Coagulation factor XI--discovery to therapeutics

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Certain GWAS findings, though not striking themselves, often open doors to literature that are fascinating and enlightening. Let's talk about factor 11, a coagulation factor, which is one of the hits in the recent stroke GWAS. 🧵 twitter.com/StrokeGenetics/status/1575841148878278656?s=20&t=A_3j6FJvrPsGllkYTd1lwg

Gene F11 codes for coagulation factor X1 that participates in the intrinsic pathway of coagulation cascade, a series of enzymatic activation of coagulation proteins that results in the formation of blood clot. ncbi.nlm.nih.gov/books/NBK482253/

Hemophilia is a group of hereditary bleeding disorders caused by coagulation factors deficiency. Hemophilia, particularly type B, the poster child for X-linked recessive inheritance, is historically famous due to its existence in European royalty. en.wikipedia.org/wiki/Haemophilia

Unlike hemophilia A and B which are severe, hemophilia C, caused by factor XI deficiency is a milder form of bleeding disorder. It can be so mild that one can live their whole life normally without even knowing its existence.

Hemophilia C has a fascinating history. The disease was first reported by Robert Rosenthal in 1953 (hence the name Rosenthal syndrome) in an American Jewish family--a maternal uncle and 2 nieces--who all had a same clinical history: abnormal bleeding after dental extraction.

Hemophilia C is extremely common in Ashkenazi Jewish community. The prevalence is 1 in 450, compared to 1 in 10^6 worldwide. Most cases can be accounted by a handful of founder mutations that rose to high frequency due to endogamy. pubmed.ncbi.nlm.nih.gov/2813350/

Unlike hemophilia A and B, C is autosomal and affects males and females equally. Though initially it was believed that, like A and B, C is also a recessive disease, it later became apparent the bleeding tendency is not restricted to only homozygotes.

However, there is no correlation between factor XI genetic severity and bleeding tendency. It's not uncommon for a homozygote to bleed less and a heterozygote to bleed more. Other factors (genetic and environmental) substantially modify the penetrance of F11 mutations.

A highly fascinating clinical feature of factor XI deficiency is some patients, mostly homozygotes, can develop auto-antibodies to factor XI protein. This is typically triggered by a blood transfusion. pubmed.ncbi.nlm.nih.gov/3687930/

Since the immune system of such patients have never seen factor XI before, the factor XI in the donor blood triggers the immune system to produce anti-factor XI antibodies. So, this complicates the treatment. Such patients will require a treatment with recombinant factors.

More than the bleeding tendency (which is never life threatening), the fact that attracted scientists' attention to factor XI is the association of factor XI deficiency with reduced risk for venous thromboembolism and ischemic stroke.

This is also true for hemophilia A and B, but the important difference is the absence of life threatening bleeding associated severe deficiency of factor XI, which means you can therapeutically target it without concerns about bleeding.

Note, almost all of the F11 mutations mapped by studying hemophilia C patients are are loss-of-function in nature (obviously). Though it's clear that increased factor XI will increase the risk for thrombosis and infarction, a genetic evidence hasn't surfaced until recently.

That's where the GWAS enter the story. Among the protective disease associations, the strongest protective effect of F11 deficiency is seen for thromboembolism, and so, not surprisingly the first GWAS signal for F11 was found for VTE in 2013. onlinelibrary.wiley.com/doi/10.1002/gepi.21731

For stroke, scientists mapped the F11 signal even in the earlier GWAS (Malik et al 2018) by peeking below the GWAS P value threshold :)

However, F11 locus officially becomes a GWAS hit for stroke in the current paper that involved >200k cases and ~2 million controls. nature.com/articles/s41586-022-05165-3

Interestingly, the index fine-mapped variant sits not within F11 gene, but within its antisense RNA F11-AS1. I wonder if the variant increases the F11 expression by interfering with F11-AS1 and F11 interaction, like the CCR5 locus for HIV. twitter.com/doctorveera/status/1409189848070582282?s=20&t=ECdPohJ46gnlAXi1HoP4fQ

Never miss an opportunity to visualize and appreciate the how strong is a GWAS signal across a range of phenotypes. Here is a PheWAS results of rs4444878 from open targets.

But using GWAS to identify genetic variants that increase F11 is painfully slower as the diseases lie far downstream in the causal path. Easiest is to just study the genetic associations with F11 protein itself in the blood.

Here is a beautiful pQTL study for factor XI blood levels. It turns out the cis signal (chr 4) is only the second strongest. The first one is a signal in chr 3 near KNG1 that codes for kininogen 1, that is closely linked to F11 via coagulation pathways. ncbi.nlm.nih.gov/pmc/articles/PMC5703348/

F11 is another example where trans signal trumps cis signal due to strongly heritable proteins linked closely via biological pathways. twitter.com/doctorveera/status/1567368017285365761?s=20&t=ECdPohJ46gnlAXi1HoP4fQ

By using the identified pQTLs as genetic instruments scientists have already established the genetic evidence that higher F11 levels increases the risk for ischemic stroke (and also VTE). ahajournals.org/doi/10.1161/STROKEAHA.118.022792

It's nice to see all these genetic evidence surface, but drug developers are way ahead in the pipelines. Many clinical trials are ongoing as we speak to test the efficacy and safety of F11 inhibitors in the treatment of stroke and other related diseases.

Nevertheless, as a human geneticist I simply enjoy just observing the genetic discoveries as they unfold over time confirming the known F11 associations and possibly revealing new genetic mechanisms.

To conclude, F11 is a fascinating gene with history that spans from Mendelian disease all the way to population genetics and a great example of a drug target inspired by human genetics.