Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis—a presymptomatic case–control study, 2021, Grut et al

Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis—a presymptomatic case–control study

Viktor Grut, Martin Biström, Jonatan Salzer, Pernilla Stridh, Daniel Jons, Rasmus Gustafsson, Anna Fogdell-Hahn, Jesse Huang, Nicole Brenner, Julia Butt, Noemi Bender, Anna Lindam, Lucia Alonso-Magdalena, Martin Gunnarsson, Magnus Vrethem, Tomas Bergström, Oluf Andersen, Ingrid Kockum, Tim Waterboer, Tomas Olsson, Peter Sundström

First published: 09 June 2021

Background and purpose
Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology.

Methods
A nested case–control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP).

Results
Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56–0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06–0.61) and EBV antigen EBNA-1 (amino acid 385–420) at age 20–39 years (AP 0.37, 95% CI 0.09–0.65).

Conclusions
Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.

Link | PDF (European Journal of Neurology) [Open Access]

 

They created matched pairs for "biobank, sex, date of blood sampling and date of birth (in order of priority)":

They also looked at strata based on age (<20 and 20-39) and divided by sex. While it's not significant in age<20, that might be due to the much smaller sample size, and it's at least still the same effect direction.




The association wasn't significant when just looking at males, but they say it may be due to the low number of males.

It's possible the blood sampling isn't actually from before the MS disease process begins.

They say their results align with previous research:

Speculation on why CMV might be protective:

 

The Ascherio study also looked at CMV. I think they found no association. Can that data not be used to analyse some of the ideas present here?

 

Ascherio 2001 was reference 13 in the above quote. Not significant, possibly due to small sample size, but included in a meta-analysis that did come out significant.

Edit: Added link

 

Here is the previous meta-analysis:

Cytomegalovirus and multiple sclerosis risk (2013, Journal of Neurology)

Ascherio, Levin, and DeLorenze are the three prospective studies here: