July 31, 2025 • 16 mins
🎙️ Episode 92: Genetic Loss of CFHR5 Function Protects Against Age-Related Macular Degeneration
🧬 In this episode of PaperCast Base by Base, we explore a genome‑wide association and fine‑mapping study in a Finnish cohort that identifies CFHR5 loss‑of‑function variants as independent protective factors against age‑related macular degeneration and investigates their impact on complement activation and retinal structure.
🔍 Study Highlights:
The researchers performed association testing, statistical finemapping, and conditional analyses in 12,495 AMD cases and 461,686 controls to resolve four major protective CFH locus haplotypes, two of which are driven by CFHR5 frameshift and missense variants. Through a recall‑by‑genotype study, carriers of CFHR5 loss‑of‑function variants were shown to have dose‑dependent reductions in circulating FHR‑5, FHR‑2, and FHR‑4 protein levels measured by SomaScan and Western blot. Functional assays demonstrated that homozygous carriers of CFHR5 frameshift variants exhibit increased classical and alternative complement pathway activation capacities, consistent with enhanced retinal debris clearance. OCT imaging analyses revealed that these carriers present photoreceptor layer thickness changes associated with reduced AMD risk.
🧠Conclusion:
Therapeutic downregulation of FHR‑5 may offer a promising strategy to prevent or treat AMD by modulating complement activation.
đź“– Reference:
Reeve MP, Loomis S, Nissilä E, Soare TW, Rausch T, Zheng Z, Della Briotta Parolo P, Ben‑Isvy D, Aho E, Cesetti E, Okunuki Y, McLaughlin H, Mäkelä J, FinnGen*, Kurki M, Talkowski ME, Korbel JO, Connor K, Meri S, Daly MJ & Runz H. Loss of CFHR5 function reduces the risk for age‑related macular degeneration. Nature Communications. 2025;16:5766. doi:10.1038/s41467-025-61193-3
đź“ś License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Imagine losing the ability to
recognize faces, maybe read a books or even drive.
Not, you know, all at once, but slowly, steadily, as your
central vision just blurs and fades away.
This isn't some far off scenario.
It's unfortunately the reality for millions of people as they
get older. They're battling a condition
(00:36):
where, well, the most common form is still stubbornly
untreatable. We're talking about age-related
macular degeneration, or AMD. It's a huge cause of
irreversible blindness affectingmaybe one in five people over 90
in Western countries. Now, there are some pretty good
treatments for the less common wet form of AMD, but the much,
much more common dry AMD, You know the kind with drusen
(00:58):
buildup and photoreceptor cells dying off.
That's like the massive gap, a real unmet medical need.
But what if the key to preventing or maybe even
treating this wasn't about adding something new, but
actually about taking something away?
A really groundbreaking deep dive into our own genes has
pointed towards just such an unexpected and honestly pretty
promising path. And the team that sort of
cracked this genetic puzzle, giving us this really surprising
(01:20):
answer, was this huge international collaboration.
So today we really want to celebrate the significant work
of Mary Pat Reeves, Stephanie Loomis, and just a large team
from places like the Institute for Molecular Medicine, Finland,
Mass General Hospital, the BroadInstitute, Biogen Inc, and many
others. They've collectively pushed our
understanding of AMD forward right down to the fundamental
(01:40):
genetic and functional level. Yeah, absolutely.
So AMD at its core, it's this slow progressive loss of your
central vision. It happens because cells in the
retina start to die off, specifically the retinal pigment
epithelium, the RPE and the photoreceptor cells themselves.
And like you said, they're, they're the two main types, wet
and dry. Wet AMD, it's serious, yes,
(02:02):
often involves abnormal blood vessel growth, but we do have
treatments that work quite well.But dry AMD, that's the vast
majority of cases. It progresses with what's called
macular atrophy and the slow buildup of these deposits under
the retina called drusen. Now, what's really crucial to
grasp about AMD is its strong genetic component.
I mean, large studies, GWA studies have shown that up to
(02:24):
maybe 71% of someone's susceptibility to AMD is
actually heritable. 71%. Yeah, it's huge.
