Why are we using association studies in 2024?
A rant on the topic:
There has been over 80 years of research on cardiovascular disease, before that infectious disease was much more important to tackle.
At the start that was important, which the Framingham Heart study in the 1950’s showed that total cholesterol was significantly associated with heart disease, funding started because of a president getting a stroke. Along that researchers found in the study associations for obesity, smoking, high blood pressure, (Lipoproteins like LDL and HDL was just starting to get measured with expensive centrifuges). Mechanistically cholesterol was also found in plaque and rabbits fed cholesterol developed disease (mice did not, but they apparently don’t have any LDL).
So by 1950’s we know mechanistic reason (cholesterol in plaque, feeding rabbits), and association (Framingham Heart study), a few decades later they found people with FH and higher total cholesterol developed disease much quicker – in their 30’s getting the first heart attack, and for those with more deleterious variants with TC up to 1000 mg/dl – in their teens.
So by the 1970’s we had mechanistic, association, and genetic studies. Race was on to develop drugs to lower cholesterol. Many weren’t that effective and then eventually statins were developed to inhibit HMGCR which would really slow down cholesterol synthesis which they found out it was a slow step in the synthesis of cholesterol. Massive blockbuster drugs, except the moronic skeptics with unpersuasive arguments for the intelligent started publishing books in the 80’s trying to refute the cholesterol hypothesis, which dampened statin sales.
Eventually large clinical trials were done showing that using statins PREVENTED heart disease – stroke, heart attacks, and as such, even lowered mortality (4S study). Which shouldn’t have been so unsurprising, but before that drugs had more side effects.
So we have mechanistic, association, genetic, and clinical trial evidence of one of the few PREVENTION drugs and strategies, this is medicine at its finest. Then the genomic revolution happens and we have so many genes to find even more genetic evidence and over longer periods, that strengthens the causality even further and shows the compounding effects of lowering early for preventing cardiovascular disease.
The LDL cholesterol deniers are literally the dumbest people in the world. There has been so much research, effort, evidence, markets and insurance signaling, that LDL cholesterol matters, by a lot. I have to say, people don’t have to do anything, just eat popcorn, I will and witness and know that these people are absolute fools. 
