Coronary artery disease

Coronary artery disease is narrowing of the heart's arteries, the main cause of heart attacks. This score sums many common variants affecting that risk.

What this coronary artery disease score reads

This is PGS004321, a 27-variant score applied by Marston and colleagues in a 2019 Circulation analysis of the FOURIER trial. Its two largest weights are both in LPA, the gene that sets lipoprotein(a) levels, followed by the 9p21 locus and SORT1.

That composition tells you what kind of score it is. Rather than thousands of tiny effects, it is a short list of the strongest known common signals, which makes it interpretable and means it captures much less of the genetic picture than modern scores built from millions of variants.

How well it predicts coronary events

In the placebo arm of FOURIER (14,298 people), a high score carried a hazard ratio of 1.10 for major vascular events and 1.17 for major coronary events compared with a low score.

Those are modest numbers, and the population matters: FOURIER enrolled people who already had established atherosclerotic disease and were taking statins. A score measured in that setting says less about a healthy person's first heart attack than a general-population validation would.

The lipoprotein(a) part of this score, and why it is measurable

The two LPA variants carrying the largest weights here, rs3798220 and rs10455872, raise lipoprotein(a), a cholesterol-carrying particle that is largely genetically fixed and not much moved by diet or statins. Carriers of either variant have been reported at around 1.5 times the coronary risk of non-carriers.

The practical point is that lipoprotein(a) is a simple blood test, usually needed only once in a lifetime, and it measures the actual particle level rather than inferring it from two variants. If this score interests you at all, that measurement is the more informative version of the same question, and it is a reasonable thing to raise with a doctor, particularly with a family history of early heart disease.

What this score does not capture

Familial hypercholesterolemia, which affects roughly 1 in 250 people and carries a 3 to 10 fold risk of early coronary disease untreated, is caused by single variants in LDLR, APOB or PCSK9 and is not read here or by a consumer chip.

The conventional risk factors also sit outside the score and outweigh it. In a study of 55,685 people across three cohorts, among those in the highest fifth of genetic risk, a favourable lifestyle (not smoking, no obesity, regular activity, healthy diet) was associated with 46% lower relative risk of coronary events, with 10-year event rates of 5.1% against 10.7% for an unfavourable lifestyle.

Ancestry and accuracy

The GWAS behind this score was multi-ancestry but its validation was in a European-ancestry trial population, and the LPA variants that dominate it differ substantially in frequency across populations. A percentile computed outside that setting should be read loosely.

How much of this score your file covers

All 27 variants in the published score are present in a standard consumer DNA file, so this reconstructs the published score in full.

Common questions

Should I get a lipoprotein(a) test because of this score? It is a reasonable question for a doctor, especially with a family history of early heart disease. Lipoprotein(a) is measured directly from blood, stays roughly stable through life so one test usually suffices, and gives you the real value rather than a two-variant estimate of it.

Can lifestyle change offset a high coronary genetic score? The evidence says it substantially can. Among people at high genetic risk in a 55,685-person study, a favourable lifestyle was associated with 46% lower relative risk of coronary events. Genetic risk and lifestyle risk act largely independently, so one does not cancel the other but neither locks you in.

Why is this score built on only 27 variants? It was assembled from the strongest established signals for a clinical trial analysis, not to maximise prediction. Contemporary coronary scores use hundreds of thousands to millions of variants and separate risk groups more sharply, which is worth knowing when reading a percentile from this one.

Related

Colorectal cancer risk (8q24) · Coronary artery disease risk (9p21) · Crohn's disease susceptibility · Depression · Type 2 diabetes · Uric acid / gout tendency · Venous thromboembolism (clots)