And get this a single region on our chromosomes right around the
complement factor H gene CFH that accounts for nearly 1/4 of
all that genetic risk. OK, so that CFH gene region is
clearly a major player. A massive player.
And that brings us right to the complement system.
(02:45):
Now many listeners will know this is a key part of our innate
immune defense. Its job is to clear out
pathages, cellular junk, things like that.
But in AMD, the problem is it's over activation or maybe just
dysregulation. It gets out of balance and
starts contributing to the damage in the retinal tissue.
So it's a system that's normallyhelpful but can go rogue in this
(03:05):
disease. Precisely.
It's a really delicate balance. You needed to clear debris early
on, but if it goes into OverDrive, it becomes
detrimental. And within the system you have
factor H or FH. That's the protein made by the
CFH gene. FH acts like a break, you know,
it inhibits complement activation, keeps it under
control. But then there are these other
genes right next door, CFH related genes one through 5 or
(03:26):
CFHR one to five. They make these FHR proteins.
And it's thought that these FHR proteins, especially FHR 5,
actually compete with factor H. Compete.
How so? They sort of counteract its
effect. They reduce factor HS braking
power which could allow the complement system to become more
active, potentially driving thatharmful information in the the
retina. It's this really complex
(03:47):
interplay in that CFH region that's made it so hard to figure
out. Right.
It sounds like a real genetic knot.
Yeah. So how did these researchers
actually managed to untangle it Figure out what's really going
on with CFHR 5 specifically? Well exactly the CFH region.
It was actually one of the very first disease spots found by G
where is way back in 2005, and since then it's only gotten more
(04:07):
complicated with more variance and structural changes linked to
AMD. People suspected CFHR 5 might be
involved, but pinning down its specific independent
contributions separate from everything else happening at
CFH, That's been the challenge until now.
OK. So that leads us to their
methods. They used Fingan, right, this
large biobank in Finland. Tell us a bit about how they
(04:29):
leverage that resource. Yes, Fingan was key.
Finland's population history involved what are called genetic
bottlenecks. This means there's generally
less genetic variation, or rather less hack low type
complexity compared to more mixed populations.
So that reduction in complexity makes it easier to find the
signal, the important variance. Exactly cuts down the genetic
(04:51):
noise and with over 12,000 AMD cases and, you know, hundreds of
thousands of controls, Fingan gave them the sheer statistical
power needed to see these effects clearly.
So a powerful cohort. What techniques did they
actually apply to it? They.
Used a really sophisticated toolkit, advanced computational
methods like association testing, statistical fine
(05:12):
mapping, conditional analysis. Basically, very smart
statistical approaches designed to tease apart those overlapping
genetic signals in the complex CFH region and isolate the
independent effects of specific variants.
OK, so they crunched the geneticdata, but they didn't just stop
there, did they? They wanted to see the real
world effects. No, absolutely not.
They did this really clever sample recall study.
(05:33):
They went back into Finngen and selected serum samples, blood
samples from 200 dry AMD patients and 200 controls, and
they were very careful to match these people based on age, sex
and crucially, their genetic status for key variants in CFH
and CFHR 5. And what do they do with those
samples? That's where the proteomics came
in. Using technologies like SOMA,
(05:55):
SCAN and OLINK, which can measure thousands of proteins at
once, they quantified the levelsof over 6600 different proteins
circulating in the blood, including of course factor H and
all the FHR proteins, FHR one through 5.
So they could directly link a specific genetic variant to the
actual amount of proteins routine someone had.
Precisely. Does the gene variant actually
change the protein level? That was a key question and.
(06:17):
Did they look at function too, not just levels?
They did. They moved on to functional
validation using complement activation assays.
They basically tested how well the complement system pathways,
the classical alternative and MBL lectin pathways could be
activated in these individual samples.
This allowed them to see if the genetic changes and the
(06:38):
resulting protein level changes actually impacted how this
crucial immune system pathway worked.
Wow. OK, Genetics, proteins,
function. Anything else?
One more. Crucial layer.
They connected it all back to the eye itself using optical
coherence tomography Oct imaging.
