MTHFR gene variants and non-MALT lymphoma development in primary Sjogren\u2019s syndrome

Sofia Fragkioudaki,Adrianos Nezos,Nikolaos Drakoulis,Angelica A Saetta,Vassilis L Souliotis,Petros P Sfikakis,Athanasios G Tzioufas,Clio P Mavragani,Ilenia Chatziandreou,Michael Voulgarelis,Haralampos M Moutsopoulos,Mary K Crow,Michael Koutsilieris

doi:10.1038/s41598-017-07347-w

Abstract

Primary Sjogren’s syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C > T and c. 1298A > C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls were genotyped for the detection of MTHFR polymorphisms. DNA methylation levels were assessed by pyrosequencing of the LINE-1 retroelement promoter in DNA from 55 salivary gland tissues from pSS patients. DNA double-strand breaks were determined in peripheral blood mononuclear cells from 13 pSS patients, using comet assay. Αnalysis according to lymphoma subtype revealed increased frequency of c. 677C > T TT genotype and T allele, as well as reduced prevalence of the c. 1298A > C C allele in the pSS non-MALT group compared to controls and patients without NHL. MTHFR c. 677C > T TT genotype was associated with reduced DNA methylation levels, while MTHFR c. 1298A > C AC genotype with reduced DNA double-strand breaks levels. MTHFR variants may be involved in SS non-MALT NHL development, through contribution to defective DNA methylation and genomic instability.

Highlights

Primary Sjogren’s syndrome is a chronic, systemic autoimmune disease affecting mainly the exocrine glands, resulting in oral and ocular dryness[1]
The current study is the first to explore the potential role of methylene tetrahydrofolate reductase (MTHFR) gene variants in both Primary Sjogren’s syndrome (pSS) and pSS-related lymphomagenesis
Whereas no differences in the prevalence of MTHFR c. 677C > T and c. 1298A > C polymorphisms were detected among pSS, pSS-lymphoma patients and healthy controls (HC), further analysis, according to the lymphoma subtype, revealed increased frequency of the MTHFR c. 677C > T TT genotype and T allele in the pSS non-mucosa-associated lymphoid tissue (MALT) group compared to pSS patients and HC respectively

Summary

Introduction

Primary Sjogren’s syndrome (pSS) is a chronic, systemic autoimmune disease affecting mainly the exocrine glands, resulting in oral and ocular dryness[1]. A growing body of evidence over the last two decades consistently revealed features associated with immunecomplex formation -as a result of B-cell hyperactivity- as adverse predictors for the development of pSS related MALT lymphomas. A recent study by Baimpa et al, suggested lymphocytopenia as an adverse predictor for SS related non-MALT lymphoma, mainly DLBCL13, with no associations between B-cell activation markers and non-MALT lymphoma development having been detected These separate disease profiles suggest that distinct underlying molecular events are involved in pSS MALT and non-MALT NHL pathogenesis. This process reduces the bioavailability of 5,10-MTHF The latter ensures the conversion of nucleotides deoxyuridine-5-monophosphate to deoxythymidine-5-monophosphate (thymidylate) leading to decreased uracil levels. GLu429Ala[18, 22, 23]

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