Nearly a hundred positions here move cholesterol, and each one moves it a little. The two things worth knowing are that very high LDL almost never has a single-gene cause — fewer than 2 in 100 do — and that genetics worked out the HDL hypothesis was wrong years before the drug trials confirmed it.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Cholesterol is the most-measured number in medicine, and it is measured in four ways at once: LDL, HDL, triglycerides and a total. This page is about the first, the second and the fourth. Triglycerides have their own page.
The catalogue behind this page is one of the largest in human genetics. A 2010 study of more than 100,000 people reported 95 loci for blood lipids. A 2013 study of 188,577 people raised that to 157, 62 of them new. A 2015 study using 9.6 million imputed variants in 62,166 samples added the low-frequency ones the earlier arrays could not see.
Each position shifts cholesterol slightly. None of them is a diagnosis, and a blood test settles in one morning what a genotype can only estimate — including everything genetics cannot see, such as what you eat, what you weigh, and whether you are already taking a statin.
This is the finding most people have never heard, and it changes how the whole page should be read.
Familial hypercholesterolaemia is the inherited condition everyone means when they say cholesterol runs in the family: one broken copy of LDLR, APOB or PCSK9, lifelong high LDL, early heart disease. It is real, it is serious, and it is treatable.
It is also, in people with high LDL, rare. One study sequenced all three genes in 20,485 people who did not have coronary disease. 1,386 of them — 6.7% — had LDL cholesterol at or above 190 mg/dl, which is the threshold that gets called severe. Of those 1,386, the number carrying a familial hypercholesterolaemia mutation was 24.
That is 1.7%. Sequence the three famous genes in a hundred people with severely high cholesterol and you will explain fewer than two of them.
Largely, the positions on this page.
Among people who carry a clinical diagnosis of familial hypercholesterolaemia, about 60% have no mutation in any of the three genes. A 2015 study built a weighted score from just six common variants — in CELSR2, APOB, ABCG5/8, LDLR and APOE — and found it separated those mutation-negative patients from healthy controls. Their conclusion: in 88% of mutation-negative patients, the high cholesterol is likely to be polygenic.
This site holds variants in five of those six genes. rs12740374 near CELSR2, rs4420638 in the APOE region and rs2479409 near PCSK9 are all on the list below.
So the common variants are not a watered-down version of the real thing. For most people with a high number, they are the thing.
The other half of that same study, and it matters. At any given LDL level, someone who does carry a familial hypercholesterolaemia mutation has substantially higher coronary risk than someone with the same number who does not. The mutation is rare, and where it is present it counts for more than the reading alone shows. Which is why a strong family history of early heart disease is a reason to see a doctor, not a reason to read a page.
For decades HDL was "good cholesterol". People with more of it had fewer heart attacks — a large, consistent, repeatedly replicated observation. Drug companies spent a great deal of money on medicines that raised it.
Genetics got there first, and the instrument was a single variant.
People carrying one copy of a change in LIPG — about 2.6% of the population — have HDL cholesterol 0.14 mmol/L higher than non-carriers, and are no different in any other lipid or non-lipid risk factor. Because the allele is dealt out at conception rather than chosen, it is as close to a randomised trial as observation gets.
From the observational relationship, that much extra HDL should reduce heart attacks by about 13% (odds ratio 0.87). The measured effect, across 20,913 heart attack cases and 95,407 controls, was an odds ratio of 0.99 — confidence interval 0.88 to 1.11, p = 0.85. No effect at all. A score built from 14 HDL-only variants gave the same answer.
Meanwhile, in plain observation, one standard deviation more HDL still tracked with an odds ratio of 0.62.
Both numbers are correct. HDL marks lower risk and does not cause it. Later trials of HDL-raising drugs found what the genetics had already implied. If you want one example of the difference between a marker and a cause, this is the best one on this site.
The HDL variants below — rs3764261 near CETP, rs1883025 in ABCA1 and the rest — should be read in that light. They move a number reliably. What that number does is a separate question, and for HDL the answer turned out to be less than everyone assumed.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Cholesterol (LDL, HDL and Total) comes down to these specific, well-studied positions — not a diagnosis. 96 positions are linked to this page; the ones this page's own text discusses are shown first.
Databases, guidelines and references
No. A blood test measures it directly, costs very little, and captures every influence genetics cannot see — diet, weight, exercise, other conditions and any medicine you already take. The variants here shift the average by small amounts and cannot substitute for a measurement.
Usually not. In one study of 20,485 adults, 1,386 had LDL cholesterol at or above 190 mg/dl and only 24 of them — 1.7% — carried a familial hypercholesterolaemia mutation. High cholesterol is common; the single-gene cause is rare. A strong family history of early heart disease is the reason to ask a doctor about testing.
For most people, many common variants each adding a little, on top of diet, weight and age. Among people with a clinical familial hypercholesterolaemia diagnosis but no mutation, one study found the raised LDL was likely polygenic in 88% of cases, and a score of six common variants was enough to show it.
It marks lower heart attack risk but does not appear to cause it. Carriers of an HDL-raising variant in LIPG have the higher HDL and not the lower risk: the expected odds ratio was 0.87 and the measured one was 0.99. Drug trials that raised HDL later found the same. The phrase is worth retiring.
No. Whether to take a statin is a decision about overall cardiovascular risk, made with a doctor from your measured cholesterol, blood pressure, age and history. Genetics has something useful to say about statin side effects rather than about starting one — see the SLCO1B1 page.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.