese extension of the Greek paradox. Where there is plenty of sun, there are few deaths from CHD regardless of cigarette smoking. Cigarette smoking cannot be regarded as the cause of CHD but it accelerates it, causing death about ten years earlier than in non-smokers.

It is also suggested that the decline in CHD deaths is due to the widespread use of statin medications. This is not likely to be the case because statins were only introduced in the 1990s. At present in the UK about 25%of people aged 70 take statins, and about 10% at the age of 50 years. We also know the small effect of statins. Even just after the height of the epidemic of CHD, in the 1980s, the benefit of treatment with a statin for five years benefitted only one in 90 very high risk men in the west of Scotland. With current much lower levels of death rate from CHD, it is likely that fewer than 1 in a 1,000 will benefit. The decline of CHD deaths would appear to have been spontaneous rather than the result of medical intervention.

The epidemic
Although there have been many descriptions of the dramatic decline of CHD deaths, such as those displayed above, these do not in themselves identify an “epidemic”. It is only when the corresponding onset  of the disease is identified that it can be called an epidemic. 

It appears to be only in the UK that good quality data are available on population mortality in the later part of the 19th and the first half of the 20th centuries, and the years leading up to 1970. These have been analysed by Dr Maurice Campbell (1891-1973), a leading cardiologist from Guy’s Hospital, London, and the first editor of the British Heart Journal. He was a highly respected physician. His important and unique work on the emergence of CHD during the 1920s seems have been forgotten - it is as though the study of CHD started only in 1980, or perhaps 1970.

Campbell’s study appeared in two short papers in the British Medical Journal in 1963. He noted the emergence of CHD in about 1924, with a doubling of deaths every few years, that is an exponential increase. He dealt with suggestions that this was just a change in diagnosis. He found evidence in the national records of an increase in total deaths from heart disease, at a time when deaths from syphilitic heart disease and rheumatic heart disease were diminishing considerably (helped by penicillin). 

I will present details of this very important work in a future Post.

We see therefore both the details of a major reduction of deaths from CHD since 1970, and also the emergence of CHD before 1970.

This data is published. Why is it not read, understood and made available to the public?

It is clear that there has been a true epidemic of CHD.

Figure 12: The 20th century epidemic of CHD in the UK


Akira et al. International Journal of Epidemiology, 2015, Vol. 44, No. 5 p1614-24
British Heart Foundation. Coronary Heart Disease Statistics, 2014 edition.
Stamler J. The marked decline in coronary heart disease mortality rates in the United States, 1968-1981; summary of findings and possible explanations. Cardiology 1985; 72: 11-22.

UK Department of Health. The National Service Framework for Coronary Heart Disease: Winning the War on Heart Disease. The Stationary Office: London 2004.

Appleby J.  Does poor health justify NHS reform?  Brit Med J 2011; 342: 310

Campbell M. Death rates from diseases of the heart: 1876 to 1959. Brit Med J. 1963; 2: 1963. 
Campbell M. The main cause of increased death rate from diseases of the heart: 1920-1959. Brit Med J. 1963; 2: 712-717. 
Grimes DS. An epidemic of coronary heart disease. Quart J Med 2012; 105: 509-518. 

Saturday, 26 December 2015

Genetics, Environment & Evolution - Part 3

Genetics, Environment & Evolution - Part 3

Examples of Sickle cell disease and thalassaemia

We have seen Familial Hypercholesterolaemia (FH), a condition characterised by a high blood level of cholesterol. We have seen that it results from a genetic mutation (one of several) that that will be continued though generations of the family. The actual moment of mutation has not been observed (investigative genetics  is new) and it could have been in the families for many generations. We have seen that FH can lead to a survival advantage for an individual and ultimately within the family, demonstrated clearly in the 19th century. However under certain circumstances it can lead to a serious health disadvantage and this has been the case during the 20th century of epidemic of coronary heart disease (CHD). Although this disadvantage might shorten life, the genetic mutation will become widespread if major disability and death occur after the years of reproduction.

Relative risk of death in families with FH

It is likely that survival advantage is the result of a higher expression of defensive LDL-cholesterol in the inflammatory process. The disadvantage during the CHD epidemic is due to the increased amount of cholesterol in the inflammatory reaction causing partial or complete blockage of one or more coronary arteries on the surface of the heart.

A parallel with FH is sickle cell disease (SCD) which has a similar genetic pattern and it also demonstrates an interaction between genes and environment.
Distribution of malaria in Africa

In tropical sub-Saharan African countries, malaria is a common and serious problem. It can lead to chronic illness and early death, often in childhood. Malaria causes more than 600,000 deaths per year, 90% in Africa, 77% in children. Much medical effort is put into finding a solution, but nature has gone some way to finding one.

