Journal
MULTIPLE SCLEROSIS JOURNAL
Volume 27, Issue 9, Pages 1332-1340Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1352458520963937
Keywords
Perforin; type 1 diabetes; multiple sclerosis; hemophagocytic lymphohistiocytosis; cytokine storm; cytotoxic lymphocytes; inflammation
Categories
Funding
- Italian Foundation for Multiple Sclerosis [2011/R/13, 2015/R/09]
- Intramural Research Program of the NIH, National Institute on Aging [N01-AG-1-2109, HHSN271201100005C]
- Horizon 2020 Research and Innovation Program of the European Union [633964]
- Fondazione di Sardegna [U1301.2015/AI.1157.BE Prat.2015-1651]
- JDRF [9-2011-253, 5-SRA-2015-130-A-N]
- Wellcome [091157, 107212]
- University of Oxford
- Wellcome Trust Case Control Consortium [076113]
- NIHR Oxford Biomedical Research Center
- H2020 Societal Challenges Programme [633964] Funding Source: H2020 Societal Challenges Programme
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The study aimed to investigate the impact of the hypomorph PRF1:p.A91V g.72360387 G > A allele on multiple sclerosis (MS) and type 1 diabetes (T1D). The findings reveal that this allele is associated with increased lymphocyte levels and has opposite effects on the risk of MS and T1D.
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 x 10(-4), odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 x 10(-5), OR = 0.82. Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
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