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. 2021 Aug;27(9):1332-1340.
doi: 10.1177/1352458520963937. Epub 2020 Oct 14.

PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity

Carlo Sidore  1 , Valeria Orrù  1 , Eleonora Cocco  2 , Maristella Steri  1 , Jamie Rj Inshaw  3 , Maristella Pitzalis  1 , Antonella Mulas  1 , Stuart McGurnaghan  4 , Jessica Frau  2 , Eleonora Porcu  5 , Fabio Busonero  1 , Mariano Dei  1 , Sandra Lai  1 , Gabriella Sole  1 , Francesca Virdis  1 , Valentina Serra  1 , Fausto Poddie  6 , Alessandro Delitala  7 , Michele Marongiu  1 , Francesca Deidda  1 , Mauro Pala  1 , Matteo Floris  6 , Marco Masala  1 , Suna Onengut-Gumuscu  8 , Catherine C Robertson  8 , Lidia Leoni  9 , Annapaola Frongia  10 , Maria Rossella Ricciardi  11 , Margherita Chessa  12 , Nazario Olla  1 , Mario Lovicu  1 , Annalisa Loizedda  1 , Andrea Maschio  1 , Luisa Mereu  13 , Paola Ferrigno  14 , Nicolo Curreli  1 , Lenuta Balaci  1 , Francesco Loi  1 , Liana Ap Ferreli  1 , Maria Grazia Pilia  1 , Antonello Pani  15 , Maria Giovanna Marrosu  2 , Goncalo R Abecasis  16 , Stephen S Rich  8 , Helen Colhoun  4 , John A Todd  3 , David Schlessinger  17 , Edoardo Fiorillo  1 , Francesco Cucca  18 , Magdalena Zoledziewska  1
Affiliations

PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity

Carlo Sidore et al. Mult Scler. 2021 Aug.

Abstract

Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm.

Objective: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D).

Methods: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians.

Results: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10-4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10-5, OR = 0.82.

Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.

Keywords: Perforin; cytokine storm; cytotoxic lymphocytes; hemophagocytic lymphohistiocytosis; inflammation; multiple sclerosis; type 1 diabetes.

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Conflict of interest statement

Declaration of Conflicting Interests

The authors declare no conflicting interests.

Figures

Figure 1.
Figure 1.. Association of the PRF1 p.Ala91Val (rs35947132) mutation with MS and T1D.
The forest plot (right) displays the distribution of the effects across study cohorts and the T1D meta-analysis result. The span of the horizontal lines corresponds to the 95% confidence interval of the log-odds ratio estimate.
Figure 2.
Figure 2.. Regional plot of genetic association of the PRF1 gene region with CD28-CD8dim absolute count phenotype.
The association strength (-log10(pvalue); y axis) is plotted versus genomic positions (on the hg19/GRCh37 genomic build; x axis). SNPs are colored to reflect their LD with rs35947132 (p.A91V) (which is indicated with a purple dot).
Figure 3
Figure 3
PheWAS data of traits associated with rs35947132 (PRF1) variant in the UK Biobank and GWAS Catalog summary statistics (p<0.05) according to Open Targets Genetics.
See this image and copyright information in PMC

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