Malaria parasite

The malaria parasite, Plasmodium, is carried by infected female Anopheles mosquitoes, which can pierce the skin and feed on human blood. In the process the malaria parasite is transmitted from the mosquito saliva into the the human blood. When it enters the blood stream it finds a home in the red blood cells within the circulation. There is also a secondary liver phase but that need not concern us at present. The malaria parasite feeds and multiplies within the red cells, and every three days (usually) the red cells burst, releasing the parasites within the blood stream. This causes a characteristic high fever with rigors. 
Malaria parasite in the salivary gland of a mosquito
When the release is every three days it is called tertian malaria (due to Plasmodium vivax or ovale), and less commonly if every four days quaternary malaria (due to Plasmodium malariae). The rigors are more frequent or perhaps more or less continuous in the much more serious Plasmodium falciparum infection.

Whichever is the variety of Plasmodium, the essential host factor is “normal” haemoglobin and thus normal red blood cells, something that is also necessary for good human health. Mutations have occurred at some stage in the past that result in an abnormal haemoglobin molecule, due to a single amino acid variation in the gene. As a result the red blood cells are abnormal in structure and function. 

Sickle cell disease (SCD) is the best-known and most serious mutation, and it is quite common in African people, where malaria is most common. The abnormal type of haemoglobin is called HbS, the normal adult haemoglobin being HbA and in the foetus HbF. The presence of HbS in the red cells results in the red cells tending to deformity, a “sickle” shape, particularly under circumstances of oxygen deprivation.
Sickle cells in the blood

People with SCD are found to be protected against malaria, and it is now known that Plasmodium parasites cannot readily reproduce within the abnormal sickle-shaped red cells, which tend to rupture prematurely before maturation of the Plasmodium offspring. Because of this, people with SCD have a distinct survival advantage when the prevalence of malaria is high, and this is why SCD is common in such countries.

We have therefore another example of a mutation that will result in a disease state, but nevertheless it gives a survival advantage under the environmental circumstance of a high risk of malaria. In West Africa the prevalence of SCD is about 4% (this can be regarded as quite common compared to other genetic abnormalities). In the USA, where there is no malaria, the prevalence of SCD (which therefore provides no advantage) has fallen to 0.25% among the black population and is thought to be still falling. Those with the mutation are now at a survival disadvantage.

SCD is generally considered to be due to a recessive gene, as two inherited genes are necessary for the full disease. It is clear that the homozygous state (two abnormal genes, one from each parent) gives a serious disease, but on the other hand a high level of protection against malaria. The two abnormal genes mean that only the abnormal HbS can be produced within the red cells.

The heterozygous state (inheritance of an abnormal gene from just one parent) is called Sickle Cell Trait. There is some advantage in protection against malaria and just mild disease. There is production of both HbS and normal HbA. The pattern of inheritance is thus similar to FH, mild disease in the heterozygous state and serious disease when homozygous. The use of terms Sickle Cell Disease - homozygous - and Sickle Cell Trait (SCT) - heterozygous - is valuable without trying to define whether the gene is recessive, partially recessive or dominant.

SCD and SCT give an advantage in Africa. But if an African person with inheritance of SCD comes to live in temperate countries such as the UK or the USA, where there is no malaria, the health and survival advantage is no longer relevant. The disease state, SCD, then becomes of over-riding importance, and it might be severe, disabling, chronic, and ultimately it might be fatal. There is no major illness in the heterozygous trait, just low-grade asymptomatic anaemia. This benefit outweighing the disadvantage in the heterozygous state can be called the "heterozygous advantage".

Similar to SCD is Thalassaemia, another genetically determined abnormality of haemoglobin (they are in general called “haemoglobinopathies”). Thalassaemia gives rise to low-grade anaemia that can be mistaken for iron deficiency. The heterozygous state is referred to as thalassaemia minor, and the homozygous state thalassaemia major.
Distribution of Thalassaemia
Thalasaemia also gives some protection against malaria, but both the protection and the disease are not as powerful as with SCD. Whereas SCD is common in Africa, thalassaemia is common in south Asia, where the threat of serious malaria is much less. It has also emerged as an evolutionary advantage but only in areas with malaria. There is again a heterozygous advantage.

Genetics and environment

The interaction between genetic change (mutation) and environment is fundamental to the progress of evolution. 

There has been a genetic advantage to a white skin in people living distant from the tropics this being Neanderthal inheritance. Vitamin D production by the action of the sun on the skin is greater when the skin is not pigmented, and this is an advantage when sun intensity is low. On the other hand a white skin in the tropics is a distinct disadvantage as lack of pigmentation of the skin fails to protect against the damaging effects of intense solar radiation.

We have seen that mutations can under certain circumstances give a survival advantage, and this is the process of evolution. Mutations creating abnormal haemoglobin and red blood cells can give a survival advantage in places where there is a high risk of malaria, but illness when there there is no malaria. It does not appear that there will be an end to malaria, and so sickle cells genes will continue.

In the case of familial hypercholesterolaemia, FH, which gives an improvement of defensive inflammatory processes, this can represent a  positive contribution to evolution. Under a 20th century  environmental circumstances the mutation resulted in a major disadvantage – during the epidemic of coronary heart disease, CHD. This disadvantage appears to have been only temporary, during the little more than 50 years. It is likely that in the future the advantage of hypercholesterolaemia will continue and the genes will spread within the population. With careful record-keeping and research, we will be able to record the effect of this – evolution in action. This is a great opportunity.