They used data from another large resource, the UK Biobank,
(06:58):
to look at the thickness of the retinal photoreceptor layers in
people carrying these key genetic variants.
So they could actually see if the genetics was linked to a
physical difference in the structure of the retina.
That's exactly right. It links the genetic finding
directly to eye structure, providing a really clear visual
endpoint. It was this incredibly
integrated, multi layered approach.
Really impressive. OK.
(07:19):
So a very thorough investigation.
What were the big results? What did they find?
Well, this comprehensive approach paid off.
They confirmed there are four major CFH haplotypes,
combinations of variants that protect against AMD.
But the really exciting part wasdigging deeper.
They found that two of these protective haplotypes were
strongly linked to specific rarevariants in the CFHR 5 gene,
(07:40):
particularly a frameshift variant enriched in fins, which
they called CFHR fives, and alsoa missense variant.
This was a breakthrough directlylinking protection to CFHR 5
itself. So CFHR 5 steps out of the
shadow of CFH? And what about the protein
levels? Did those variants affect FHR 5
protein? Dramatically, carriers of these
(08:01):
protective CFHR 5 variants showed what's called a dose
dependent reduction in their serum FHR 5.
Level those dependent meaning. Meaning if you had one copy of
the protective variant, your FHR5 levels were lower.
If you had two copies, they wereeven lower.
And incredibly. And people who are homozygous
for that frameshift variant. CFHR fives 2 copies.
FHR 5 protein was undetectable in their.
Blood undetectable. Wow.
(08:22):
Undetectable and interestingly, they also saw lower levels of
FHR 2 and FHR 4 in these individuals, suggesting maybe a
broader effect on these related proteins.
OK, so lists FHR 5 protein. Now you said FHR 5 might compete
with factor H, sort of taking the brakes off complement.
So less FHR 5 should mean more breaking, less complement
(08:44):
activation. That's what you might
intuitively think, right? But here's where it got really
fascinating and maybe a bit counterintuitive.
They found that this genetic reduction in FHR 5 actually
correlated with a higher capacity to activate the
classical and alternative complement pathway.
Higher activation, but isn't over activation the problem in
AMD? Exactly.
It seems paradoxical at first, but the thinking is perhaps with
(09:06):
less FHR 5 around interfering, the main inhibitor factor H
works fine, but the system overall becomes more efficient
at its unofficial job, clearing out that retinal debris before
it triggers the really damaging chronic inflammation.
It's like removing a specific bottleneck that was hindering a
useful process. OK.
So it's like boosting the good kind of complement activity, the
(09:26):
cleanup crew function. That seems to be the
implication, yes. A more efficient clearance
mechanism early on. And did this translate to
physical changes in the eye likeyou mentioned with the Oct
scans? It did.
When they analyzed the retinal imaging data from the UK
Biobank. People carrying these protective
CFHR 5 variants actually had a thicker retinal photoreceptor
(09:47):
layer. Thicker.
That sounds protective. It is that morphology, having a
thicker layer of those crucial light sensing cells, is directly
associated with protection from AMD.
It suggests these variants help maintain a healthier, more
robust retinal structure over a person's lifetime.
Were they absolutely sure this effect was just from CFHR 5 and
not tangled up with other known protective factors in that
(10:09):
region? They went to great lengths to
check that they did careful conditional analysis.
The protective effects of these CFHR 5 variants were shown to be
truly independent of other knownvariations at the CFH locus
itself. This includes things like the
large deletions in CFHR 1 and CFHR 3, or CFHR 1 and CFH 4,
which have been debated a lot inthis Finnish population.
(10:30):
Those deletions didn't seem to have a substantial independent
protective effect. The deep dive found no other
hidden genetic variants driving this.
It really pointed squarely at CFHR 5.
OK. That's very convincing.
And what about safety? If lowering AKR 5 is protective,
could targeting it cause problems elsewhere in the body?
That's always the critical question for potential drug
targets. They performed A Phenomenalite
(10:52):
association study, or FIAS in Fingan.
