B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren’s syndrome Adrianos Nezos a, 1 , Aristea Papageorgiou b,1 , George Fragoulis b , Dimitrios Ioakeimidis c , Michael Koutsilieris a , Athanasios G. Tzioufas b , Haralampos M. Moutsopoulos b , Michael Voulgarelis b, 2 , Clio P. Mavragani a, * , 2 a Department of Physiology, School of Medicine, University of Athens, Athens, Greece b Department of Pathophysiology, School of Medicine, University of Athens, Athens, Greece c Department of Rheumatology, General Hospital of Athens “G.Gennimatas”, Athens, Greece article info Article history: Received 14 March 2013 Received in revised form 23 April 2013 Accepted 29 April 2013 Keywords: B-lymphocyte activator factor (BAFF) Lymphoma Primary Sjogren’s syndrome (SS) Single nucleotide polymorphisms (SNPs) Genetics abstract Primary Sjogren’s syndrome (pSS) is complicated by B-cell lymphoma in 5e10% of patients. Several clinical and serological features are proposed as adverse predictors for such complication and define a high risk pSS phenotype. We aimed to explore whether previously described polymorphisms of the B-cell activating factor (BAFF) could be related to pSS-related lymphomagenesis. Five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) were evaluated in 111 low risk pSS patients (type II), 82 high risk/lymphoma patients (type I) and 137 healthy controls (HC) by PCR-based assays. The classification of pSS patients into types I and II was based on the presence or absence of risk factors or lymphoma development, respectively. Genotype and haplotype analysis was performed for all variants in the pSS groups. Since the rs1041569 SNP was not in HardyeWeinberg equilibrium in the HC group (p < 0.001), haplotype analysis was performed in the remaining four out of the five SNPs tested when comparisons with HC individuals were performed. The high risk pSS group was characterized by higher frequency of the minor T allele of the rs9514828 BAFF polymorphism compared to HC. Compared to the low risk pSS patients but not the HC, the high risk pSS group exhibited lower frequencies of the AA genotype of the rs12583006 polymorphism as well as the TACAC and TACC haplotypes and higher frequency of the TTTC haplotype. The low risk pSS group exhibited higher frequency of the minor A allele and AA genotype of the rs12583006 variant compared to HC. Both pSS groups were characterized by increased frequency of the haplotype TATT and GTTC and decreased frequency of the TTCT when compared to HC. Taken together, these findings suggest the implication of the host’s genetic background in pSS-related lymphomagenesis. The interaction of pSS- related BAFF gene haplotypes together with distinct BAFF genetic variants appears to contribute to this complication. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands mainly salivary and lacrimal glands with ensuing oral and ocular dryness [1,2]. The hallmark of the syndrome is B-cell hyperactivity, manifested by the presence of hypergammaglobulinemia and various autoantibodies with BAFF or BLyS, a survival factor for B- cells being a central contributor [3,4]. It is well recognized that approximately 5e8% of these patients constitute a high risk group for B-cell lymphoma development, with peripheral neuropathy, palpable purpura, low complement C4 levels and cryoglobulinemia Abbreviations: BAFF, B-cell activating factor; BLyS, B lymphocyte stimulator; pSS, primary Sjogren’s syndrome; SNPs, single nucleotide polymorphisms; HC, healthy controls; NHL, non-Hodgkin lymphoma; CLL, chronic lymphocytic leuke- mia; TNF, tumor necrosis factor; SLE, systemic lupus erythematosus; PCR, poly- merase chain reaction; ORs, odds ratios; CIs, confidence intervals. * Corresponding author. Department of Physiology, School of Medicine, Univer- sity of Athens, M.Asias 75,11527 Athens, Greece. Tel.: þ30 210 746 2714; fax: þ30 210 746 2571. E-mail address: kmauragan@med.uoa.gr (C.P. Mavragani). 1 Equally contributed as first co-authors. 2 Equally contributed as senior co-authors. Contents lists available at SciVerse ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm 0896-8411/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2013.04.005 Journal of Autoimmunity xxx (2013) 1e10 Please cite this article in press as: Nezos A, et al., B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren’s syndrome, Journal of Autoimmunity (2013), http://dx.doi.org/10.1016/j.jaut.2013.04.005