Three of the positions here were found by asking three different questions — who develops furred arteries, who has a heart attack early, and who has a heart attack given furred arteries. The answers were not the same genes, which is the most useful thing this page has to say.
Coronary artery disease is the narrowing of the vessels that feed the heart, and a heart attack is what happens when one of them closes. Those are two events, not one, and the genetics has been able to tell them apart — which is unusual and worth the page on its own.
A 2011 study did something clever: instead of comparing people with heart disease against everyone else, it used coronary angiograms to ask two separate questions. Who develops coronary atherosclerosis at all (12,393 with it against 7,383 without)? And among people who already have it, who goes on to have a heart attack (5,783 against 3,644)?
The answers differed. rs1994016, near ADAMTS7, came out of the first question — the disease of the artery wall itself. ADAMTS7 encodes an enzyme that acts on the matrix around vascular smooth muscle cells, which is the tissue that thickens as a plaque grows.
The other two came from studies of heart attack. rs12526453 (PHACTR1) and rs1746048 (near CXCL12) were both identified in a genome-wide study of early-onset myocardial infarction — 2,967 cases against 3,075 controls, with replication in up to 19,492 more — where nine loci reached significance and these were among them.
Modest, and the field says so plainly. The largest meta-analysis of its era combined 22,233 cases and 64,762 controls and then tested the top hits in 56,682 more people. It found 13 new loci, each raising risk by 6% to 17% per copy.
Two details from that paper are worth keeping. Only three of the thirteen were associated with traditional risk factors — cholesterol, blood pressure, diabetes — so most of them act through something the standard clinic measurements do not see. And most sat in regions nobody had previously connected to the disease at all.
The things you can measure: blood pressure, cholesterol, smoking, diabetes, weight, activity, age, and family history — which captures the genetics without needing any of it sequenced. Risk calculators built on those are what clinics use, and adding common variants to them has produced small improvements at best.
Nothing on this page changes a statin decision, a blood-pressure target, or whether chest pain needs seeing today. Chest pain that is new, severe or comes with breathlessness or sweating is an emergency, and no genotype is relevant to that call.
Distinguishing atherosclerosis from infarction. The 2011 Lancet analysis used angiographic phenotyping to separate two comparisons: individuals with angiographic CAD (n = 12,393) against controls without it (n = 7,383), and, within those with CAD, those who had had a myocardial infarction (n = 5,783) against those who had not (n = 3,644). ADAMTS7 emerged from the first comparison (P = 4.98 x 10-13) — a locus for the arterial disease rather than for the event — while ABO was associated with infarction in the presence of atherosclerosis. That design is why this page treats plaque and thrombosis as distinct phenotypes.
Early-onset myocardial infarction. Kathiresan et al. tested SNPs and copy number variants in 2,967 early-onset MI cases and 3,075 controls with replication in an effective sample of up to 19,492. Nine loci reached genome-wide significance: three new (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1, 2q33 in WDR12) and six replicating earlier work (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR, 1p32 near PCSK9). No common copy number polymorphism met the replication threshold, and rare CNV burden did not differ between cases and controls.
Scale and effect size. The CARDIoGRAM meta-analysis of 14 GWAS (22,233 cases, 64,762 controls, plus 56,682 in follow-up genotyping) identified 13 new CAD loci and confirmed 10 of 12 previously reported. Risk allele frequencies ranged 0.13-0.91 with per-allele risk increases of 6-17%. Only three of the new loci showed significant association with traditional risk factors, and five showed pleiotropy with other diseases or traits.
Clinical position. Risk assessment uses validated equations built on age, sex, lipids, blood pressure, smoking and diabetes, with family history as a modifier. Polygenic scores for CAD have been studied extensively and are not part of standard guidelines; where they add discrimination it is incremental. Secondary prevention, revascularisation and acute management are unaffected by any variant on this page.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Coronary Artery Disease comes down to these specific, well-studied positions — not a diagnosis.
Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| CYP2C19 | Clopidogrel | One of the few gene-drug pairs where a guideline names a different medicine. Clopidogrel is a prodrug — it does nothing until CYP2C19 converts it into the molecule that actually keeps platelets from clumping. People carrying no-function alleles (CYP2C19*2 and *3 are the common ones) make less of that active metabolite, and CPIC reports that intermediate and poor metabolisers on clopidogrel have reduced platelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Where an alternative antiplatelet is not contraindicated, CPIC recommends using one. The 2022 update strengthened the recommendation for intermediate metabolisers and widened the indications it covers. This is a conversation for the cardiologist who prescribed it, not a reason to stop taking anything: stopping an antiplatelet after a stent is dangerous in a way this genotype is not. (CPIC Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update, Clinical Pharmacology & Therapeutics (PMID 35034351)) |
No. Each shifts risk by a few per cent per copy, against risk factors that move it far more and that can be changed. Blood pressure, cholesterol, smoking and diabetes are where the leverage is.
Because they are the same disease asked about in three ways: who develops furred arteries, who has an early heart attack, and who has a heart attack given furred arteries. Keeping them apart would suggest three conditions where there is one process with different endpoints.
It is not part of any standard guideline. The equations clinics use — age, cholesterol, blood pressure, smoking, diabetes, family history — already capture most of what can be predicted, and adding common variants improves them modestly at best.
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