They basically scanned across thousands, 2404 other health
conditions and traits to see if the CFHR 5S variant was
associated with anything else, good or bad, and they found no
significant associations. Nothing popped up.
This lack of obvious adverse effects is really encouraging.
(11:13):
It suggests that targeting FHR 5might be a potentially safe
therapeutic strategy without major unintended consequences
elsewhere. So this incredible detective
work yielded some truly eye opening results.
Let's back this a bit. What does this all mean for how
we understand AMD and maybe moreimportantly, for potential
treatments? This feels like a big shift.
(11:34):
It really does. I mean, the clearest implication
is that therapeutically down regulating FHR 5 looks like a
very promising strategy either to prevent AMD in high risk
individuals or perhaps even treat it.
It firmly establishes CFHR 5 as an independent, important player
in AMD risk, and it suggests a different kind of therapeutic
approach. Instead of broadly blocking
(11:55):
complement, maybe we just need to reduce this one specific
protein, FHR 5, that seems to behindering the system's
protective functions. Right, so it's not about
shutting the whole system down, which we know we need for
immunity, but more like fine tuning it, removing a specific
impediment to let it work betterin the eye.
Exactly that. It reinforces this idea of the
complement system's delicate balance.
(12:16):
You know early on it's good for clearing debris, but if it gets
out of control it drives disease.
Lowering FHR 5 seems to tip the balance back towards that
beneficial debris clearance without letting it run wild into
damaging inflammation. It's optimization, not
elimination. And the way they untangled this
using Finnian, that must have implications for studying other
(12:37):
complex diseases too. Oh, absolutely.
It's a fantastic demonstration of the power of these large,
well phenotyped biobanks, especially those from
populations with reduced geneticcomplexity like Finns.
It shows how in value people they are for dissecting these
really challenging genetic regions.
It provides a kind of road map for tackling other complex
genetic puzzles. And another really interesting
(12:58):
finding was the additive protection.
They saw that people who are lucky enough to carry protective
variants in both CFH and CFHR 5 had even stronger protection
against AMD. So the benefits stack up.
It seems so. The combination offers enhanced
defense. This could be really important
down the line for, you know, identifying people at highest
risk or maybe even designing therapies that target multiple
(13:19):
points in the pathway for greater effect.
And you mentioned CFHR 5 looks like an attractive drug target
because lowering it doesn't seemto cause other problems.
That's huge for drug development, isn't?
It it's critical, identifying itas an allelic series gene where
different variants naturally lead to different levels of the
protein, including complete absence without apparent harm.
(13:39):
That's very encouraging. The lack of obvious safety
signals in that fiwas makes it areally compelling target, and
it's different from some currentAMD approaches that try to
broadly inhibit complement. Here the idea is to just reduce
the amount of this one protein FHR 5.
It's a more subtle approach, potentially with fewer side
effects. So where does the research go
next? What are the immediate next
(14:01):
steps scientifically or maybe even clinically?
Well, there's still a need to nail down the precise molecular
details. How exactly does lowering FHR 5
boost the good complement activity and protect the retina?
More research is needed there, but looking ahead, this
definitely opens the door to developing novel therapy things
like neutralizing antibodies designed to bind and block FHR
(14:24):
5, or perhaps oligonucleotide therapies that reduce its
production. And how would those be delivered
directly into the eye? That's another fascinating
angle. FHR 5 is mainly made in the
liver, not the eye, so there's this really intriguing
possibility that a treatment could be given systemically,
like an injection elsewhere in the body, rather than needing
repeated injections directly into the eye, which is how many
(14:46):
current wet AMD treatments work.That would be a huge advantage
for patients. That would be a game changer.
Are there limitations to consider from this study?
Of course, like any study, the recall study, while focused, was
still limited in size, so they couldn't analyze every rare
genetic combination. And importantly, because this
was primarily in the Finnish population, we need more studies
to confirm these findings hold true in people of other
(15:09):
ancestries. Genetics can vary.
Also, we need more longitudinal data following people over time
with retinal scans to really understand who would benefit
most from lowering FHR 5 and whether it's best for prevention
or for treating established disease.
