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Primary Sjögren's syndrome (SS) is a chronic autoimmune disease that affects primarily the salivary and lacrimal glands. Nitric oxide (NO) has been implicated in the pathogenesis of SS and raised nitrite concentrations have been observed in the saliva of patients with SS.1 NO is a molecule that plays a key role in many physiological and pathological processes. It is produced in vivo from the aminoacid l‐arginine by a family of nitric oxide synthases (NOS), of which three isoforms have been identified, i.e. neuronal, endothelial and inducible.2 Endothelial nitric oxide synthase (eNOS) is a constitutively expressed isoform of NOS. The eNOS gene entails several polymorphisms, of which for example the +894 T>G polymorphism is of functional significance, the T allele having been associated with high NO production.3
We sought to establish whether the eNOS +894 polymorphism is associated with susceptibility to primary SS or to the salivary manifestations of the disease, and after informed consent analysed the genetic polymorphism of eNOS (+894T>G, rs1799983) in 64 (62 female, two male) patients with primary SS fulfilling three or more modified Californian criteria4 (histological findings were graded on the Chisholm–Mason scale,5 grades 3 and 4 being regarded as diagnostic) and in 400 healthy blood donor controls. The genotyping was performed by the 5′nucleotidase method (TaqMan, Applied Biosystems, Foster City, California, USA). A careful clinical examination and interview had previously been conducted with these patients.6 The study protocol was approved by the Ethical Committee of Tampere University Hospital. The genotype distributions followed the Hardy–Weinberg equilibrium.
The eNOS genotype or allele frequencies between primary SS patients (GG 53%, GT 41%, TT 6%) and controls (GG 57%, GT 35%, TT 8%) did not differ (p=0.642, chi‐square test).
The primary SS patients carrying the high NO producer allele T of the eNOS +894 had a history of parotid or submandibular gland swelling significantly more frequently than non‐carriers, and age at disease onset was significantly lower in T allele carriers compared with others (table 11).). The presence of extraglandular manifestations of primary SS did not differ between the groups (data not shown).
There are previous data on the role of NO in various oral diseases,2 but the observed association of eNOS polymorphism with effects on the salivary gland has not previously been reported. Immunohistochemical studies have demonstrated the presence of eNOS in ductal epithelial cells in normal human salivary glands.7
Salivary gland swelling has previously been associated with the early onset of primary SS.8 Our present results on the effects of the eNOS polymorphism on both age at disease onset and recurrence of salivary gland swellings would be in line with the concept of a persistent salivary gland infection in the pathogenesis of primary SS.9 The association between eNOS genetics and age at onset of primary SS could be explained by a possible influence of the high producer genotype on the timepoint of a viral infection triggering the pathogenesis of primary SS. NO has been shown to play a physiological role in human B‐cell biology by inhibiting programmed cell death and maintaining Epstein–Barr virus latency.10
The authors would like to thank Ms Sinikka Repo‐Koskinen and Ms Eija Spåre for skilful technical assistance.
eNOS - Endothelial nitric oxide synthase
NO - nitric oxide
NOS - nitric oxide synthase
SS - Sjögren's syndrome
This study was supported by the Medical Research Fund of Tampere University Hospital, Tampere, Finland.