Fibrinogen is one of the oldest predictors of heart disease there is, and a third to a half of the difference between people is inherited. Genetics has found more than forty places that move it — and no strong evidence that moving it changes cardiovascular risk at all.
What this condition connects to
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.
Prevalence
Heritability of plasma fibrinogen concentration is estimated at 34% to 50%. A multiethnic meta-analysis of 28 genome-wide studies in more than 90,000 people of European ancestry, plus 8,289 black participants and a Hispanic study, identified 23 fibrinogen-associated loci and found no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease (Sabater-Lleal et al., Circulation 2013, PMID 23969696). A meta-analysis of 34 studies in 120,246 individuals across about 10.7 million variants, with X-chromosome data in 95,806, identified 18 further loci (de Vries et al., Human Molecular Genetics 2016, PMID 26561523).
Inheritance
Common variants, each shifting a measured clotting protein slightly, on a trait that is a third to a half heritable. Distinct from the inherited thrombophilias — Factor V Leiden, prothrombin G20210A, antithrombin, protein C and protein S deficiency — which act on clot risk directly and are tested for by name.
Fibrinogen is the protein a clot is built from. Thrombin converts it to fibrin, fibrin forms the mesh, and the mesh plus platelets is what stops a bleed. Its concentration in blood is measured routinely, varies a great deal between people, and predicts cardiovascular disease.
A third to a half of it is inherited
Estimates of the heritability of plasma fibrinogen concentration run from 34% to 50%. A multiethnic meta-analysis of 28 studies in more than 90,000 people of European ancestry — together with the first such analysis in black participants, at 8,289 samples, and one in Hispanic participants — identified 23 loci. A later analysis of 34 studies and 120,246 individuals, using better imputation across about 10.7 million variants and reading the X chromosome in 95,806 of them, added 18 more.
And then the sentence in the title
The 2013 paper that found those 23 loci put its conclusion in its own title: 23 fibrinogen-associated loci, but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
Fibrinogen predicts heart attacks. It has done so consistently for decades. What the genetics could not find was evidence that the level itself is doing the damage.
This is the third time on this site, from three unrelated directions.HDL cholesterol predicts lower heart attack risk and the variants that raise it do not lower the risk. Several of the blood cell indices track cardiovascular disease and the same analysis found those associations may not be causal. Now fibrinogen. Three separate measurements, three real predictions, and in none of them does the number appear to be the thing that acts.
The repetition is not a coincidence. A quantity that rises with inflammation, with age and with being unwell will predict bad outcomes whether or not it causes any of them. That is worth carrying away from this page even if you never look at a variant.
What is genuinely causal, for contrast
Clotting genetics does contain variants that act rather than merely mark. Factor V Leiden is a single common change that makes a clotting factor resistant to being switched off, and it raises the risk of venous clots substantially. It is on this site, on its own page, and it is the right thing to compare the fibrinogen variants against.
Both are "clotting genetics". One changes a number that predicts disease. The other changes the disease.
Clinical detail
The genes here, and what they are
FGB and FGG — two of the three chains fibrinogen is built from. Variants in the genes for a protein changing the amount of that protein is the least surprising result on the page, and it is a useful sanity check that the method works.
F7, F3, F13A1 — factor VII, tissue factor and factor XIII, all part of the cascade that ends in a clot. These appear under end-stage coagulation and D-dimer rather than under fibrinogen level.
PLG — plasminogen, which is the other direction: the system that dissolves a clot once it has done its job.
Where clotting genetics does reach a disease
The EuroCLOT study took variants associated with end-stage coagulation and fibrin structure in 2,100 healthy twins and tested them in 4,200 cases of ischaemic stroke. The locus that came through was ABO — the blood group gene, which this site covers on its own page and which turns up in more places than anyone expects.
So the honest summary of this page is not that clotting genetics is empty. It is that the routinely measured number and the disease are connected by less than the correlation suggests, and that where a real connection has been found it ran through a different gene than the one being measured.
What this page cannot do
It cannot tell you your fibrinogen level. A blood test does, and it captures inflammation, infection, pregnancy, smoking and age — all of which move it, and none of which are genetic.
It cannot assess your clotting risk. If clots run in your family, the useful questions are about Factor V Leiden, prothrombin G20210A and the rarer inherited thrombophilias, tested for directly.
It cannot be read as a reason to lower fibrinogen. That is precisely the inference the causality result argues against.
Related variants MyGeneLog checks for
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Fibrinogen and Blood Clotting comes down to these specific, well-studied positions — not a diagnosis. 46 positions are linked to this page; the ones this page's own text discusses are shown first.
Annals of neurology · 2013 · PMID 23381943 · open access
Frequently asked questions
My fibrinogen was high. Does that mean I am at risk of a heart attack?
High fibrinogen does predict cardiovascular disease, consistently and over decades. What genetics has not found is evidence that the level itself causes it: a large multiethnic study reported 23 loci and no strong evidence of a causal association. It is also raised by inflammation, infection, pregnancy, smoking and age, so the number is best interpreted by a doctor who knows the rest of the picture.
Should I try to lower my fibrinogen?
That is exactly the inference the causality result argues against. Nothing here supports treating a number whose own genetics does not show it acting. The things that lower it — not smoking, treating infection and inflammation — are worth doing for their own reasons.
Is any clotting genetics actually causal?
Yes, and this site has it. Factor V Leiden is a single common change that makes a clotting factor resistant to being switched off and substantially raises the risk of venous clots. It is the right contrast to the variants on this page, which move a measurement rather than a disease.
Why does ABO keep coming up?
Because it is one of the most pleiotropic loci in the genome. In the EuroCLOT study, coagulation variants found in 2,100 healthy twins were tested in 4,200 ischaemic stroke cases and ABO was the locus that came through. It also appears in studies of cancer, infection and lipids, and the mechanism is not one thing.
Is this evidence only from people of European ancestry?
Mostly, but less so than usual here. The 2013 meta-analysis included the first genome-wide fibrinogen analysis in black participants, at 8,289 samples, and one in Hispanic participants alongside the European-ancestry studies.
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