But even with those caveats, thedirection this points is
extremely promising. OK, so wrapping this up, what
does this all mean for you, for our listeners, and potentially
(15:30):
for the millions affected by AMD?
Well, this deep dive really shows that a specific genetic
tweak, a loss of function in theCFHR 5 gene leading to less FHR
5 protein, gives significant protection against age-related
macular degeneration. It seems to work by letting the
body's own complement system do a better job of cleaning up
cellular debris in the eye and by helping maintain a healthier
(15:53):
retina. It's a groundbreaking insight
that points towards a completelynew and potentially safer
therapeutic path for AMD. So what does this mean for the
future of eye care and maybe howwe think about precision
medicine for preventing age-related diseases more
broadly? It really makes you think.
This episode was based on an Open Access article under the
CCBY 4 Point O license. You can find a direct link to
(16:14):
the paper and the license in ourepisode description.
If you enjoyed this analysis, the best way to support Base by
Base is to subscribe or follow in your favorite podcast app and
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show. Thanks for listening and join us
next time as we explore more science base by base.
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Imagine losing the ability to
recognize faces, maybe read a books or even drive.
Not, you know, all at once, but slowly, steadily, as your
central vision just blurs and fades away.
This isn't some far off scenario.
It's unfortunately the reality for millions of people as they
get older. They're battling a condition
(00:36):
where, well, the most common form is still stubbornly
untreatable. We're talking about age-related
macular degeneration, or AMD. It's a huge cause of
irreversible blindness affectingmaybe one in five people over 90
in Western countries. Now, there are some pretty good
treatments for the less common wet form of AMD, but the much,
much more common dry AMD, You know the kind with drusen
(00:58):
buildup and photoreceptor cells dying off.
That's like the massive gap, a real unmet medical need.
But what if the key to preventing or maybe even
treating this wasn't about adding something new, but
actually about taking something away?
A really groundbreaking deep dive into our own genes has
pointed towards just such an unexpected and honestly pretty
promising path. And the team that sort of
cracked this genetic puzzle, giving us this really surprising
(01:20):
answer, was this huge international collaboration.
So today we really want to celebrate the significant work
of Mary Pat Reeves, Stephanie Loomis, and just a large team
from places like the Institute for Molecular Medicine, Finland,
Mass General Hospital, the BroadInstitute, Biogen Inc, and many
others. They've collectively pushed our
understanding of AMD forward right down to the fundamental
(01:40):
genetic and functional level. Yeah, absolutely.
So AMD at its core, it's this slow progressive loss of your
central vision. It happens because cells in the
retina start to die off, specifically the retinal pigment
epithelium, the RPE and the photoreceptor cells themselves.
And like you said, they're, they're the two main types, wet
and dry. Wet AMD, it's serious, yes,
(02:02):
often involves abnormal blood vessel growth, but we do have
treatments that work quite well.But dry AMD, that's the vast
majority of cases. It progresses with what's called
macular atrophy and the slow buildup of these deposits under
the retina called drusen. Now, what's really crucial to
grasp about AMD is its strong genetic component.
I mean, large studies, GWA studies have shown that up to
(02:24):
maybe 71% of someone's susceptibility to AMD is
actually heritable. 71%. Yeah, it's huge.
And get this a single region on our chromosomes right around the
complement factor H gene CFH that accounts for nearly 1/4 of
all that genetic risk. OK, so that CFH gene region is
clearly a major player. A massive player.
And that brings us right to the complement system.
(02:45):
Now many listeners will know this is a key part of our innate
immune defense. Its job is to clear out
pathages, cellular junk, things like that.
But in AMD, the problem is it's over activation or maybe just
dysregulation. It gets out of balance and
starts contributing to the damage in the retinal tissue.
So it's a system that's normallyhelpful but can go rogue in this
(03:05):
disease. Precisely.
It's a really delicate balance. You needed to clear debris early
on, but if it goes into OverDrive, it becomes
detrimental. And within the system you have
factor H or FH. That's the protein made by the
CFH gene. FH acts like a break, you know,
it inhibits complement activation, keeps it under
control. But then there are these other
genes right next door, CFH related genes one through 5 or
(03:26):
CFHR one to five. They make these FHR proteins.
