Familial hypercholesterolemia and statins

Perhaps the most dramatic example of monogenic diseases leading to treatments for common disease concerns familial hypercholesterolemia (FH) and the development of statins (Goldstein et al., 2001). FH is a relatively common dominant condition affecting 1:500 of the population. Individuals with FH have high levels of cholesterol at birth and will develop atherosclerosis and vascular disease in childhood. The risk of fatal heart disease before the age of 40 years is significantly higher than among the general population. Approximately one-third of patients with FH show no symptoms until sudden cardiac death.

Through the pioneering work of Brown and Goldstein, we know that FH is caused by loss of function mutations in the LDL receptor gene (LDLR). The LDL receptor removes cholesterol from the blood stream. This piece of genetic detective work proved that high cholesterol is the cause of coronary disease in these patients. Extrapolating from this monogenic condition, these findings provide incontestable support for the epidemiological studies showing that high cholesterol is associated with coronary artery disease in the general population.

Brown and Goldstein argued that if cholesterol levels could be lowered in children with FH, this might prevent disease onset. To do this they screened for drugs that would inhibit the enzyme, HMGCoA reductase, which synthesizes most of the circulating cholesterol in the liver. This screen led to the identification and production of statins which reduced cholesterol levels in patients with FH and essentially cured them. Now of course statins are used to lower cholesterol levels in people at increased risk of coronary disease in the general population. Hopefully this remarkable success story is a harbinger of many more such developments in the future.

Familial hypercholesterolemia as a model for the way environmental factors working together with single gene mutations modify phenotype

In a remarkable study, Sijbrands et al. (2001) were able to analyse the mortality rates associated with FH in a large Netherlands pedigree over the course of 200 years. The starting point was three probands who had mean fasting levels of serum cholesterol of 10.2, 9.2 and 12.8 mmol/l, respectively. All carried a V408M mutation on an identical haplotype suggesting they were distantly related. All maternal and paternal ancestors of the three carriers were traced and one pair of ancestors connecting all three probands was identified. Secondly, the descendents of this pair were traced and all living descendents were screened for V408M. The main finding as shown in Figure 10.1 was that mortality rates for individuals with this mutation varied dramatically over two centuries. In fact, mortality prior to the beginning of the twentieth century did not differ significantly from standard mortality rates and most individuals with the mutation had a normal life span. It was only during the twentieth century that mortality rates of carriers increased dramatically over the standard rate. The increase in mortality in the twentieth century is likely to have been caused by environmental factors such as smoking and high fat diet working in conjunction with the LDL receptor mutation.

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