Background/Purpose: Sjogren’s syndrome (SS) exhibits the highest susceptibility, among systemic autoimmune diseases, to non-Hodgkin lymphoma (NHL) development. Genetic instability and DNA methylation have been previously implicated in the pathogenesis of lymphoproliferative disorders. Methylene tetrahydrofolate reductase (MTHFR) is an enzyme essential in DNA synthesis and methylation pathways. Two common polymorphisms of the MTHFR gene, C677T and A1298C, have been implicated in the development of NHL, as they reduce the MTHFR enzyme activity and may affect DNA methylation and stability. The aim of this study was to investigate the possible contribution of the MTHFR C677T and A1298C polymorphisms in SS-related lymphomagenesis.

Methods: 189 SS patients without NHL, 72 SS patients with NHL (57 with MALT and 15 with non-MALT lymphoma), 160 healthy controls (HC) and 124 rheumatoid arthritis (RA) patients were genotyped for the detection of the MTHFR gene polymorphisms (C677T and A1298C) using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Methylation levels of CpG islands of the promoter of the long interspersed nuclear element 1 (LINE-1) -a marker of global methylation status- were also evaluated by pyrosequencing in genomic DNA derived from 23 salivary gland tissues from SS (10 with NHL and 13 without) patients.  

Results: Non NHL SS patients had significantly reduced rates of the A1298C AC heterozygous genotype compared to both RA patients and HC (OR=0.57, 95%CI=0.36-0.91, p=0.02 and OR=0.57, 95%CI=0.37-0.88, p=0.01 respectively). In contrast, the prevalence of both MTHFR C677T and A1298C polymorphisms did not significantly differ between SS patients complicated by NHL compared to uncomplicated SS, RA and HC groups. Further analysis according to the lymphoma subtype revealed  677 T as a risk allele and the 1298 C as a protective allele for non-MALT NHL development in patients with SS (OR=2.1, 95%CI=0.99-4.45, p=0.05 and OR=0.19, 95%CI=0.04-0.80, p=0.01). The concomitant presence of 1298 AA and 677 TT genotype conferred an increased risk for non-MALT NHL development among SS patients (OR: 3.4, 95%CI: 1.1-10.9, p=0.04). Of interest, an association was observed between the presence of the MTHFR 677 T -but not MTHFR 1298 C allele- with lower methylation levels (TT vs CT vs CC: 67.9±2.2 vs 69.7±2.9 vs 72.3±2.1, p=0.027, by Kruskal Wallis-test), implying methylation defects as potential underlying mechanisms in the pathogenesis of SS related non-MALT lymphoma.

Conclusion: In the current study, we identified novel associations of MTHFR polymorphisms with non NHL SS as well as with SS complicated by non-MALT lymphoma. Preliminary data suggest that alterations of global methylation related to the presence of MTHFR 677 T variants may contribute to the pathogenesis of non-MALT lymphoma among SS patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/contribution-of-mthfr-gene-polymorphisms-in-sjogrens-syndrome-related-lymphomagenesis/