3.1.2. Genetic Predisposition

Genetic predisposition to SS plays a role in the trigger phase of the disease. A strong association between human leucocyte antigen (HLA)-DR and HLA-DQ alleles belonging to the group of major histocompatibility genes (MHC) class II genes and SS was observed throughout different populations including Caucasian, Japanese and Chinese populations [27]. All discovered haplotypes are in strong linkage disequilibrium, causing difficulties in establishing which of them contain the locus that confers the risk. SS patients with HLA-DQ1/HLA-DQ2 alleles display more severe autoimmune disease than patients with any other allelic combination at HLA-DQ [28]. In addition to the HLA system, most recent studies have focused their attention on polymorphic genes that code for molecules physiologically involved in apoptosis such as Fas and Fas ligand (FasL). Using MRL/lpr-murine model, a retrotransposon inserted in Fas gene was identified as playing a role in cell apoptosis and induction of progressive sialadenitis [29,30]. Fas/FasL gene polymorphisms have also been found in SS patients [31] but have not clearly been identified as disease-determining factors. Ro52 gene encoding the 52-kd Ro autoantigen display single nucleotide polymorphism (SNP) located 13bp upstream of exon 4 identified as significantly associated with the presence of anti-Ro 52kD autoantibodies in SS patients [32]. Numerous additional genes including IL-10 [33], TNF alpha [34], alpha chain of the IL-4 receptor [35], IRF5, STAT4 [36] and CXCL13 [37] also display a gene polymorphism possibly associated with SS as well. Recent studies carried out in several SS cohorts of different ethnicity have revealed additional candidate genes probably associated with the risk to develop the lymphoma in SS patients. The presence of a polymorphism in the tumour necrosis factor alpha induced protein 3 (TNFAIP3) gene is associated with the risk to develop the non-Hodkin's lymphoma in a SS Caucasian cohort [38–40]. In addition, two polymorphisms of methylene-tetrapholate reductase (MTHFR) gene are considered risk factors for lymphoma in SS patients [41]. While gene polymorphism plays an indisputable role in the triggering phase of SS, the individual contribution of each genetic factor remains to be assessed [42].