Thursday, 17 December 2015

Environment & Evolution: Part 2 - Mechanisms of genetics

Genetics, Environment and Evolution

Part 2:       Mechanisms of genetics

We have already seen: 
Part 1 - Example of Familial Hypercholesterolaemia (FH)

This showed how a mutation led initially to a health and survival advantage in members of a large family, but during the 20th century epidemic of coronary heart disease (CHD) this changed into a major disadvantage. The inheritance pattern was recessive with partial penetration in the heterozygous state. This requires further explanation, an understanding of the genetics of inheritance. 

Uni-parent (asexual) reproduction is effectively cloning, meaning that the offspring, starting as a single cell, will be genetically identical to the parent. The cell divides into two offspring, a process of cell division, mitosis. It appears to be simple process, but inheritance can easily go wrong. It is necessary for the chromosomes (strings of genes) to double, to replicate, before cell division occurs. In unicellular organisms this results in two identical offspring from one parent, diploid meaning each has two sets of chromosomes. 

Figure 1: cell division, uni-parent reproduction

However whenever chromosomes replicate there is the opportunity for an error. If the error is a fault in the sequence of amino-acids on a gene then this will be a mutation. It might cause no apparent harm but if it results in a disadvantage to the organism then cell death will occur and the reproductive line will come to an end.

We are familiar with sexual reproduction, in which there are two parents (there does not appear to be any advantage to having more than two parents). It entails gene interchange and genetic recombination. The parents each have genes that occur in pairs, and the offspring acquire one of the pair from each parent, so that a different pair continues in each of the next generation. 

There is a considerable advantage in having bi-parent reproduction, namely dilution of a genetic abnormality, and it came about very early in the evolutionary story. A remarkable but highly detailed and technical account of this is found in the book The Vital Question, by Nick Lane.

In uni-parent reproduction a genetic mutation that occurs in a “parent” will be passed to all offspring and all offspring are identical to the parent. A mutation would bring the line to a rapid end, unless it were to provide a significant evolutionary advantage and this would be exceptionally rare. 

Figure 2: Uni-parent inheritance

But if there are two parents, then although the mutation would be passed from one parent to each offspring, it is unlikely to have an effect as the corresponding gene from the other parent would be normal. It will provide the necessary function in the offspring. This is characteristic of a recessive gene - an abnormal gene will not usually cause a problem unless the corresponding gene from the other parent is similarly abnormal. The reproductive line would continue.
Figure 3: Inheritance of a recessive gene

If a gene is recessive it is only when both genes of the pair are abnormal, one from each parent, that the health change, usually disease, will occur. This would be the homozygous state (homo- = same) and only one in four of the offspring would be affected. If the offspring inherits just one abnormal gene, there will be no disease but the individual will be a heterozygous unaffected carrier. 

Sometimes things are not quite so straightforward. In some genetic conditions, and familial hypercholesterolaemia (FH) is an example of this, there will be severe disease in the homozygous state, but just a milder form of disease in the heterozygous state. This represents partial penetrance of a recessive gene.

Figure 4: Inheritance of a recessive gene that has partial penetrance

A dominant genetic disease will occur if only one of a pair of genes is abnormal, the heterozygous state (hetero- = different), but the abnormality is sufficient to cause disease, two normal genes being necessary for the disease-free state. One abnormal gene of the pair will cause disease. In inheritance of a dominant abnormal gene half of the offspring will have the disease.
Figure 5: Inheritance of a dominant genetic abnormality 

This is very much more rare than a recessive genetic characteristic, as the genetic disadvantage of a dominant gene usually causes early death in 50% of the offspring, before reproduction can occur. An exception is Huntington's disease, a serious early onset neurological disorder with dementia and onset at about the age of 40 years, when reproduction will already have taken place. Being dominant inheritance, it will affect one in two of the offspring. There is no carrier state as a single abnormal gene will cause disease.

Genes code for proteins, many of which are enzymes. If only one of a pair of genes will code for an adequate amount of a specific functioning protein or enzyme, then a mutation would create a recessive gene and the heterozygous state would have no disease. 

If we are to understand familial hypercholesterolaemia, FH, we must be aware of the recessive gene with partial penetration. In heterozygous FH with one abnormal gene there is moderate elevation of serum cholesterol and an increased risk of age-related CHD death. But in homozygous FH, when both genes of the pair are abnormal, there is much more important genetic abnormality, with a very high cholesterol and a very high risk of early death from CHD. This means that in families with FH all offspring will have an elevated cholesterol, but some higher than others.

But do not forget that this genetic “abnormality” was, before the epidemic of CHD, a significant evolutionary step forward giving an important survival advantage.

Further details of the inheritance of Familial Hyercholesterolaemia and also Sickle Cell Disease will follow in a further Blog Post.