Familial hypercholesterolaemia (FH) is a common genetic disease. That says something quite profound to me. If it is both genetic and common there cannot be too strong a disadvantage to it on an evolutionary basis. There are also lots and lots and lots of variants. All affect the LDL-C receptor. If you get one copy of any one of a large selection of defective receptor genes, you have quite high levels of cholesterol in your blood and... well, you know the story about clogged arteries and heart attacks. In fact, if LDL-C is such lethal stuff you would have thought that evolution would not have been so careless with the stability of the crucial piece of DNA coding for its receptor. But it wasn't careful and there are a myriad of FH variant genes. Oddly enough people in the 1800s with FH lived as long as, or even longer than, "normal" people, check out the Dutch pedigree and Utah pedigree studies.
Now this is interesting. In 1807 LDL-C at above normal levels was beneficial, particularly in Holland. In 2007 it is an automatic statin deficiency and don't try to get life insurance. What's going on?
If you ask a cardiologist about the function of the LDL-C receptor you will find that it is used by the liver to mop up that horribly artery clogging LDL-C before the patient secumbs. However, there are LDL-C receptors in other places than the liver. Such as on the endothelial cells lining the arteries. If FH sufferers have non functional receptors in their livers I am willing to bet they have poor receptors on their endothelial cells too. But wait a minute, this should be good! If you have reduced receptors you should have reduced stickiness and LESS clogging of the arteries.
But there again, the receptor is normally present and evolution does not go to the effort of building a complex structure just for the fun of wasting protein resources. No, that receptor is there for a reason, and that reason is to stick LDL-C to endothelial cells when they need it. Interestingly, isolated endothelial cells produce lots of LDL-C receptors, where as endothelial cells in contact with their brethren don't. The conclusion from this is that in areas of damage, the endothelial cells are isolated and express lots of receptors which cry out for cholesterol. In FH they don't get the cholesterol they need because the receptors don't work. Cell repair is difficult without a handy supply of lipids.
So, if you had to suggest what sort of problem might be caused by a defective cholesterol receptor, then vascular problems might be a good guess. Possibly heart attack.
NB What do you think might happen if you got two genes for a defective LDL-C receptor? This is homozygous FH. It's bad. You can see why.
So why wasn't heart attack common in FH carriers in 1807? How common was sugar in 1807? Not very. Perhaps there is a link here.
Just a minute. Where did all of that cholesterol come from in the arteries of modern sufferers? Well, you can stick LDL-C to vascular tissue with things other than the apoB-100 receptor. Try the LOX1 receptor for a start. This binds oxidised LDL-C rather nicely. Oxidised cholesterol is seriously nasty stuff. What oxidises cholesterol in your bloodstream? Try fruit and vegetables. Try sugar. Try a low fat diet. My guess is that these were thin on the ground in 1807 in Utah or Holland.