Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis, 2025, Pukaj et al.

[SNT Gatchaman]

Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis

Spoiler: Authors

Pukaj, Albert; Harroud, Adil; Shchetynsky, Klementy; Wirsching, Laura; Peters, Lucy; Andlauer, Till Fm; Pääkkönen, Kimmo; Bos, Steffan D; Moylett, Sinéad; Dubois, Bénédicte; Llufriu, Sara; Luessi, Felix; Tackenberg, Björn; Kowarik, Markus C; Then Bergh, Florian; Trebst, Corinna; Tumani, Hayrettin; Wildemann, Brigitte; Bayas, Antonios; Havla, Joachim; Kümpfel, Tania; Knop, Matthias; Genetics Center, Regeneron; Stridh, Pernilla; Hillert, Jan A; Olsson, Tomas; Alfredsson, Lars; Cotsapas, Chris; Flinstad Harbo, Hanne; Zipp, Frauke; Saarela, Janna; Baranzini, Sergio E; Berthele, Achim; Kockum, Ingrid; Hemmer, Bernhard; Gasperi, Christiane; null, null; Zinevych, Iaroslav; Grummel, Verena; Uibel, Paula; Flaskamp, Martina; Mühlau, Mark; Martinelli-Boneschi, Filippo; Oturai, Anette; Villoslada, Pablo; Esposito, Federica; d’Alfonso, Sandra; Henry, Roland G; Jagodic, Maja; Goris, An; Sawcer, Stephen J; Jónsdóttir, Ingileif; Stefánsson, Kári

BACKGROUND AND OBJECTIVES
Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions—the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14—associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood.

METHODS
We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk—quantified through polygenic risk scores—is associated with intrathecal IgG synthesis.

RESULTS
In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10−8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10−11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.

DISCUSSION
Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.

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[SNT Gatchaman]

The first signal mapped to the MHC region, with the lead variant rs3135461 (OR = 1.938, SE log(OR)= 0.067, p = 2.17 × 10−23, Figure 1A).

 

[Hutan]

Intrathecal - the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. The fluid doing the filling is cerebrospinal fluid.

So that impressive association is for people who are producing immunoglobulin G in that intrathecal space

In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.

And they report finding that people with genes increasing the risk of MS are more likely to also have genes increasing the risk of intrathecal IgG production, and more likely to actually have substantial intrathecal IgG production.

That gets pretty interesting, as I guess they can then look at people who have MS risk genes and intrathecal IgG production risk genes, but who don't have intrathecal IgG production or MS, in order to see what might protect against MS (genes/environment).


I don't think we have seen any evidence of any sort of immunoglobulins in the cerebrospinal fluid of people with ME/CFS?

There was a 2020 study by Bynke et al (with Bergquist and Scheibenbogen) that reported

No evidence for intrathecal antibody production was found in cerebrospinal fluid. The role of increased autoantibodies in the pathogenesis of ME is still uncertain and further research is needed to evaluate their clinical significance.

I'm not sure though if they looked for all sorts of immunoglobulins. It looks as though they only tested for anti-adrenergic receptors and anti-muscarinic receptors.

All samples were analysed for IgG autoantibodies directed against Alpha- (α1, α2) and Beta- (β1-3) adrenergic receptors and Muscarinic (M) 1–5 acetylcholine receptors using an ELISA technique.

 

[Jonathan Edwards]

I don't think we have seen any evidence of any sort of immunoglobulins in the cerebrospinal fluid of people with ME/CFS?

There are a number of SCF studies, including Natelson and Baraniuk I think. ALso, a good number of ME/CFS patients will have had lumbar punctures and testing for IgG levels and monoclonal bands would be routine at least if MS was on the differential diagnosis, which it would tend to be.

I think we can be reasonably sure that immunoglobulin production in brain tissue /meninges (with IgG in CSF) is not a feature of ME/CFS. It is not entirely specific to MS but I think in other conditions where it is found there is inflammatory pathology as in MS.

The genetic link to Ig production is certainly interesting. It would fit with MS being as much as anything a situation where B/plasma cell survival in brain is allowed when it should not be, regardless of what the antibody recognises.

There may be nothing protecting the other people fro MS beyond random chance. I don't know what the monozygotic twin data say but for RA a monozygotic twin of someone with RA has only about a 1 in 4 chance of getting RA.