And it's thought that these FHR proteins, especially FHR 5,
actually compete with factor H. Compete.
How so? They sort of counteract its
effect. They reduce factor HS braking
power which could allow the complement system to become more
active, potentially driving thatharmful information in the the
retina. It's this really complex
(03:47):
interplay in that CFH region that's made it so hard to figure
out. Right.
It sounds like a real genetic knot.
Yeah. So how did these researchers
actually managed to untangle it Figure out what's really going
on with CFHR 5 specifically? Well exactly the CFH region.
It was actually one of the very first disease spots found by G
where is way back in 2005, and since then it's only gotten more
(04:07):
complicated with more variance and structural changes linked to
AMD. People suspected CFHR 5 might be
involved, but pinning down its specific independent
contributions separate from everything else happening at
CFH, That's been the challenge until now.
OK. So that leads us to their
methods. They used Fingan, right, this
large biobank in Finland. Tell us a bit about how they
(04:29):
leverage that resource. Yes, Fingan was key.
Finland's population history involved what are called genetic
bottlenecks. This means there's generally
less genetic variation, or rather less hack low type
complexity compared to more mixed populations.
So that reduction in complexity makes it easier to find the
signal, the important variance. Exactly cuts down the genetic
(04:51):
noise and with over 12,000 AMD cases and, you know, hundreds of
thousands of controls, Fingan gave them the sheer statistical
power needed to see these effects clearly.
So a powerful cohort. What techniques did they
actually apply to it? They.
Used a really sophisticated toolkit, advanced computational
methods like association testing, statistical fine
(05:12):
mapping, conditional analysis. Basically, very smart
statistical approaches designed to tease apart those overlapping
genetic signals in the complex CFH region and isolate the
independent effects of specific variants.
OK, so they crunched the geneticdata, but they didn't just stop
there, did they? They wanted to see the real
world effects. No, absolutely not.
They did this really clever sample recall study.
(05:33):
They went back into Finngen and selected serum samples, blood
samples from 200 dry AMD patients and 200 controls, and
they were very careful to match these people based on age, sex
and crucially, their genetic status for key variants in CFH
and CFHR 5. And what do they do with those
samples? That's where the proteomics came
in. Using technologies like SOMA,
(05:55):
SCAN and OLINK, which can measure thousands of proteins at
once, they quantified the levelsof over 6600 different proteins
circulating in the blood, including of course factor H and
all the FHR proteins, FHR one through 5.
So they could directly link a specific genetic variant to the
actual amount of proteins routine someone had.
Precisely. Does the gene variant actually
change the protein level? That was a key question and.
(06:17):
Did they look at function too, not just levels?
They did. They moved on to functional
validation using complement activation assays.
They basically tested how well the complement system pathways,
the classical alternative and MBL lectin pathways could be
activated in these individual samples.
This allowed them to see if the genetic changes and the
(06:38):
resulting protein level changes actually impacted how this
crucial immune system pathway worked.
Wow. OK, Genetics, proteins,
function. Anything else?
One more. Crucial layer.
They connected it all back to the eye itself using optical
coherence tomography Oct imaging.
They used data from another large resource, the UK Biobank,
(06:58):
to look at the thickness of the retinal photoreceptor layers in
people carrying these key genetic variants.
So they could actually see if the genetics was linked to a
physical difference in the structure of the retina.
That's exactly right. It links the genetic finding
directly to eye structure, providing a really clear visual
endpoint. It was this incredibly
integrated, multi layered approach.
Really impressive. OK.
(07:19):
So a very thorough investigation.
What were the big results? What did they find?
Well, this comprehensive approach paid off.
They confirmed there are four major CFH haplotypes,
combinations of variants that protect against AMD.
But the really exciting part wasdigging deeper.
They found that two of these protective haplotypes were
strongly linked to specific rarevariants in the CFHR 5 gene,
(07:40):
particularly a frameshift variant enriched in fins, which
they called CFHR fives, and alsoa missense variant.
