Markers / Condition
Which genes affect heart disease and cholesterol?
Most genetic risk for heart disease is spread thinly across many variants, but a handful stand out, and two of them point at things a standard cholesterol panel does not measure. Lipoprotein(a) is set almost entirely by genetics and barely moves with diet or statins, and most people are never tested for it.
The markers
| Marker | Gene | What it does | Evidence |
|---|---|---|---|
| rs4977574 | CDKN2B-AS1 | The 9p21 heart disease locus | established |
| rs3798220 | LPA | Lipoprotein(a), the cholesterol nobody measures | established |
| rs12740374 | SORT1 | SORT1, the LDL variant whose mechanism was actually solved | established |
| rs662799 | APOA5 | Triglycerides, and how sharply they respond to diet | established |
| rs1799983 | NOS3 | The enzyme that tells blood vessels to relax | moderate |
| rs5186 | AGTR1 | The salt-and-water system, and why it now works against us | moderate |
| rs2228145 | IL6R | The interleukin-6 receptor, and a drug target found by genetics | established |
| rs1205 | CRP | Your baseline C-reactive protein | established |
The 9p21 heart disease locus
rs4977574 · CDKN2B-AS1
The first common variant ever linked to coronary artery disease, and still one of the strongest. Remarkably, it acts independently of cholesterol, blood pressure, diabetes and smoking, which is why it was missed for so long.
Two copies: Two higher-risk copies, roughly 1.5 times the background risk
Lipoprotein(a), the cholesterol nobody measures
rs3798220 · LPA
Lp(a) is a cholesterol-carrying particle whose level is set almost entirely by genetics and barely moves with diet, exercise or statins. High Lp(a) is a genuinely independent risk factor for heart disease, and it is not on a standard cholesterol panel unless you ask.
Two copies: Two copies, and an Lp(a) blood test is the clear next step
SORT1, the LDL variant whose mechanism was actually solved
rs12740374 · SORT1
Most common variants are found by statistics and their mechanism stays unknown. This one was chased all the way down: it creates a binding site for a liver transcription factor, changing how much SORT1 the liver makes, which changes how much LDL cholesterol the liver clears.
Two copies: You have the lower-LDL version on both copies
Triglycerides, and how sharply they respond to diet
rs662799 · APOA5
APOA5 controls how fast triglyceride-rich particles are cleared from blood. The variant version clears them more slowly, and it is around three times more common in East Asian than European populations, which is part of why triglyceride patterns differ between them.
Two copies: You have the slower-clearing version on both copies
The enzyme that tells blood vessels to relax
rs1799983 · NOS3
NOS3 makes nitric oxide in the lining of your blood vessels, which is the signal that widens them. It is the pathway nitrate-rich foods like beetroot act on, and the one that several blood pressure drugs work through.
Two copies: You have the variant version on both copies
The salt-and-water system, and why it now works against us
rs5186 · AGTR1
The renin-angiotensin system evolved to hold on to salt and water, which was the right instinct for almost all of human history. In an environment of abundant salt it contributes to high blood pressure, and it is the system that ACE inhibitors and angiotensin blockers act on.
Two copies: You have the variant version on both copies
The interleukin-6 receptor, and a drug target found by genetics
rs2228145 · IL6R
IL-6 is a central inflammation signal. This variant shifts receptors off cell surfaces into the blood, which dampens the signal, and carriers have a slightly lower risk of coronary heart disease. That finding is a large part of why IL-6 blockade was pursued as a heart drug at all.
Two copies: You carry two copies
Your baseline C-reactive protein
rs1205 · CRP
CRP is the inflammation marker most often measured in a blood test. Part of your baseline is genetic rather than a reflection of how inflamed you are, which matters when a doctor reads the number.
Two copies: You have the lower-CRP version on both copies
Which versions do you carry?
All of these are readable from an ordinary home DNA test file, in your browser, without uploading it anywhere.
Read my fileCommon questions
Which genes affect heart disease and cholesterol?
Most genetic risk for heart disease is spread thinly across many variants, but a handful stand out, and two of them point at things a standard cholesterol panel does not measure. Lipoprotein(a) is set almost entirely by genetics and barely moves with diet or statins, and most people are never tested for it. The markers most often cited are rs4977574 in CDKN2B-AS1, rs3798220 in LPA, rs12740374 in SORT1, rs662799 in APOA5, rs1799983 in NOS3.
What does rs4977574 do?
The first common variant ever linked to coronary artery disease, and still one of the strongest. Remarkably, it acts independently of cholesterol, blood pressure, diabetes and smoking, which is why it was missed for so long. Carrying two copies: two higher-risk copies, roughly 1.5 times the background risk.
What does rs3798220 do?
Lp(a) is a cholesterol-carrying particle whose level is set almost entirely by genetics and barely moves with diet, exercise or statins. High Lp(a) is a genuinely independent risk factor for heart disease, and it is not on a standard cholesterol panel unless you ask. Carrying two copies: two copies, and an lp(a) blood test is the clear next step.
What does rs12740374 do?
Most common variants are found by statistics and their mechanism stays unknown. This one was chased all the way down: it creates a binding site for a liver transcription factor, changing how much SORT1 the liver makes, which changes how much LDL cholesterol the liver clears. Carrying two copies: you have the lower-ldl version on both copies.
What does rs662799 do?
APOA5 controls how fast triglyceride-rich particles are cleared from blood. The variant version clears them more slowly, and it is around three times more common in East Asian than European populations, which is part of why triglyceride patterns differ between them. Carrying two copies: you have the slower-clearing version on both copies.
Reference information, not medical advice and not a diagnosis. See the medical disclaimer.