This was a breakthrough directlylinking protection to CFHR 5
itself. So CFHR 5 steps out of the
shadow of CFH? And what about the protein
levels? Did those variants affect FHR 5
protein? Dramatically, carriers of these
(08:01):
protective CFHR 5 variants showed what's called a dose
dependent reduction in their serum FHR 5.
Level those dependent meaning. Meaning if you had one copy of
the protective variant, your FHR5 levels were lower.
If you had two copies, they wereeven lower.
And incredibly. And people who are homozygous
for that frameshift variant. CFHR fives 2 copies.
FHR 5 protein was undetectable in their.
Blood undetectable. Wow.
(08:22):
Undetectable and interestingly, they also saw lower levels of
FHR 2 and FHR 4 in these individuals, suggesting maybe a
broader effect on these related proteins.
OK, so lists FHR 5 protein. Now you said FHR 5 might compete
with factor H, sort of taking the brakes off complement.
So less FHR 5 should mean more breaking, less complement
(08:44):
activation. That's what you might
intuitively think, right? But here's where it got really
fascinating and maybe a bit counterintuitive.
They found that this genetic reduction in FHR 5 actually
correlated with a higher capacity to activate the
classical and alternative complement pathway.
Higher activation, but isn't over activation the problem in
AMD? Exactly.
It seems paradoxical at first, but the thinking is perhaps with
(09:06):
less FHR 5 around interfering, the main inhibitor factor H
works fine, but the system overall becomes more efficient
at its unofficial job, clearing out that retinal debris before
it triggers the really damaging chronic inflammation.
It's like removing a specific bottleneck that was hindering a
useful process. OK.
So it's like boosting the good kind of complement activity, the
(09:26):
cleanup crew function. That seems to be the
implication, yes. A more efficient clearance
mechanism early on. And did this translate to
physical changes in the eye likeyou mentioned with the Oct
scans? It did.
When they analyzed the retinal imaging data from the UK
Biobank. People carrying these protective
CFHR 5 variants actually had a thicker retinal photoreceptor
(09:47):
layer. Thicker.
That sounds protective. It is that morphology, having a
thicker layer of those crucial light sensing cells, is directly
associated with protection from AMD.
It suggests these variants help maintain a healthier, more
robust retinal structure over a person's lifetime.
Were they absolutely sure this effect was just from CFHR 5 and
not tangled up with other known protective factors in that
(10:09):
region? They went to great lengths to
check that they did careful conditional analysis.
The protective effects of these CFHR 5 variants were shown to be
truly independent of other knownvariations at the CFH locus
itself. This includes things like the
large deletions in CFHR 1 and CFHR 3, or CFHR 1 and CFH 4,
which have been debated a lot inthis Finnish population.
(10:30):
Those deletions didn't seem to have a substantial independent
protective effect. The deep dive found no other
hidden genetic variants driving this.
It really pointed squarely at CFHR 5.
OK. That's very convincing.
And what about safety? If lowering AKR 5 is protective,
could targeting it cause problems elsewhere in the body?
That's always the critical question for potential drug
targets. They performed A Phenomenalite
(10:52):
association study, or FIAS in Fingan.
They basically scanned across thousands, 2404 other health
conditions and traits to see if the CFHR 5S variant was
associated with anything else, good or bad, and they found no
significant associations. Nothing popped up.
This lack of obvious adverse effects is really encouraging.
(11:13):
It suggests that targeting FHR 5might be a potentially safe
therapeutic strategy without major unintended consequences
elsewhere. So this incredible detective
work yielded some truly eye opening results.
Let's back this a bit. What does this all mean for how
we understand AMD and maybe moreimportantly, for potential
treatments? This feels like a big shift.
(11:34):
It really does. I mean, the clearest implication
is that therapeutically down regulating FHR 5 looks like a
very promising strategy either to prevent AMD in high risk
individuals or perhaps even treat it.
It firmly establishes CFHR 5 as an independent, important player
in AMD risk, and it suggests a different kind of therapeutic
approach. Instead of broadly blocking
(11:55):
complement, maybe we just need to reduce this one specific
protein, FHR 5, that seems to behindering the system's
protective functions. Right, so it's not about
shutting the whole system down, which we know we need for
immunity, but more like fine tuning it, removing a specific
impediment to let it work betterin the eye.
Exactly that. It reinforces this idea of the
complement system's delicate balance.
(12:16):
You know early on it's good for clearing debris, but if it gets
out of control it drives disease.
Lowering FHR 5 seems to tip the balance back towards that
beneficial debris clearance without letting it run wild into
damaging inflammation. It's optimization, not
elimination. And the way they untangled this
using Finnian, that must have implications for studying other
(12:37):
complex diseases too. Oh, absolutely.
It's a fantastic demonstration of the power of these large,
well phenotyped biobanks, especially those from
populations with reduced geneticcomplexity like Finns.
It shows how in value people they are for dissecting these
really challenging genetic regions.
It provides a kind of road map for tackling other complex
genetic puzzles. And another really interesting
(12:58):
finding was the additive protection.
They saw that people who are lucky enough to carry protective
variants in both CFH and CFHR 5 had even stronger protection
against AMD. So the benefits stack up.
It seems so. The combination offers enhanced
defense. This could be really important
down the line for, you know, identifying people at highest
risk or maybe even designing therapies that target multiple
(13:19):
points in the pathway for greater effect.
And you mentioned CFHR 5 looks like an attractive drug target
because lowering it doesn't seemto cause other problems.
That's huge for drug development, isn't?
It it's critical, identifying itas an allelic series gene where
different variants naturally lead to different levels of the
protein, including complete absence without apparent harm.
(13:39):
That's very encouraging. The lack of obvious safety
signals in that fiwas makes it areally compelling target, and
it's different from some currentAMD approaches that try to
broadly inhibit complement. Here the idea is to just reduce
the amount of this one protein FHR 5.
It's a more subtle approach, potentially with fewer side
effects. So where does the research go
next? What are the immediate next
(14:01):
steps scientifically or maybe even clinically?
Well, there's still a need to nail down the precise molecular
details. How exactly does lowering FHR 5
boost the good complement activity and protect the retina?
More research is needed there, but looking ahead, this
definitely opens the door to developing novel therapy things
like neutralizing antibodies designed to bind and block FHR
(14:24):
5, or perhaps oligonucleotide therapies that reduce its
production. And how would those be delivered
directly into the eye? That's another fascinating
angle. FHR 5 is mainly made in the
liver, not the eye, so there's this really intriguing
possibility that a treatment could be given systemically,
like an injection elsewhere in the body, rather than needing
repeated injections directly into the eye, which is how many
(14:46):
current wet AMD treatments work.That would be a huge advantage
for patients. That would be a game changer.
Are there limitations to consider from this study?
Of course, like any study, the recall study, while focused, was
still limited in size, so they couldn't analyze every rare
genetic combination. And importantly, because this
was primarily in the Finnish population, we need more studies
to confirm these findings hold true in people of other
(15:09):
ancestries. Genetics can vary.
Also, we need more longitudinal data following people over time
with retinal scans to really understand who would benefit
most from lowering FHR 5 and whether it's best for prevention
or for treating established disease.
But even with those caveats, thedirection this points is
extremely promising. OK, so wrapping this up, what
does this all mean for you, for our listeners, and potentially
(15:30):
for the millions affected by AMD?
Well, this deep dive really shows that a specific genetic
tweak, a loss of function in theCFHR 5 gene leading to less FHR
5 protein, gives significant protection against age-related
macular degeneration. It seems to work by letting the
body's own complement system do a better job of cleaning up
cellular debris in the eye and by helping maintain a healthier
(15:53):
retina. It's a groundbreaking insight
that points towards a completelynew and potentially safer
therapeutic path for AMD. So what does this mean for the
future of eye care and maybe howwe think about precision
medicine for preventing age-related diseases more
broadly? It really makes you think.
This episode was based on an Open Access article under the
CCBY 4 Point O license. You can find a direct link to
(16:14):
the paper and the license in ourepisode description.
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